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Kalinski P, Kokolus KM, Gandhi S. Paclitaxel, interferons and functional reprogramming of tumor-associated macrophages in optimized chemo-immunotherapy. J Immunother Cancer 2025; 13:e010960. [PMID: 40389375 PMCID: PMC12090863 DOI: 10.1136/jitc-2024-010960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 04/24/2025] [Indexed: 05/21/2025] Open
Abstract
Immune checkpoint inhibition (ICI) targeting programmed cell death protein-1 (PD1) prevents the elimination of activated cytotoxic T lymphocytes (CTLs) by programmed death-ligand 1/2-expressing cancer and myeloid cells in the tumor microenvironment (TME). ICI has shown its effectiveness in many solid tumors, but it lacks activity against "cold" tumors which lack CTL infiltration, including most of the colon, prostate, lung and breast cancers. Metastatic triple-negative breast cancer (TNBC) responds to PD-1 blockade only in 5-20% cases. Chemotherapy has been shown to have a PD1-sensitizing effect in a fraction of patients with TNBC but the underlying mechanism and the reasoning behind its limitation to only a subset of patients are unknown. Recent data demonstrate the key roles played by paclitaxel-driven Toll-like receptor 4 (TLR4) signaling and the resulting activation of type-1 and type-2 interferon pathways in tumor-associated macrophages, resulting in local M2 to M1 transition and enhanced tumor antigen cross-presentation, in the paclitaxel-driven sensitization of "cold" tumors to ICI. These data and the known ability of the TLR4-activated MyD88-NFκB pathway to mobilize both antitumor and tumor-promoting events in the TME provide new tools to enhance the efficacy of chemo-immunotherapy for metastatic, and potentially early, TNBC and other taxane-sensitive cancers.
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Affiliation(s)
- Pawel Kalinski
- Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Kathleen M Kokolus
- Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Shipra Gandhi
- Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
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Shi J, Li S, Yi L, Gao M, Cai J, Yang C, Ma Y, Mo Y, Wang Q. Levistolide a Attenuates Acute Kidney Injury in Mice by Inhibiting the TLR-4/NF-κB Pathway. Drug Des Devel Ther 2024; 18:5583-5597. [PMID: 39654604 PMCID: PMC11625643 DOI: 10.2147/dddt.s476548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 11/24/2024] [Indexed: 12/12/2024] Open
Abstract
Introduction Acute kidney injury (AKI) is characterized by a significant reduction in kidney function and the accumulation of metabolites such as Creatinine (CRE) and Blood Urea Nitrogen (BUN). Levistolide A (LA), an active component of Ligusticum chuanxiong, offers multiple therapeutic benefits, including cardiovascular and neuroprotection, antitumor and analgesic effects, as well as anti-inflammatory, antioxidant, antifibrotic, and proapoptotic actions. However, the underlying mechanism of LA in treating AKI has not been fully elucidated. Methods In this study, we established a glycerol-induced AKI model in mice to evaluate the protective effects of LA. Renal function was assessed by measuring levels of CRE and BUN. Histological analyses were performed to evaluate kidney tissue damage. Additionally, oxidative stress markers, apoptosis indicators, inflammatory cell infiltration, and inflammatory mediator levels were assessed. The involvement of the TLR-4/NF-κB signaling pathway was investigated through molecular assays. Results LA treatment significantly ameliorated glycerol-induced AKI in mice, evidenced by reduced levels of CRE and BUN. Histological examination revealed decreased renal tissue damage in LA-treated groups. LA exerted antioxidant effects by increasing the levels of Glutathione (GSH) and Superoxide Dismutase (SOD), while reducing Reactive Oxygen Species (ROS) accumulation. Apoptosis in renal tissues was attenuated, as indicated by decreased caspase-3 activation. Furthermore, LA reduced the infiltration of inflammatory cells and the release of inflammatory mediators such as TNF-α and IL-6. Mechanistically, LA suppressed the inflammatory response by inhibiting the TLR-4/NF-κB signaling pathway, as demonstrated by reduced NF-κB activation and decreased expression of TLR-4. Conclusion Levistolide A mitigates acute kidney injury through its antioxidative properties and modulation of the TLR-4/NF-κB signaling pathway. These findings provide valuable insights into the therapeutic potential of LA for AKI treatment and lay the groundwork for further mechanistic studies.
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Affiliation(s)
- Jiahui Shi
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Shuangwei Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Langping Yi
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Minghuang Gao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Jiaying Cai
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Cong Yang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Yujie Ma
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Yousheng Mo
- Department of Hepatology, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China
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Dilber Y, Çeker HT, Öztüzün A, Çırçırlı B, Kırımlıoğlu E, Barut Z, Aslan M. Sparstolonin B Reduces Estrogen-Dependent Proliferation in Cancer Cells: Possible Role of Ceramide and PI3K/AKT/mTOR Inhibition. Pharmaceuticals (Basel) 2024; 17:1564. [PMID: 39770406 PMCID: PMC11677571 DOI: 10.3390/ph17121564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/13/2024] [Accepted: 11/18/2024] [Indexed: 01/11/2025] Open
Abstract
Background: The aim of this study was to determine the effect of Sparstolonin B (SsnB) on cell proliferation and apoptosis in human breast cancer (MCF-7) and human ovarian epithelial cancer (OVCAR-3) cell lines in the presence and absence of estradiol hemihydrate (ES). Phosphoinositol-3 kinase (PI3K), phosphorylated protein kinase B alpha (p-AKT), phosphorylated mTOR (mechanistic target of rapamycin) signaling proteins, and sphingomyelin/ceramide metabolites were also measured within the scope of the study. Methods: The anti-proliferative effects of SsnB therapy were evaluated over a range of times and concentrations. Cell proliferation was determined by measuring the Proliferating Cell Nuclear Antigen (PCNA). PCNA was quantified by ELISA and cell distribution was assessed by immunofluorescence microscopy. MTT analysis was used to test the vitality of the cells, while LC-MS/MS was used to analyze the amounts of ceramides (CERs), sphingosine-1-phosphate (S1P), and sphingomyelins (SMs). TUNEL labeling was used to assess apoptosis, while immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA) were used to measure the levels of PI3K, p-AKT, and p-mTOR proteins. Results: Sparstolonin B administration significantly decreased cell viability in MCF-7 and OVCAR-3 cells both in the presence and absence of ES, while it did not cause toxicity in healthy human fibroblasts. In comparison to controls, cancer cells treated with SsnB showed a significant drop in the levels of S1P, PI3K, p-AKT, and p-mTOR. In cancer cells cultured with SsnB, a significant increase in intracellular concentrations of C16-C24 CERs and apoptosis was observed. Conclusions: SsnB downregulated the levels of S1P, PI3K, p-AKT, and p-mTOR while reducing cell proliferation and promoting ceramide buildup and apoptosis.
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Affiliation(s)
- Yağmur Dilber
- Department of Medical Biochemistry, Faculty of Medicine, Akdeniz University, Antalya 07070, Turkey; (Y.D.); (H.T.Ç.); (A.Ö.)
| | - Hanife Tuğçe Çeker
- Department of Medical Biochemistry, Faculty of Medicine, Akdeniz University, Antalya 07070, Turkey; (Y.D.); (H.T.Ç.); (A.Ö.)
| | - Aleyna Öztüzün
- Department of Medical Biochemistry, Faculty of Medicine, Akdeniz University, Antalya 07070, Turkey; (Y.D.); (H.T.Ç.); (A.Ö.)
| | - Bürke Çırçırlı
- Department of Medical Biotechnology, Institute of Health Sciences, Akdeniz University, Antalya 07070, Turkey;
| | - Esma Kırımlıoğlu
- Department of Histology and Embryology, Faculty of Medicine, Akdeniz University, Antalya 07070, Turkey;
| | - Zerrin Barut
- Faculty of Dentistry, Antalya Bilim University, Antalya 07070, Turkey;
| | - Mutay Aslan
- Department of Medical Biochemistry, Faculty of Medicine, Akdeniz University, Antalya 07070, Turkey; (Y.D.); (H.T.Ç.); (A.Ö.)
- Department of Medical Biotechnology, Institute of Health Sciences, Akdeniz University, Antalya 07070, Turkey;
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Hurst R, Brewer DS, Gihawi A, Wain J, Cooper CS. Cancer invasion and anaerobic bacteria: new insights into mechanisms. J Med Microbiol 2024; 73:001817. [PMID: 38535967 PMCID: PMC10995961 DOI: 10.1099/jmm.0.001817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 02/27/2024] [Indexed: 04/07/2024] Open
Abstract
There is growing evidence that altered microbiota abundance of a range of specific anaerobic bacteria are associated with cancer, including Peptoniphilus spp., Porphyromonas spp., Fusobacterium spp., Fenollaria spp., Prevotella spp., Sneathia spp., Veillonella spp. and Anaerococcus spp. linked to multiple cancer types. In this review we explore these pathogenic associations. The mechanisms by which bacteria are known or predicted to interact with human cells are reviewed and we present an overview of the interlinked mechanisms and hypotheses of how multiple intracellular anaerobic bacterial pathogens may act together to cause host cell and tissue microenvironment changes associated with carcinogenesis and cancer cell invasion. These include combined effects on changes in cell signalling, DNA damage, cellular metabolism and immune evasion. Strategies for early detection and eradication of anaerobic cancer-associated bacterial pathogens that may prevent cancer progression are proposed.
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Affiliation(s)
- Rachel Hurst
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, NR4 7TJ, UK
| | - Daniel S. Brewer
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, NR4 7TJ, UK
- Earlham Institute, Norwich Research Park Innovation Centre, Colney Lane, Norwich NR4 7UZ, UK
| | - Abraham Gihawi
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, NR4 7TJ, UK
| | - John Wain
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, NR4 7TJ, UK
- Quadram Institute Biosciences, Colney Lane, Norwich, Norfolk, NR4 7UQ, UK
| | - Colin S. Cooper
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, NR4 7TJ, UK
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Shaker SA, Alshufta SM, Gowayed MA, El-Salamouni NS, Bassam SM, Megahed MA, El-Tahan RA. Propolis-loaded nanostructured lipid carriers halt breast cancer progression through miRNA-223 related pathways: an in-vitro/in-vivo experiment. Sci Rep 2023; 13:15752. [PMID: 37735586 PMCID: PMC10514043 DOI: 10.1038/s41598-023-42709-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 09/13/2023] [Indexed: 09/23/2023] Open
Abstract
The most frequent malignant tumor in women is breast cancer, and its incidence has been rising every year. Propolis has been used for its antibacterial, antifungal, and anti-inflammatory properties. The present study aimed to examine the effect of the Egyptian Propolis Extract (ProE) and its improved targeting using nanostructured lipid carriers (ProE-NLC) in Ehrlich Ascites Carcinoma (EAC) bearing mice, the common animal model for mammary tumors. EAC mice were treated either with 5-fluorouracil (5-FU), ProE, ProE-NLC, or a combination of ProE-NLC and 5-FU. Their effect on different inflammatory, angiogenic, proliferation and apoptotic markers, as well as miR-223, was examined. ProE and ProE-NLC have shown potential anti-breast cancer activity through multiple interrelated mechanisms including, the elevation of antioxidant levels, suppression of angiogenesis, inflammatory and mTOR pathways, and induction of the apoptotic pathway. All of which is a function of increased miRNA-223 expression. The efficiency of propolis was enhanced when loaded in nanostructured lipid carriers, increasing the effectiveness of the chemotherapeutic agent 5-FU. In conclusion, this study is the first to develop propolis-loaded NLC for breast cancer targeting and to recommend propolis as an antitumor agent against breast cancer or as an adjuvant treatment with chemotherapeutic agents to enhance their antitumor activity and decrease their side effects. Tumor targeting by ProE-NLC should be considered as a future therapeutic perspective in breast cancer.
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Affiliation(s)
- Sara A Shaker
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Shadi M Alshufta
- Department of Clinical Pathology, Faculty of Medicine, Aden University, Aden, Yemen
| | - Mennatallah A Gowayed
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Canal El-Mahmoudia Str., Smouha, Alexandria, Egypt.
| | - Noha S El-Salamouni
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Samar M Bassam
- Department of Pharmacognosy and Natural Products, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Magda A Megahed
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Rasha A El-Tahan
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt
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Ekeuku SO, Etim EP, Pang KL, Chin KY, Mai CW. Vitamin E in the management of pancreatic cancer: A scoping review. World J Gastrointest Oncol 2023; 15:943-958. [PMID: 37389119 PMCID: PMC10302993 DOI: 10.4251/wjgo.v15.i6.943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 02/03/2023] [Accepted: 04/07/2023] [Indexed: 06/14/2023] Open
Abstract
Pancreatic cancer is the leading cause of cancer mortality worldwide. Research investigating effective management strategies for pancreatic cancer is ongoing. Vitamin E, consisting of both tocopherol and tocotrienol, has demonstrated debatable effects on pancreatic cancer cells. Therefore, this scoping review aims to summarize the effects of vitamin E on pancreatic cancer. In October 2022, a literature search was conducted using PubMed and Scopus since their inception. Original studies on the effects of vitamin E on pancreatic cancer, including cell cultures, animal models and human clinical trials, were considered for this review. The literature search found 75 articles on this topic, but only 24 articles met the inclusion criteria. The available evidence showed that vitamin E modulated proliferation, cell death, angiogenesis, metastasis and inflammation in pancreatic cancer cells. However, the safety and bioavailability concerns remain to be answered with more extensive preclinical and clinical studies. More in-depth analysis is necessary to investigate further the role of vitamin E in the management of pancreatic cancers.
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Affiliation(s)
- Sophia Ogechi Ekeuku
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Effiong Paul Etim
- Faculty of Applied Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
| | - Kok-Lun Pang
- Newcastle University Medicine Malaysia, Iskandar Puteri 79200, Johor, Malaysia
| | - Kok-Yong Chin
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Chun-Wai Mai
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
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Velasco WV, Khosravi N, Castro-Pando S, Torres-Garza N, Grimaldo MT, Krishna A, Clowers MJ, Umer M, Tariq Amir S, Del Bosque D, Daliri S, De La Garza MM, Ramos-Castaneda M, Evans SE, Moghaddam SJ. Toll-like receptors 2, 4, and 9 modulate promoting effect of COPD-like airway inflammation on K-ras-driven lung cancer through activation of the MyD88/NF-ĸB pathway in the airway epithelium. Front Immunol 2023; 14:1118721. [PMID: 37283745 PMCID: PMC10240392 DOI: 10.3389/fimmu.2023.1118721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 05/02/2023] [Indexed: 06/08/2023] Open
Abstract
Introduction Toll-like receptors (TLRs) are an extensive group of proteins involved in host defense processes that express themselves upon the increased production of endogenous damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) due to the constant contact that airway epithelium may have with pathogenic foreign antigens. We have previously shown that COPD-like airway inflammation induced by exposure to an aerosolized lysate of nontypeable Haemophilus influenzae (NTHi) promotes tumorigenesis in a K-ras mutant mouse model of lung cancer, CCSPCre/LSL-K-rasG12D (CC-LR) mouse. Methods In the present study, we have dissected the role of TLRs in this process by knocking out TLR2, 4, and 9 and analyzing how these deletions affect the promoting effect of COPD-like airway inflammation on K-ras-driven lung adenocarcinoma. Results We found that knockout of TLR 2, 4, or 9 results in a lower tumor burden, reduced angiogenesis, and tumor cell proliferation, accompanied by increased tumor cell apoptosis and reprogramming of the tumor microenvironment to one that is antitumorigenic. Additionally, knocking out of downstream signaling pathways, MyD88/NF-κB in the airway epithelial cells further recapitulated this initial finding. Discussion Our study expands the current knowledge of the roles that TLR signaling plays in lung cancer, which we hope, can pave the way for more reliable and efficacious prevention and treatment modalities for lung cancer.
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Affiliation(s)
- Walter V. Velasco
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Nasim Khosravi
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Susana Castro-Pando
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Nelly Torres-Garza
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico
| | - Maria T. Grimaldo
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
| | - Avantika Krishna
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
| | - Michael J. Clowers
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
| | - Misha Umer
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sabah Tariq Amir
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Diana Del Bosque
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Soudabeh Daliri
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Maria Miguelina De La Garza
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico
| | - Marco Ramos-Castaneda
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico
| | - Scott E. Evans
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
| | - Seyed Javad Moghaddam
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
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Manilla V, Di Tommaso N, Santopaolo F, Gasbarrini A, Ponziani FR. Endotoxemia and Gastrointestinal Cancers: Insight into the Mechanisms Underlying a Dangerous Relationship. Microorganisms 2023; 11:microorganisms11020267. [PMID: 36838231 PMCID: PMC9963870 DOI: 10.3390/microorganisms11020267] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 01/14/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
Lipopolysaccharide (LPS), also known as endotoxin, is a component of the membrane of gram-negative bacteria and a well-recognized marker of sepsis. In case of disruption of the intestinal barrier, as occurs with unhealthy diets, alcohol consumption, or during chronic diseases, the microbiota residing in the gastrointestinal tract becomes a crucial factor in amplifying the systemic inflammatory response. Indeed, the translocation of LPS into the bloodstream and its interaction with toll-like receptors (TLRs) triggers molecular pathways involved in cytokine release and immune dysregulation. This is a critical step in the exacerbation of many diseases, including metabolic disorders and cancer. Indeed, the role of LPS in cancer development is widely recognized, and examples include gastric tumor related to Helicobacter pylori infection and hepatocellular carcinoma, both of which are preceded by a prolonged inflammatory injury; in addition, the risk of recurrence and development of metastasis appears to be associated with endotoxemia. Here, we review the mechanisms that link the promotion and progression of tumorigenesis with endotoxemia, and the possible therapeutic interventions that can be deployed to counteract these events.
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Affiliation(s)
- Vittoria Manilla
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Natalia Di Tommaso
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Catholic University of the Sacred Heart, 00168 Rome, Italy
- Correspondence:
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Molecular and Cellular Mechanisms of Propolis and Its Polyphenolic Compounds against Cancer. Int J Mol Sci 2022; 23:ijms231810479. [PMID: 36142391 PMCID: PMC9499605 DOI: 10.3390/ijms231810479] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 08/31/2022] [Accepted: 09/05/2022] [Indexed: 12/12/2022] Open
Abstract
In recent years, interest in natural products such as alternative sources of pharmaceuticals for numerous chronic diseases, including tumors, has been renewed. Propolis, a natural product collected by honeybees, and polyphenolic/flavonoid propolis-related components modulate all steps of the cancer progression process. Anticancer activity of propolis and its compounds relies on various mechanisms: cell-cycle arrest and attenuation of cancer cells proliferation, reduction in the number of cancer stem cells, induction of apoptosis, modulation of oncogene signaling pathways, inhibition of matrix metalloproteinases, prevention of metastasis, anti-angiogenesis, anti-inflammatory effects accompanied by the modulation of the tumor microenvironment (by modifying macrophage activation and polarization), epigenetic regulation, antiviral and bactericidal activities, modulation of gut microbiota, and attenuation of chemotherapy-induced deleterious side effects. Ingredients from propolis also "sensitize" cancer cells to chemotherapeutic agents, likely by blocking the activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In this review, we summarize the current knowledge related to the the effects of flavonoids and other polyphenolic compounds from propolis on tumor growth and metastasizing ability, and discuss possible molecular and cellular mechanisms involved in the modulation of inflammatory pathways and cellular processes that affect survival, proliferation, invasion, angiogenesis, and metastasis of the tumor.
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Effects of a novel toll-like receptor 4 antagonist IAXO-102 in a murine model of chemotherapy-induced gastrointestinal toxicity. Cancer Chemother Pharmacol 2022; 90:267-278. [PMID: 35962138 PMCID: PMC9402738 DOI: 10.1007/s00280-022-04463-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 08/03/2022] [Indexed: 11/02/2022]
Abstract
INTRODUCTION Gastrointestinal mucositis (GIM) is a side effect of high-dose irinotecan (CPT-11), causing debilitating symptoms that are often poorly managed. The role of TLR4 in the development of GIM has been clearly demonstrated. We, therefore, aimed to investigate the potential of the TLR4 antagonist, IAXO-102, to attenuate gastrointestinal inflammation as well as supress tumour activity in a colorectal-tumour-bearing mouse model of GIM induced by CPT-11. METHODS 24 C57BL/6 mice received a vehicle, daily i.p. IAXO-102 (3 mg/kg), i.p. CPT-11 (270 mg/kg) or a combination of CPT-11 and IAXO-102. GIM was assessed using validated toxicity markers. At 72 h, colon and tumour tissue were collected and examined for histopathological changes and RT-PCR for genes of interest; TLR4, MD-2, CD-14, MyD88, IL-6, IL-6R, CXCL2, CXCR1, and CXCR2. RESULTS IAXO-102 prevented diarrhoea in mice treated with CPT-11. Tumour volume in IAXO-102-treated mice was lower compared to vehicle at 48 h (P < 0.05). There were no differences observed in colon and tumour weights between the treatment groups. Mice who received the combination treatment had improved tissue injury score (P < 0.05) in the colon but did not show any improvements in cell proliferation or apoptotic rate. Expression of all genes was similar across all treatment groups in the tumour (P > 0.05). In the colon, there was a difference in transcript expression in vehicle vs. IAXO-102 (P < 0.05) and CPT-11 vs. combination (P < 0.01) in MD-2 and IL-6R, respectively. CONCLUSION IAXO-102 was able to attenuate symptomatic parameters of GIM induced by CPT-11 as well as reduce tissue injury in the colon. However, there was no effect on cell proliferation and apoptosis. As such, TLR4 activation plays a partial role in GIM development but further research is required to understand the specific inflammatory signals underpinning tissue-level changes.
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Luo W, Guo S, Zhou Y, Zhao J, Wang M, Sang L, Chang B, Wang B. Hepatocellular Carcinoma: How the Gut Microbiota Contributes to Pathogenesis, Diagnosis, and Therapy. Front Microbiol 2022; 13:873160. [PMID: 35572649 PMCID: PMC9092458 DOI: 10.3389/fmicb.2022.873160] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 04/05/2022] [Indexed: 12/12/2022] Open
Abstract
The gut microbiota is gaining increasing attention, and the concept of the "gut-liver axis" is gradually being recognized. Leaky gut resulting from injury and/or inflammation can cause the translocation of flora to the liver. Microbiota-associated metabolites and components mediate the activation of a series of signalling pathways, thereby playing an important role in the development of hepatocellular carcinoma (HCC). For this reason, targeting the gut microbiota in the diagnosis, prevention, and treatment of HCC holds great promise. In this review, we summarize the gut microbiota and the mechanisms by which it mediates HCC development, and the characteristic alterations in the gut microbiota during HCC pathogenesis. Furthermore, we propose several strategies to target the gut microbiota for the prevention and treatment of HCC, including antibiotics, probiotics, faecal microbiota transplantation, and immunotherapy.
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Affiliation(s)
- Wenyu Luo
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, China
- The Second Clinical College, China Medical University, Shenyang, China
| | - Shiqi Guo
- The Second Clinical College, China Medical University, Shenyang, China
| | - Yang Zhou
- The Second Clinical College, China Medical University, Shenyang, China
| | - Jingwen Zhao
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Mengyao Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lixuan Sang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Bing Chang
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Bingyuan Wang
- Department of Geriatric Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
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12
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Seely KD, Morgan AD, Hagenstein LD, Florey GM, Small JM. Bacterial Involvement in Progression and Metastasis of Colorectal Neoplasia. Cancers (Basel) 2022; 14:1019. [PMID: 35205767 PMCID: PMC8870662 DOI: 10.3390/cancers14041019] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 02/06/2023] Open
Abstract
While the gut microbiome is composed of numerous bacteria, specific bacteria within the gut may play a significant role in carcinogenesis, progression, and metastasis of colorectal carcinoma (CRC). Certain microbial species are known to be associated with specific cancers; however, the interrelationship between bacteria and metastasis is still enigmatic. Mounting evidence suggests that bacteria participate in cancer organotropism during solid tumor metastasis. A critical review of the literature was conducted to better characterize what is known about bacteria populating a distant site and whether a tumor depends upon the same microenvironment during or after metastasis. The processes of carcinogenesis, tumor growth and metastatic spread in the setting of bacterial infection were examined in detail. The literature was scrutinized to discover the role of the lymphatic and venous systems in tumor metastasis and how microbes affect these processes. Some bacteria have a potent ability to enhance epithelial-mesenchymal transition, a critical step in the metastatic cascade. Bacteria also can modify the microenvironment and the local immune profile at a metastatic site. Early targeted antibiotic therapy should be further investigated as a measure to prevent metastatic spread in the setting of bacterial infection.
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Affiliation(s)
- Kevin D. Seely
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT 84738, USA; (A.D.M.); (L.D.H.)
| | - Amanda D. Morgan
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT 84738, USA; (A.D.M.); (L.D.H.)
| | - Lauren D. Hagenstein
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT 84738, USA; (A.D.M.); (L.D.H.)
| | - Garrett M. Florey
- College of Osteopathic Medicine, Rocky Vista University, Parker, CO 80134, USA;
| | - James M. Small
- Department of Biomedical Sciences, Rocky Vista University, Parker, CO 80134, USA;
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13
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Merali N, Chouari T, Kayani K, Rayner CJ, Jiménez JI, Krell J, Giovannetti E, Bagwan I, Relph K, Rockall TA, Dhillon T, Pandha H, Annels NE, Frampton AE. A Comprehensive Review of the Current and Future Role of the Microbiome in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2022; 14:1020. [PMID: 35205769 PMCID: PMC8870349 DOI: 10.3390/cancers14041020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/11/2022] [Accepted: 02/15/2022] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second most common cause of cancer death in the USA by 2030, yet progress continues to lag behind that of other cancers, with only 9% of patients surviving beyond 5 years. Long-term survivorship of PDAC and improving survival has, until recently, escaped our understanding. One recent frontier in the cancer field is the microbiome. The microbiome collectively refers to the extensive community of bacteria and fungi that colonise us. It is estimated that there is one to ten prokaryotic cells for each human somatic cell, yet, the significance of this community in health and disease has, until recently, been overlooked. This review examines the role of the microbiome in PDAC and how it may alter survival outcomes. We evaluate the possibility of employing microbiomic signatures as biomarkers of PDAC. Ultimately this review analyses whether the microbiome may be amenable to targeting and consequently altering the natural history of PDAC.
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Affiliation(s)
- Nabeel Merali
- Minimal Access Therapy Training Unit (MATTU), Leggett Building, University of Surrey, Daphne Jackson Road, Guildford GU2 7WG, UK; (N.M.); (T.A.R.)
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK; (T.C.); (K.K.); (C.J.R.)
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - Tarak Chouari
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK; (T.C.); (K.K.); (C.J.R.)
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - Kayani Kayani
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK; (T.C.); (K.K.); (C.J.R.)
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Charles J. Rayner
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK; (T.C.); (K.K.); (C.J.R.)
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - José I. Jiménez
- Department of Life Sciences, South Kensington Campus, Imperial College London, London SW7 2AZ, UK;
| | - Jonathan Krell
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK;
| | - Elisa Giovannetti
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands;
- Fondazione Pisa per la Scienza, 56017 San Giuliano, Italy
| | - Izhar Bagwan
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - Kate Relph
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - Timothy A. Rockall
- Minimal Access Therapy Training Unit (MATTU), Leggett Building, University of Surrey, Daphne Jackson Road, Guildford GU2 7WG, UK; (N.M.); (T.A.R.)
| | - Tony Dhillon
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - Hardev Pandha
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - Nicola E. Annels
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - Adam E. Frampton
- Minimal Access Therapy Training Unit (MATTU), Leggett Building, University of Surrey, Daphne Jackson Road, Guildford GU2 7WG, UK; (N.M.); (T.A.R.)
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK; (T.C.); (K.K.); (C.J.R.)
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK;
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14
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Pedrosa LDF, Raz A, Fabi JP. The Complex Biological Effects of Pectin: Galectin-3 Targeting as Potential Human Health Improvement? Biomolecules 2022; 12:289. [PMID: 35204790 PMCID: PMC8961642 DOI: 10.3390/biom12020289] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/04/2022] [Accepted: 02/07/2022] [Indexed: 02/07/2023] Open
Abstract
Galectin-3 is the only chimeric representative of the galectin family. Although galectin-3 has ubiquitous regulatory and physiological effects, there is a great number of pathological environments where galectin-3 cooperatively participates. Pectin is composed of different chemical structures, such as homogalacturonans, rhamnogalacturonans, and side chains. The study of pectin's major structural aspects is fundamental to predicting the impact of pectin on human health, especially regarding distinct molecular modulation. One of the explored pectin's biological activities is the possible galectin-3 protein regulation. The present review focuses on revealing the structure/function relationship of pectins, their fragments, and their biological effects. The discussion highlighted by this review shows different effects described within in vitro and in vivo experimental models, with interesting and sometimes contradictory results, especially regarding galectin-3 interaction. The review demonstrates that pectins are promissory food-derived molecules for different bioactive functions. However, galectin-3 inhibition by pectin had been stated in literature before, although it is not a fully understood, experimentally convincing, and commonly agreed issue. It is demonstrated that more studies focusing on structural analysis and its relation to the observed beneficial effects, as well as substantial propositions of cause and effect alongside robust data, are needed for different pectin molecules' interactions with galectin-3.
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Affiliation(s)
- Lucas de Freitas Pedrosa
- Department of Food Science and Experimental Nutrition, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508000, SP, Brazil;
| | - Avraham Raz
- Department of Oncology and Pathology, School of Medicine, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA;
| | - João Paulo Fabi
- Department of Food Science and Experimental Nutrition, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508000, SP, Brazil;
- Food and Nutrition Research Center (NAPAN), University of São Paulo, São Paulo 05508080, SP, Brazil
- Food Research Center (FoRC), CEPID-FAPESP (Research, Innovation and Dissemination Centers, São Paulo Research Foundation), São Paulo 05508080, SP, Brazil
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15
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Zheng S, Zou Y, Tang Y, Yang A, Liang JY, Wu L, Tian W, Xiao W, Xie X, Yang L, Xie J, Wei W, Xie X. Landscape of cancer-associated fibroblasts identifies the secreted biglycan as a protumor and immunosuppressive factor in triple-negative breast cancer. Oncoimmunology 2022; 11:2020984. [PMID: 35003899 PMCID: PMC8741292 DOI: 10.1080/2162402x.2021.2020984] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/28/2021] [Accepted: 12/16/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) are essential for tumor microenvironment remodeling and correlate with tumor progression. However, interactions between CAFs and tumor cells and immune cells in triple-negative breast cancer (TNBC) are still poorly explored. Here, we investigate the role of CAFs in TNBC and potential novel mediators of their functions. The clustering of classic markers was applied to estimate the relative abundance of CAFs in TNBC cohorts. Primary fibroblasts were isolated from normal and tumor samples. The RNA and culture medium of fibroblasts were subjected to RNA sequencing and mass spectrometry to explore the upregulated signatures in CAFs. Microdissection and single-cell RNA sequencing datasets were used to examine the expression profiles. CAFs were associated with hallmark signalings and immune components in TNBC. Clustering based on CAF markers in the literature revealed different CAF infiltration groups in TNBC: low, medium and high. Most of the cancer hallmark signaling pathways were enriched in the high CAF infiltration group. Furthermore, RNA sequencing and mass spectrometry identified biglycan (BGN), a soluble secreted protein, as upregulated in CAFs compared to normal cancer-adjacent fibroblasts (NAFs). The expression of biglycan was negatively correlated with CD8 + T cells. Biglycan indicated poor prognostic outcomes and might be correlated with the immunosuppressive tumor microenvironment (TME). In conclusion, CAFs play an essential role in tumor progression and the TME. We identified an extracellular protein, biglycan, as a prognostic marker and potential therapeutic target in TNBC.
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Affiliation(s)
- Shaoquan Zheng
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Yutian Zou
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Yuhui Tang
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Anli Yang
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Jie-Ying Liang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Linyu Wu
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Wenwen Tian
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Weikai Xiao
- Department of Breast Cancer, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China
| | - Xinhua Xie
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Lu Yang
- Department of Radiotherapy, Cancer Center, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China
| | - Jindong Xie
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Weidong Wei
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Xiaoming Xie
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
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16
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Interaction of Opioids with TLR4-Mechanisms and Ramifications. Cancers (Basel) 2021; 13:cancers13215274. [PMID: 34771442 PMCID: PMC8582379 DOI: 10.3390/cancers13215274] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 10/09/2021] [Accepted: 10/17/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Recent evidence indicates that opioids can be active at a receptor that is abundantly expressed on innate immune cells as well as cancer cells: the receptor is termed toll-like receptor 4 (TLR4). TLR4 is increasingly recognised as playing key roles in tumour biology and anticancer defences. However, the issue of whether TLR4 mediates some of the effects of opioids on tumour growth and metastasis is entirely unknown. We review existing evidence, mechanisms, and functional consequences of the action of opioids at TLR4. This opens new avenues of research on the role of opioids in cancer. Abstract The innate immune receptor toll-like receptor 4 (TLR4) is known as a sensor for the gram-negative bacterial cell wall component lipopolysaccharide (LPS). TLR4 activation leads to a strong pro-inflammatory response in macrophages; however, it is also recognised to play a key role in cancer. Recent studies of the opioid receptor (OR)-independent actions of opioids have identified that TLR4 can respond to opioids. Opioids are reported to weakly activate TLR4, but to significantly inhibit LPS-induced TLR4 activation. The action of opioids at TLR4 is suggested to be non-stereoselective, this is because OR-inactive (+)-isomers of opioids have been shown to activate or to inhibit TLR4 signalling, although there is some controversy in the literature. While some opioids can bind to the lipopolysaccharide (LPS)-binding cleft of the Myeloid Differentiation factor 2 (MD-2) co-receptor, pharmacological characterisation of the inhibition of opioids on LPS activation of TLR4 indicates a noncompetitive mechanism. In addition to a direct interaction at the receptor, opioids affect NF-κB activation downstream of both TLR4 and opioid receptors and modulate TLR4 expression, leading to a range of in vivo outcomes. Here, we review the literature reporting the activity of opioids at TLR4, its proposed mechanism(s), and the complex functional consequences of this interaction.
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Hu J, Xu J, Feng X, Li Y, Hua F, Xu G. Differential Expression of the TLR4 Gene in Pan-Cancer and Its Related Mechanism. Front Cell Dev Biol 2021; 9:700661. [PMID: 34631699 PMCID: PMC8495169 DOI: 10.3389/fcell.2021.700661] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 07/27/2021] [Indexed: 01/03/2023] Open
Abstract
Previous studies have revealed the relationship between toll-like receptor 4 (TLR4) polymorphisms and cancer susceptibility. However, the relationship between TLR4 and prognosis and immune cell infiltration in pan-cancer patients is still unclear. Through the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases, the distinct expression of the TLR4 gene in 24 tumors and normal tissues was analyzed. Univariate Cox proportional hazards regression analysis was used to identify the cancer types whose TLR4 gene expression was related to prognosis. The relationship between TLR4 and tumor cell immune invasion was studied. Spearman's rank correlation coefficient was used to analyze the relationship among TLR4 and immune neoantigens, tumor mutation burden (TMB), microsatellite instability (MSI), DNA repair genes, and DNA methylation. Gene Set Enrichment Analysis (GSEA) was used to identify the tumor-related pathways that the TLR4 gene was highly expressed in; the expression of the TLR4 gene was verified with the Human Protein Atlas (HPA) database. Low expression of TLR4 was associated with an inferior prognosis in kidney renal clear cell carcinoma (KIRC), skin cutaneous melanoma (SKCM), and uterine corpus endometrial carcinoma (UCEC), while high expression was related to a poor prognosis in head and neck squamous cell carcinoma (HNSC), prostate adenocarcinoma (PRAD), stomach adenocarcinoma (STAD), and testicular germ cell tumor (TGCT). The expression of TLR4 was negatively correlated with the expression of B cells in STAD. The expression of TLR4 was positively correlated with the infiltration of B cells, CD4 and CD8 T cells, neutrophils, macrophages, and dendritic cells in STAD, KIRC, UCEC, TGCT, and SKCM. The expression of the TLR4 gene in KIRC, SKCM, STAD, TGCT, and UCEC was highly correlated with inducible T-cell costimulator (ICOS), cytotoxic T lymphocyte-associated molecule 4 (CTLA4), and CD28 immune checkpoints. Spearman's rank correlation coefficient showed that the expression of TLR4 gene was significantly correlated with TMB in STAD and UCEC and was prominently correlated with MSI in TGCT, STAD, and SKCM. The expression of the TLR4 gene was highly correlated with MLH1, MSH2, and MSH6 in KIRC, SKCM, and STAD. The expression of the TLR4 gene was remarkably correlated with the methyltransferases DNA methyltransferase 2 (DNMT2) and DNA methyltransferase 3-beta (DNMT3B) in SKCM and STAD. Enrichment analysis showed that TLR4 was highly expressed in the chemokine signaling pathway and the cell adhesion molecule and cytokine receptor interaction pathway. In summary, the expression of TLR4 is linked to the prognosis of KIRC, SKCM, STAD, TGCT, and UCEC patients and the level of immune infiltration of CD4, CD8 T cells, macrophages, neutrophils, and dendritic cells.
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Affiliation(s)
- Jialing Hu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jiasheng Xu
- Department of Surgical Oncology, Zhejiang University Cancer Center, Hangzhou, China
| | - Xiaojin Feng
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yiran Li
- Queen Mary College, Nanchang University, Nanchang, China
| | - Fuzhou Hua
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Guohai Xu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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18
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Qi Y, Fang Q, Li Q, Ding H, Shu Q, Hu Y, Xin W, Fang L. MD2 blockage prevents the migration and invasion of hepatocellular carcinoma cells via inhibition of the EGFR signaling pathway. J Gastrointest Oncol 2021; 12:1873-1883. [PMID: 34532135 PMCID: PMC8421902 DOI: 10.21037/jgo-21-362] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 07/29/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The toll-like receptor (TLR) is an emerging signaling pathway in tumor invasion and metastasis. The activation of TLRs requires specific accessory proteins, such as the small secreted glycoprotein myeloid differentiation protein 2 (MD2), which contributes to ligand responsiveness. However, the role of MD2 in tumorigenesis and metastasis has rarely been reported. This study aimed to investigate the effects and underlying mechanisms of MD2 on the proliferation, migration, and invasion of hepatocellular carcinoma (HCC). METHODS Cell counting kit 8 (CCK8), cell colony formation, wound healing, and transwell assays were conducted to determine cell viability, proliferation, migration, and invasion, respectively. Quantitative real-time PCR (qRT-PCR) was performed to assess the expression of MD2 in HCC cell lines and human normal liver cell lines as well as the silencing efficiency of MD2 blockage. Western blot and qRT-PCR assays were performed to detect the protein and mRNA expression levels of epithelial mesenchymal transformation (EMT) markers and epidermal growth factor receptor (EGFR) signaling molecules. RESULTS MD2 was highly expressed in HCC tissues and cell lines. High expression of MD2 was associated with poor prognosis of HCC patients. In addition, MD2 silencing slightly inhibited the proliferation of HepG2 and HCCLM3, and significantly suppressed cell migration and invasion. Furthermore, MD2 blockage could distinctly prevent the EMT process by increasing the protein and mRNA levels of E-cadherin and Occludin, and decreasing the levels of Vimentin, N-cadherin, and Snail. Finally, the phosphorylation level of EGFR as well as its downstream molecular Src, Akt, I-κBα, and p65 were downregulated in HCC cells with MD2 silencing. CONCLUSIONS Our findings suggest that high expression of MD2 may affect the EMT, migration, and invasion via modulation of the EGFR pathway in HCC cells.
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Affiliation(s)
- Yajun Qi
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Qilu Fang
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Qinglin Li
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Department of Comprehensive Medical Oncology, Key Laboratory of Head and Neck Translational Research of Zhejiang Province, Zhejiang Cancer Hospital, Hangzhou, China
| | - Haiying Ding
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Qi Shu
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Yan Hu
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Wenxiu Xin
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Department of Comprehensive Medical Oncology, Key Laboratory of Head and Neck Translational Research of Zhejiang Province, Zhejiang Cancer Hospital, Hangzhou, China
| | - Luo Fang
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
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Looi CK, Hii LW, Chung FFL, Mai CW, Lim WM, Leong CO. Roles of Inflammasomes in Epstein-Barr Virus-Associated Nasopharyngeal Cancer. Cancers (Basel) 2021; 13:1786. [PMID: 33918087 PMCID: PMC8069343 DOI: 10.3390/cancers13081786] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/08/2021] [Accepted: 03/08/2021] [Indexed: 02/05/2023] Open
Abstract
Epstein-Barr virus (EBV) infection is recognised as one of the causative agents in most nasopharyngeal carcinoma (NPC) cases. Expression of EBV viral antigens can induce host's antiviral immune response by activating the inflammasomes to produce pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18. These cytokines are known to be detrimental to a wide range of virus-infected cells, in which they can activate an inflammatory cell death program, called pyroptosis. However, aberrant inflammasome activation and production of its downstream cytokines lead to chronic inflammation that may contribute to various diseases, including NPC. In this review, we summarise the roles of inflammasomes during viral infection, how EBV evades inflammasome-mediated immune response, and progress into tumourigenesis. The contrasting roles of inflammasomes in cancer, as well as the current therapeutic approaches used in targeting inflammasomes, are also discussed in this review. While the inflammasomes appear to have dual roles in carcinogenesis, there are still many questions that remain unanswered. In particular, the exact molecular mechanism responsible for the regulation of the inflammasomes during carcinogenesis of EBV-associated NPC has not been explored thoroughly. Furthermore, the current practical application of inflammasome inhibitors is limited to specific tumour types, hence, further studies are warranted to discover the potential of targeting the inflammasomes for the treatment of NPC.
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Affiliation(s)
- Chin King Looi
- School of Postgraduate Studies, International Medical University, Kuala Lumpur 57000, Malaysia; (C.K.L.); (L.-W.H.)
- Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur 57000, Malaysia; (C.-W.M.); (W.-M.L.)
| | - Ling-Wei Hii
- School of Postgraduate Studies, International Medical University, Kuala Lumpur 57000, Malaysia; (C.K.L.); (L.-W.H.)
- Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur 57000, Malaysia; (C.-W.M.); (W.-M.L.)
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia
| | - Felicia Fei-Lei Chung
- Mechanisms of Carcinogenesis Section (MCA), Epigenetics Group (EGE), International Agency for Research on Cancer World Health Organisation, CEDEX 08 Lyon, France;
| | - Chun-Wai Mai
- Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur 57000, Malaysia; (C.-W.M.); (W.-M.L.)
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Wei-Meng Lim
- Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur 57000, Malaysia; (C.-W.M.); (W.-M.L.)
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia
| | - Chee-Onn Leong
- Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur 57000, Malaysia; (C.-W.M.); (W.-M.L.)
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia
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Wang W, Yan L, Guan X, Dong B, Zhao M, Wu J, Tian X, Hao C. Identification of an Immune-Related Signature for Predicting Prognosis in Patients With Pancreatic Ductal Adenocarcinoma. Front Oncol 2021; 10:618215. [PMID: 33718118 PMCID: PMC7945593 DOI: 10.3389/fonc.2020.618215] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 12/31/2020] [Indexed: 12/26/2022] Open
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is one of the highest fatality rate cancers with poor survival rates. The tumor microenvironment (TME) is vital for tumor immune responses, leading to resistance to chemotherapy and poor prognosis of PDAC patients. This study aimed to provide a comprehensive evaluation of the immune genes and microenvironment in PDAC that might help in predicting prognosis and guiding clinical treatments. METHODS We developed a prognosis-associated immune signature (i.e., PAIS) based on immune-associated genes to predict the overall survival of patients with PDAC. The clinical significance and immune landscapes of the signature were comprehensively analyzed. RESULTS Owing to gene expression profiles from TCGA database, functional enrichment analysis revealed a significant difference in the immune response between PDAC and normal pancreas. Using transcriptome data analysis of a training set, we identified an immune signature represented by 5 genes (ESR2, IDO1, IL20RB, PPP3CA, and PLAU) related to the overall survival of patients with PDAC, significantly. This training set was well-validated in a test set. Our results indicated a clear association between a high-risk score and a very poor prognosis. Stratification analysis and multivariate Cox regression analysis revealed that PAIS was an important prognostic factor. We also found that the risk score was positively correlated with the inflammatory response, antigen-presenting process, and expression level of some immunosuppressive checkpoint molecules (e.g., CD73, PD-L1, CD80, and B7-H3). These results suggested that high-risk patients had a suppressed immune response. However, they could respond better to chemotherapy. In addition, PAIS was positively correlated with the infiltration of M2 macrophages in PDAC. CONCLUSIONS This study highlighted the relationship between the immune response and prognosis in PDAC and developed a clinically feasible signature that might serve as a powerful prognostic tool and help further optimize the cancer therapy paradigm.
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Affiliation(s)
- Weijia Wang
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Liang Yan
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiaoya Guan
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Bin Dong
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Central Laboratory, Peking University Cancer Hospital & Institute, Beijing, China
| | - Min Zhao
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jianhui Wu
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiuyun Tian
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Chunyi Hao
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
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21
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Assessment on the influence of TLR4 and DNA repair genes in laryngeal cancer susceptibility: a selective examination in a Romanian case control study. REV ROMANA MED LAB 2021. [DOI: 10.2478/rrlm-2021-0005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Abstract
Background: Tumor characterization through the study of molecular biology has become an invaluable tool in understanding cancer development and evolution due to its relationship with chromosomal mutations, alterations or aberrations. The purpose of this study was to investigate the involvement of genes such as TLR-4 and DNA repair pathways (XRCC1 and XPD) in laryngeal cancer susceptibility in a Romanian population. Method: We performed a case-control study on 157 laryngeal cancer patients and 101 healthy controls. Genetic testing was carried out using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. Results: We identified the Gln allele of the XPDLys751Gln polymorphism as an individual risk factor in laryngeal cancer development (Gln vs Lys, adjusted OR=1.65, 95%CI=1.13–2.40, P=0.008). Subjects with the mutant homozygote variant (Gln/Gln) had a two fold increase in cancer risk (adjusted OR=2.18, 95%CI=1.06–4.47, p=0.028) when compared to the reference wild type genotype (Lys/Lys). Stratification by sex and age, identified males under 62 years as the most susceptible group with an almost three fold risk (adjusted OR=2.94, 95%CI=1.31–6.59, p=0.007) for the dominant model (Lys/Gln+Gln/Gln). No associations were found for TLR-4Thr399Ile, XRCC1Arg194Trp and XRCC1Arg399Gln. Conclusion: The results of the study show that the XPDLys751Gln polymorphism may be among other independent risk factors for developing laryngeal cancer where as TLR-4Thr399Ile, XRCC1Arg194Trp and XRCC1 Arg399Gln show no such association. However, we consider the relative small number of the subjects selected for this analyses a possible limitation towards the real influence the obtain results may pertain in laryngeal cancer evolution.
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22
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Cui L, Wang X, Zhang D. TLRs as a Promise Target Along With Immune Checkpoint Against Gastric Cancer. Front Cell Dev Biol 2021; 8:611444. [PMID: 33469538 PMCID: PMC7813757 DOI: 10.3389/fcell.2020.611444] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 12/07/2020] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer (GC) is one of the most common cancers in the world, and the incidence of gastric cancer in Asia appears to increase in recent years. Although there is a lot of improvement in treatment approaches, the prognosis of GC is poor. So it is urgent to search for a novel and more effective treatment to improve the survival rate of patients. Both innate immunity and adaptive immunity are important in cancer. In the innate immune system, pattern recognition receptors (PRRs) activate immune responses by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Toll-like receptors (TLRs) are a class of pattern recognition receptors (PRRs). Many studies have reported that TLRs are involved in the occurrence, development, and treatment of GC. Therefore, TLRs are potential targets for immunotherapy to gastric cancer. However, gastric cancer is a heterogeneous disorder, and TLRs function in GC is complex. TLRs agonists can be potentially used not only as therapeutic agents to treat gastric cancer but also as adjuvants in conjunction with other immunotherapies. They might provide a promising new target for GC treatment. In the review, we sort out the mechanism of TLRs involved in tumor immunity and summarize the current progress in TLRs-based therapeutic approaches and other immunotherapies in the treatment of GC.
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Affiliation(s)
- Lin Cui
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Xiuqing Wang
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Dekai Zhang
- Center for Infectious and Inflammatory Diseases, Texas A&M University, Houston, TX, United States
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Gan LL, Hii LW, Wong SF, Leong CO, Mai CW. Molecular Mechanisms and Potential Therapeutic Reversal of Pancreatic Cancer-Induced Immune Evasion. Cancers (Basel) 2020; 12:1872. [PMID: 32664564 PMCID: PMC7408947 DOI: 10.3390/cancers12071872] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/06/2020] [Accepted: 07/09/2020] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer ranks high among the causes of cancer-related mortality. The prognosis of this grim condition has not improved significantly over the past 50 years, despite advancement in imaging techniques, cancer genetics and treatment modalities. Due to the relative difficulty in the early detection of pancreatic tumors, as low as 20% of patients are eligible for potentially curative surgery; moreover, chemotherapy and radiotherapy (RT) do not confer a great benefit in the overall survival of the patients. Currently, emerging developments in immunotherapy have yet to bring a significant clinical advantage among pancreatic cancer patients. In fact, pancreatic tumor-driven immune evasion possesses one of the greatest challenges leading to immunotherapeutic resistance. Most of the immune escape pathways are innate, while poor priming of hosts' immune response and immunoediting constitute the adaptive immunosuppressive machinery. In this review, we extensively discuss the pathway perturbations undermining the anti-tumor immunity specific to pancreatic cancer. We also explore feasible up-and-coming therapeutic strategies that may restore immunity and address therapeutic resistance, bringing hope to eliminate the status quo in pancreatic cancer prognosis.
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Affiliation(s)
- Li-Lian Gan
- School of Postgraduate Study, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (L.-L.G.); (L.-W.H.)
| | - Ling-Wei Hii
- School of Postgraduate Study, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (L.-L.G.); (L.-W.H.)
- School of Pharmacy, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
| | - Shew-Fung Wong
- School of Medicine, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
- Centre for Environmental and Population Health, Institute for Research, Development and Innovation (IRDI), International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Chee-Onn Leong
- School of Pharmacy, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
- Centre for Cancer and Stem Cells Research, Institute for Research, Development and Innovation (IRDI), International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Chun-Wai Mai
- School of Pharmacy, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
- Centre for Cancer and Stem Cells Research, Institute for Research, Development and Innovation (IRDI), International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia
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Ou T, Zhou Z, Turner DP, Zhu B, Lilly M, Jiang W. Increased Preoperative Plasma Level of Microbial 16S rDNA Translocation Is Associated With Relapse After Prostatectomy in Prostate Cancer Patients. Front Oncol 2020; 9:1532. [PMID: 32010622 PMCID: PMC6974797 DOI: 10.3389/fonc.2019.01532] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 12/19/2019] [Indexed: 12/13/2022] Open
Abstract
Background: The environmental factors for promoting prostate cancer (PCa) recurrence remain unknown. Methods: A retrospective cross-sectional study was conducted in healthy men (n = 12) and PCa patients undergoing prostatectomy (n = 27). Plasma preoperative level of total cell-free bacterial 16S rDNA, a marker of microbial translocation, was evaluated by qPCR. Plasma levels of prostate-specific antigen (PSA) were evaluated by ELISA. Results: Similar degrees of microbial translocation were found in healthy men and patients. However, the levels of microbial 16S rDNA were increased in patients with cancer relapse (n = 10) compared to patients without relapse (n = 17) after prostatectomy. Furthermore, the levels of microbial 16S rDNA were marginally increased in patients with pT3 or pT4 tumors compared to those with pT 2 or less. The levels of microbial 16S rDNA tended to increase in patients with higher pathologic tumor stage, Gleason score, and margin and lymph node involvements; but these differences did not reach significance. Conclusion: The plasma 16S rDNA levels increased in patients with PCa who have biochemical recurrence and 16S rDNA levels were higher in patients with higher-grade PCa.
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Affiliation(s)
- Tongwen Ou
- Department of Urology, Capital Medical University Affiliated XuanWu Hospital, Beijing, China
| | - Zejun Zhou
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, China
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
| | - David P. Turner
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States
| | - Baoli Zhu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Beijing Key Laboratory of Antimicrobial Resistance and Pathogen Genomics, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
- Department of Pathogenic Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Michael Lilly
- Division of Hematology and Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, United States
| | - Wei Jiang
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC, United States
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Wang Y, Yang G, You L, Yang J, Feng M, Qiu J, Zhao F, Liu Y, Cao Z, Zheng L, Zhang T, Zhao Y. Role of the microbiome in occurrence, development and treatment of pancreatic cancer. Mol Cancer 2019; 18:173. [PMID: 31785619 PMCID: PMC6885316 DOI: 10.1186/s12943-019-1103-2] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most lethal malignancies. Recent studies indicated that development of pancreatic cancer may be intimately connected with the microbiome. In this review, we discuss the mechanisms through which microbiomes affect the development of pancreatic cancer, including inflammation and immunomodulation. Potential therapeutic and diagnostic applications of microbiomes are also discussed. For example, microbiomes may serve as diagnostic markers for pancreatic cancer, and may also play an important role in determining the efficacies of treatments such as chemo- and immunotherapies. Future studies will provide additional insights into the various roles of microbiomes in pancreatic cancer.
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Affiliation(s)
- Yicheng Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730 China
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730 China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730 China
| | - Jinshou Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730 China
| | - Mengyu Feng
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730 China
| | - Jiangdong Qiu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730 China
| | - Fangyu Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730 China
| | - Yueze Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730 China
| | - Zhe Cao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730 China
| | - Lianfang Zheng
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730 China
- Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730 China
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Hii LW, Lim SHE, Leong CO, Chin SY, Tan NP, Lai KS, Mai CW. The synergism of Clinacanthus nutans Lindau extracts with gemcitabine: downregulation of anti-apoptotic markers in squamous pancreatic ductal adenocarcinoma. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 19:257. [PMID: 31521140 PMCID: PMC6744713 DOI: 10.1186/s12906-019-2663-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 08/30/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Clinacanthus nutans extracts have been consumed by the cancer patients with the hope that the extracts can kill cancers more effectively than conventional chemotherapies. Our previous study reported its anti-inflammatory effects were caused by inhibiting Toll-like Receptor-4 (TLR-4) activation. However, we are unsure of its anticancer effect, and its interaction with existing chemotherapy. METHODS We investigated the anti-proliferative efficacy of polar leaf extracts (LP), non-polar leaf extracts (LN), polar stem extract (SP) and non-polar stem extracts (SN) in human breast, colorectal, lung, endometrial, nasopharyngeal, and pancreatic cancer cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT assay. The most potent extracts was tested along with gemcitabine using our established drug combination analysis. The effect of the combinatory treatment in apoptosis were quantified using enzyme-linked immunosorbent assay (ELISA), Annexin V assay, antibody array and immunoblotting. Statistical significance was analysed using one-way analysis of variance (ANOVA) and post hoc Dunnett's test. A p-value of less than 0.05 (p < 0.05) was considered statistical significance. RESULTS All extracts tested were not able to induce potent anti-proliferative effects. However, it was found that pancreatic ductal adenocarcinoma, PDAC (AsPC1, BxPC3 and SW1990) were the cell lines most sensitive cell lines to SN extracts. This is the first report of C. nutans SN extracts acting in synergy with gemcitabine, the first line chemotherapy for pancreatic cancer, as compared to conventional monotherapy. In the presence of SN extracts, we can reduce the dose of gemcitabine 2.38-5.28 folds but still maintain the effects of gemcitabine in PDAC. SN extracts potentiated the killing of gemcitabine in PDAC by apoptosis. Bax was upregulated while bcl-2, cIAP-2, and XIAP levels were downregulated in SW1990 and BxPC3 cells treated with gemcitabine and SN extracts. The synergism was independent of TLR-4 expression in pancreatic cancer cells. CONCLUSION These results provide strong evidence of C. nutans extracts being inefficacious as monotherapy for cancer. Hence, it should not be used as a total substitution for any chemotherapy agents. However, SN extracts may synergise with gemcitabine in the anti-tumor mechanism.
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Affiliation(s)
- Ling-Wei Hii
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, 57000 Malaysia
| | - Swee-Hua Erin Lim
- Perdana University-Royal College of Surgeons in Ireland, Seri Kembangan, 43400 Selangor Malaysia
- Health Sciences Division, Abu Dhabi Women’s College, Higher Colleges of Technology, Abu Dhabi, United Arab Emirates
| | - Chee-Onn Leong
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, 57000 Malaysia
- Centre for Cancer and Stem Cells Research, Institute for Research Development and Innovation, International Medical University, Kuala Lumpur, 57000 Malaysia
| | - Swee-Yee Chin
- Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, 57000 Kuala Lumpur, Malaysia
| | - Ngai-Paing Tan
- Department of Land Management, Faculty of Agriculture, Universiti Putra Malaysia, Seri Kembangan, 43400 Selangor Malaysia
| | - Kok-Song Lai
- Health Sciences Division, Abu Dhabi Women’s College, Higher Colleges of Technology, Abu Dhabi, United Arab Emirates
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400 Seri Kembangan, Selangor Malaysia
| | - Chun-Wai Mai
- Centre for Cancer and Stem Cells Research, Institute for Research Development and Innovation, International Medical University, Kuala Lumpur, 57000 Malaysia
- Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, 57000 Kuala Lumpur, Malaysia
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Ploypetch S, Roytrakul S, Jaresitthikunchai J, Phaonakrop N, Krobthong S, Suriyaphol G. Salivary proteomics of canine oral tumors using MALDI-TOF mass spectrometry and LC-tandem mass spectrometry. PLoS One 2019; 14:e0219390. [PMID: 31318878 PMCID: PMC6638856 DOI: 10.1371/journal.pone.0219390] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 06/22/2019] [Indexed: 02/07/2023] Open
Abstract
Canine oral tumors are relatively common neoplasms in dogs. For disease monitoring and early diagnosis, salivary biomarkers are appropriate because saliva collection is non-invasive and requires no professional skills. In the era of omics, matrix-assisted laser desorption/ionization with time-of-flight mass spectrometry (MALDI-TOF MS) coupled with liquid chromatography-tandem MS (LC-MS/MS) are suitable to identify potential disease-associated peptides and proteins. The present study aimed to use MALDI-TOF MS and LC-MS/MS to search for particular peptide mass fingerprints (PMFs) and conceivable biomarkers in saliva of dogs with early- and late-stage oral melanoma (EOM and LOM, respectively), oral squamous cell carcinoma (OSCC), benign oral tumors (BN), and periodontitis and healthy controls (CP). Pooled saliva samples in each group were used to be representative of population change. Unique PMFs were obtained and specific peptide fragments were sequenced by LC-MS/MS and BLAST-searched with mammalian protein databases. Seven peptide fragments appeared in the tumor groups (EOM, LOM, OSCC and BN) at 1096, 1208, 1322, 1794, 1864, 2354 and 2483 Da, two peptide fragments appeared in the LOM and OSCC groups at 2450 and 3492 Da, and in the CP controls at 2544 and 3026 Da. Also, protein–chemotherapy drug interaction networks were exhibited. Using western blot analysis, the expression of sentrin-specific protease 7 (SENP7), a peptide fragment at 1096 Da, in OSCC was significantly increased, as was the expression of TLR4, a peptide fragment at 3492 Da, in LOM and OSCC, compared with the CP group. The expression of nuclear factor kappa B (NF-κB), a TLR4 partner, was notably increased in OSCC compared with CP, BN and EOM. The expression was also enhanced in LOM compared with EOM. Expressed protein sequences from western blots were verified by LC-MS/MS. Western blots were then performed with individual samples in each group. The results showed the elevated expression of TLR4 in LOM and OSCC, compared with that in CP and BN, the increased expression of NF-κB in LOM and OSCC, compared with CP and in LOM compared with BN, and the enhanced expression of SENP7 in LOM and OSCC, compared with that in CP and BN. In conclusion, discrete clusters of EOM, LOM, OSCC, BN and CP groups and potential protein candidates associated with the diseases were demonstrated by salivary proteomics. Western blot analysis verified SENP7, TLR4 and NF-κB as potential salivary biomarkers of canine oral tumors.
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Affiliation(s)
- Sekkarin Ploypetch
- Biochemistry Unit, Department of Physiology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
- Companion Animal Cancer Research Unit, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | - Sittiruk Roytrakul
- Proteomics Research Laboratory, Genome Institute, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Janthima Jaresitthikunchai
- Proteomics Research Laboratory, Genome Institute, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Narumon Phaonakrop
- Proteomics Research Laboratory, Genome Institute, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Sucheewin Krobthong
- Proteomics Research Laboratory, Genome Institute, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Gunnaporn Suriyaphol
- Biochemistry Unit, Department of Physiology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
- Companion Animal Cancer Research Unit, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
- * E-mail:
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Dickinson SE, Wondrak GT. TLR4 in skin cancer: From molecular mechanisms to clinical interventions. Mol Carcinog 2019; 58:1086-1093. [PMID: 31020719 DOI: 10.1002/mc.23016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 03/22/2019] [Accepted: 03/29/2019] [Indexed: 12/15/2022]
Abstract
The health and economic burden imposed by skin cancer is substantial, creating an urgent need for the development of improved molecular strategies for its prevention and treatment. Cutaneous exposure to solar ultraviolet (UV) radiation is a causative factor in skin carcinogenesis, and TLR4-dependent inflammatory dysregulation is an emerging key mechanism underlying detrimental effects of acute and chronic UV exposure. Direct and indirect TLR4 activation, upstream of inflammatory signaling, is elicited by a variety of stimuli, including pathogen-associated molecular patterns (such as lipopolysaccharide) and damage-associated molecular patterns (such as HMGB1) that are formed upon exposure to environmental stressors, such as solar UV. TLR4 involvement has now been implicated in major types of skin malignancies, including nonmelanoma skin cancer, melanoma and Merkel cell carcinoma. Targeted molecular interventions that positively or negatively modulate TLR4 signaling have shown promise in translational, preclinical, and clinical investigations that may benefit skin cancer patients in the near future.
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Affiliation(s)
- Sally E Dickinson
- Department of Pharmacology, College of Medicine and The University of Arizona Cancer Center, University of Arizona, Tucson, Arizona
| | - Georg T Wondrak
- Department of Pharmacology and Toxicology, College of Pharmacy and The University of Arizona Cancer Center, University of Arizona, Tucson, Arizona
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Looi CK, Chung FFL, Leong CO, Wong SF, Rosli R, Mai CW. Therapeutic challenges and current immunomodulatory strategies in targeting the immunosuppressive pancreatic tumor microenvironment. J Exp Clin Cancer Res 2019; 38:162. [PMID: 30987642 PMCID: PMC6463646 DOI: 10.1186/s13046-019-1153-8] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 03/22/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Pancreatic cancer is one of the most lethal type of cancers, with an overall five-year survival rate of less than 5%. It is usually diagnosed at an advanced stage with limited therapeutic options. To date, no effective treatment options have demonstrated long-term benefits in advanced pancreatic cancer patients. Compared with other cancers, pancreatic cancer exhibits remarkable resistance to conventional therapy and possesses a highly immunosuppressive tumor microenvironment (TME). MAIN BODY In this review, we summarized the evidence and unique properties of TME in pancreatic cancer that may contribute to its resistance towards immunotherapies as well as strategies to overcome those barriers. We reviewed the current strategies and future perspectives of combination therapies that (1) promote T cell priming through tumor associated antigen presentation; (2) inhibit tumor immunosuppressive environment; and (3) break-down the desmoplastic barrier which improves tumor infiltrating lymphocytes entry into the TME. CONCLUSIONS It is imperative for clinicians and scientists to understand tumor immunology, identify novel biomarkers, and optimize the position of immunotherapy in therapeutic sequence, in order to improve pancreatic cancer clinical trial outcomes. Our collaborative efforts in targeting pancreatic TME will be the mainstay of achieving better clinical prognosis among pancreatic cancer patients. Ultimately, pancreatic cancer will be a treatable medical condition instead of a death sentence for a patient.
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Affiliation(s)
- Chin-King Looi
- School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia
| | - Felicia Fei-Lei Chung
- Mechanisms of Carcinogenesis Section (MCA), Epigenetics Group (EGE) International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Chee-Onn Leong
- School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
- Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur, Malaysia
| | - Shew-Fung Wong
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia
| | - Rozita Rosli
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Sri Kembangan, Selangor Malaysia
| | - Chun-Wai Mai
- School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
- Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur, Malaysia
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Tham SY, Loh HS, Mai CW, Fu JY. Tocotrienols Modulate a Life or Death Decision in Cancers. Int J Mol Sci 2019; 20:372. [PMID: 30654580 PMCID: PMC6359475 DOI: 10.3390/ijms20020372] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 01/05/2019] [Accepted: 01/10/2019] [Indexed: 02/06/2023] Open
Abstract
Malignancy often arises from sophisticated defects in the intricate molecular mechanisms of cells, rendering a complicated molecular ground to effectively target cancers. Resistance toward cell death and enhancement of cell survival are the common adaptations in cancer due to its infinite proliferative capacity. Existing cancer treatment strategies that target a single molecular pathway or cancer hallmark fail to fully resolve the problem. Hence, multitargeted anticancer agents that can concurrently target cell death and survival pathways are seen as a promising alternative to treat cancer. Tocotrienols, a minor constituent of the vitamin E family that have previously been reported to induce various cell death mechanisms and target several key survival pathways, could be an effective anticancer agent. This review puts forward the potential application of tocotrienols as an anticancer treatment from a perspective of influencing the life or death decision of cancer cells. The cell death mechanisms elicited by tocotrienols, particularly apoptosis and autophagy, are highlighted. The influences of several cell survival signaling pathways in shaping cancer cell death, particularly NF-κB, PI3K/Akt, MAPK, and Wnt, are also reviewed. This review may stimulate further mechanistic researches and foster clinical applications of tocotrienols via rational drug designs.
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Affiliation(s)
- Shiau-Ying Tham
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia Campus, Jalan Broga, Semenyih 43500, Selangor, Malaysia.
| | - Hwei-San Loh
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia Campus, Jalan Broga, Semenyih 43500, Selangor, Malaysia.
- Biotechnology Research Centre, University of Nottingham Malaysia Campus, Jalan Broga, Semenyih 43500, Selangor, Malaysia.
| | - Chun-Wai Mai
- School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia.
- Centre for Cancer and Stem Cell Research, Institute for Research, Development and Innovation, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia.
| | - Ju-Yen Fu
- Nutrition Unit, Product Development and Advisory Services Division, Malaysian Palm Oil Board, 6 Persiaran Institusi, Bandar Baru Bangi, Kajang 43000, Selangor, Malaysia.
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Abstract
Pancreatic cancer is a devastating disease with poor prognosis in the modern era. Inflammatory processes have emerged as key mediators of pancreatic cancer development and progression. Recently, studies have been carried out to investigate the underlying mechanisms that contribute to tumorigenesis induced by inflammation. In this review, the role of inflammation in the initiation and progression of pancreatic cancer is discussed.
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Affiliation(s)
- Kamleshsingh Shadhu
- Pancreas Center of The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China
- Pancreas Institute of Nanjing Medical University, Nanjing, P.R. China
- School of International Education of Nanjing Medical University, Nanjing, P.R. China
| | - Chunhua Xi
- Pancreas Center of The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China
- Pancreas Institute of Nanjing Medical University, Nanjing, P.R. China
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Bernardini C, Zannoni A, Bertocchi M, Tubon I, Fernandez M, Forni M. Water/ethanol extract of Cucumis sativus L. fruit attenuates lipopolysaccharide-induced inflammatory response in endothelial cells. Altern Ther Health Med 2018; 18:194. [PMID: 29941006 PMCID: PMC6019722 DOI: 10.1186/s12906-018-2254-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 06/10/2018] [Indexed: 02/07/2023]
Abstract
Background It is widely accepted the key role of endothelium in the onset of many chronic and acute vascular and cardiovascular diseases. In the last decade, traditional compounds utilized in “folk medicine” were considered with increasing interest to discover new bioactive molecules potentially effective in a wide range of diseases including cardiovascular ones. Since ancient times different parts of the Cucumis sativus L. plant were utilized in Ayurvedic medicine, among these, fruits were traditionally used to alleviate skin problem such as sunburn irritation and inflammation. The main purpose of the present research was, in a well-defined in vitro model of endothelial cells, to investigate whether a water/ethanol extract of Cucumis sativus L. (CSE) fruit can attenuate the damaging effect of pro-inflammatory lipopolysaccharide (LPS). Methods Cell viability, gene expression of endothelial cell markers, cytokines secretion and in vitro angiogenesis assay were performed on porcine Aortic Endothelial Cells exposed to increasing doses (0.02; 02; 2 mg/ml) of CSE in the presence of pro-inflammatory lipopolysaccharide (LPS 10 μg/ml). Results CSE reduced LPS-induced cytotoxicity and decreased the cellular detachment, restoring the expression of tight junction ZO-1. The increase of TLR4 expression induced by LPS was counterbalanced by the presence of CSE, while the protective gene Hemeoxygenase (HO)-1 was increased. Cucumis sativus L. inhibited the early robust secretion of inflammatory IL-8 and GM-CSFs, furthermore inhibition of inflammatory IL-6 and IL-1α occurred late at 7 and 24 h respectively. On the contrary, the secretion of anti-inflammatory IL-10, together with IL-18 and IFN-γ was increased. Moreover, the in vitro angiogenesis induced by inflammatory LPS was prevented by the presence of Cucunis sativus L. extract, at any doses tested. Conclusions Our results have clearly demonstrated that Cucumis sativus L. extract has attenuated lipopolysaccharide-induced inflammatory response in endothelial cells.
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Ou T, Lilly M, Jiang W. The Pathologic Role of Toll-Like Receptor 4 in Prostate Cancer. Front Immunol 2018; 9:1188. [PMID: 29928275 PMCID: PMC5998742 DOI: 10.3389/fimmu.2018.01188] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 05/14/2018] [Indexed: 01/01/2023] Open
Abstract
Toll-like receptor (TLR) 4 is expressed on normal and malignant prostate epithelial cells. The TLR4 and its downstream signaling pathways mediate innate immune responses in the host against invading pathogens. However, multiple lines of evidence shows that TLR4 expression is increased in prostate tissues from prostate cancer patients, and altered TLR4 signals may promote cancer development, as well as antitumor effects. In this review, we have summarized key features of the TLR4 signaling pathway and its associated immune responses and focused on the pathologic role of TLR4 in prostate carcinogenesis and tumor progression.
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Affiliation(s)
- Tongwen Ou
- Department of Urology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Michael Lilly
- Division of Hematology and Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, United States
| | - Wei Jiang
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC, United States
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34
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Block MS, Vierkant RA, Rambau PF, Winham SJ, Wagner P, Traficante N, Tołoczko A, Tiezzi DG, Taran FA, Sinn P, Sieh W, Sharma R, Rothstein JH, Ramón Y Cajal T, Paz-Ares L, Oszurek O, Orsulic S, Ness RB, Nelson G, Modugno F, Menkiszak J, McGuire V, McCauley BM, Mack M, Lubiński J, Longacre TA, Li Z, Lester J, Kennedy CJ, Kalli KR, Jung AY, Johnatty SE, Jimenez-Linan M, Jensen A, Intermaggio MP, Hung J, Herpel E, Hernandez BY, Hartkopf AD, Harnett PR, Ghatage P, García-Bueno JM, Gao B, Fereday S, Eilber U, Edwards RP, de Sousa CB, de Andrade JM, Chudecka-Głaz A, Chenevix-Trench G, Cazorla A, Brucker SY, Alsop J, Whittemore AS, Steed H, Staebler A, Moysich KB, Menon U, Koziak JM, Kommoss S, Kjaer SK, Kelemen LE, Karlan BY, Huntsman DG, Høgdall E, Gronwald J, Goodman MT, Gilks B, García MJ, Fasching PA, de Fazio A, Deen S, Chang-Claude J, Candido Dos Reis FJ, Campbell IG, Brenton JD, Bowtell DD, Benítez J, Pharoah PDP, Köbel M, Ramus SJ, Goode EL. MyD88 and TLR4 Expression in Epithelial Ovarian Cancer. Mayo Clin Proc 2018; 93:307-320. [PMID: 29502561 PMCID: PMC5870793 DOI: 10.1016/j.mayocp.2017.10.023] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 09/14/2017] [Accepted: 10/16/2017] [Indexed: 12/28/2022]
Abstract
OBJECTIVE To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. PATIENTS AND METHODS We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). RESULTS Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively). CONCLUSION Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.
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Affiliation(s)
| | | | - Peter F Rambau
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada; Pathology Department, Catholic University of Health and Allied Sciences-Bugando, Mwanza, Tanzania
| | - Stacey J Winham
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN
| | - Philipp Wagner
- Tübingen University Hospital, Department of Women's Health, Tübingen, Germany
| | - Nadia Traficante
- Sir Peter MacCallum Department of Oncology, the University of Melbourne, Parkville, Victoria, Australia
| | - Aleksandra Tołoczko
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Daniel G Tiezzi
- Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Florin Andrei Taran
- Tübingen University Hospital, Department of Women's Health, Tübingen, Germany
| | - Peter Sinn
- Department of Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Weiva Sieh
- Department of Population Health Science and Policy, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Raghwa Sharma
- Pathology West ICPMR Westmead, Westmead Hospital, the University of Sydney, Sydney, Australia; University of Western Sydney at Westmead Hospital, Westmead, New South Wales, Australia
| | - Joseph H Rothstein
- Department of Population Health Science and Policy, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | | | - Luis Paz-Ares
- H12O-CNIO Lung Cancer Clinical Research Unit, Madrid, Spain; Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Oleg Oszurek
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Sandra Orsulic
- Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | | | - Gregg Nelson
- Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Francesmary Modugno
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA; Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA; Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA
| | - Janusz Menkiszak
- Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland
| | - Valerie McGuire
- Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA
| | - Bryan M McCauley
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN
| | - Marie Mack
- Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
| | - Jan Lubiński
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | | | - Zheng Li
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN; Department of Gynecologic Oncology, the Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital), Kunming, China
| | - Jenny Lester
- Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Catherine J Kennedy
- Centre for Cancer Research, the Westmead Institute for Medical Research, the University of Sydney, Sydney, New South Wales, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia
| | | | - Audrey Y Jung
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sharon E Johnatty
- Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | | | - Allan Jensen
- Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Maria P Intermaggio
- School of Women's and Children's Health, University of New South Wales, Sydney, Australia
| | - Jillian Hung
- Centre for Cancer Research, the Westmead Institute for Medical Research, the University of Sydney, Sydney, New South Wales, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia
| | - Esther Herpel
- Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany; Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | | | - Andreas D Hartkopf
- Tübingen University Hospital, Department of Women's Health, Tübingen, Germany
| | - Paul R Harnett
- Centre for Cancer Research, the Westmead Institute for Medical Research, the University of Sydney, Sydney, New South Wales, Australia; Crown Princess Mary Cancer Centre, Westmead Hospital, the University of Sydney, Sydney, Australia
| | - Prafull Ghatage
- Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | | | - Bo Gao
- Centre for Cancer Research, the Westmead Institute for Medical Research, the University of Sydney, Sydney, New South Wales, Australia; Crown Princess Mary Cancer Centre, Westmead Hospital, the University of Sydney, Sydney, Australia
| | - Sian Fereday
- Department of Cancer Genomics and Genetics, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
| | - Ursula Eilber
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Robert P Edwards
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Christiani B de Sousa
- Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Jurandyr M de Andrade
- Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Anita Chudecka-Głaz
- Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland
| | | | - Alicia Cazorla
- Pathology Department, Fundación Jiménez Díaz, Madrid, Spain
| | - Sara Y Brucker
- Tübingen University Hospital, Department of Women's Health, Tübingen, Germany
| | - Jennifer Alsop
- Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
| | - Alice S Whittemore
- Department of Health Research and Policy and Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA
| | - Helen Steed
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Royal Alexandra Hospital, Edmonton, Alberta, Canada
| | - Annette Staebler
- Tübingen University Hospital, Institute of Pathology, Tübingen, Germany
| | - Kirsten B Moysich
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY
| | - Usha Menon
- Gynaecological Cancer Research Centre, Department of Women's Cancer, Institute for Women's Health, University College London, London, UK
| | | | - Stefan Kommoss
- Tübingen University Hospital, Department of Women's Health, Tübingen, Germany
| | - Susanne K Kjaer
- Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Linda E Kelemen
- Department of Public Health Sciences, Medical University of South Carolina and Hollings Cancer Center, Charleston, SC
| | - Beth Y Karlan
- Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - David G Huntsman
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Estrid Høgdall
- Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Jacek Gronwald
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Marc T Goodman
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Blake Gilks
- Genetic Pathology Evaluation Centre, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada
| | - María José García
- Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Peter A Fasching
- David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles; University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany
| | - Anna de Fazio
- Centre for Cancer Research, the Westmead Institute for Medical Research, the University of Sydney, Sydney, New South Wales, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia
| | - Suha Deen
- Department of Histopathology, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Francisco J Candido Dos Reis
- Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Ian G Campbell
- Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia; Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
| | - James D Brenton
- Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK; Cambridge Experimental Cancer Medicine Centre, Cambridge, UK
| | - David D Bowtell
- Sir Peter MacCallum Department of Oncology, the University of Melbourne, Parkville, Victoria, Australia; Cancer Genomics Program, Research Department, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Garvan Institute, Sydney, New South Wales, Australia
| | - Javier Benítez
- Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Paul D P Pharoah
- Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK; Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
| | - Martin Köbel
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Susan J Ramus
- School of Women's and Children's Health, University of New South Wales, Sydney, Australia; Garvan Institute, Sydney, New South Wales, Australia
| | - Ellen L Goode
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
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35
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Blohm-Mangone K, Burkett NB, Tahsin S, Myrdal PB, Aodah A, Ho B, Janda J, McComas M, Saboda K, Roe DJ, Dong Z, Bode AM, Petricoin EF, Calvert VS, Curiel-Lewandrowski C, Alberts DS, Wondrak GT, Dickinson SE. Pharmacological TLR4 Antagonism Using Topical Resatorvid Blocks Solar UV-Induced Skin Tumorigenesis in SKH-1 Mice. Cancer Prev Res (Phila) 2018; 11:265-278. [PMID: 29437671 DOI: 10.1158/1940-6207.capr-17-0349] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 01/02/2018] [Accepted: 01/19/2018] [Indexed: 02/06/2023]
Abstract
An urgent need exists for the development of more efficacious molecular strategies targeting nonmelanoma skin cancer (NMSC), the most common malignancy worldwide. Inflammatory signaling downstream of Toll-like receptor 4 (TLR4) has been implicated in several forms of tumorigenesis, yet its role in solar UV-induced skin carcinogenesis remains undefined. We have previously shown in keratinocyte cell culture and SKH-1 mouse epidermis that topical application of the specific TLR4 antagonist resatorvid (TAK-242) blocks acute UV-induced AP-1 and NF-κB signaling, associated with downregulation of inflammatory mediators and MAP kinase phosphorylation. We therefore explored TLR4 as a novel target for chemoprevention of UV-induced NMSC. We selected the clinical TLR4 antagonist resatorvid based upon target specificity, potency, and physicochemical properties. Here, we confirm using ex vivo permeability assays that topical resatorvid can be effectively delivered to skin, and using in vivo studies that topical resatorvid can block UV-induced AP-1 activation in mouse epidermis. We also report that in a UV-induced skin tumorigenesis model, topical resatorvid displays potent photochemopreventive activity, significantly suppressing tumor area and multiplicity. Tumors harvested from resatorvid-treated mice display reduced activity of UV-associated signaling pathways and a corresponding increase in apoptosis compared with tumors from control animals. Further mechanistic insight on resatorvid-based photochemoprevention was obtained from unsupervised hierarchical clustering analysis of protein readouts via reverse-phase protein microarray revealing a significant attenuation of key UV-induced proteomic changes by resatorvid in chronically treated high-risk SKH-1 skin prior to tumorigenesis. Taken together, our data identify TLR4 as a novel molecular target for topical photochemoprevention of NMSC. Cancer Prev Res; 11(5); 265-78. ©2018 AACRSee related editorial by Sfanos, p. 251.
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Affiliation(s)
| | | | - Shekha Tahsin
- The University of Arizona Cancer Center, Tucson, Arizona
| | - Paul B Myrdal
- Department of Pharmacy Practice and Science, The University of Arizona, Tucson, Arizona
| | - Alhassan Aodah
- Department of Pharmacy Practice and Science, The University of Arizona, Tucson, Arizona.,The National Center for Pharmaceutical Technology, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Brenda Ho
- The University of Arizona Cancer Center, Tucson, Arizona
| | - Jaroslav Janda
- The University of Arizona Cancer Center, Tucson, Arizona
| | | | | | - Denise J Roe
- The University of Arizona Cancer Center, Tucson, Arizona.,Mel and Enid Zuckerman College of Public Health, The University of Arizona, Tucson, Arizona
| | - Zigang Dong
- Department of Molecular Medicine and Biopharmaceutical Sciences, The Hormel Institute, The University of Minnesota, Austin, Minnesota
| | - Ann M Bode
- Department of Molecular Medicine and Biopharmaceutical Sciences, The Hormel Institute, The University of Minnesota, Austin, Minnesota
| | - Emanuel F Petricoin
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia
| | - Valerie S Calvert
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia
| | - Clara Curiel-Lewandrowski
- The University of Arizona Cancer Center, Tucson, Arizona.,Department of Medicine, The University of Arizona, Tucson, Arizona
| | - David S Alberts
- The University of Arizona Cancer Center, Tucson, Arizona.,Department of Medicine, The University of Arizona, Tucson, Arizona
| | - Georg T Wondrak
- The University of Arizona Cancer Center, Tucson, Arizona.,Department of Pharmacology and Toxicology, The University of Arizona, Tucson, Arizona
| | - Sally E Dickinson
- The University of Arizona Cancer Center, Tucson, Arizona. .,Department of Pharmacology, The University of Arizona, Tucson, Arizona
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Wu K, Yang Y, Liu D, Qi Y, Zhang C, Zhao J, Zhao S. Activation of PPARγ suppresses proliferation and induces apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway. Oncotarget 2018; 7:44572-44582. [PMID: 27323819 PMCID: PMC5190119 DOI: 10.18632/oncotarget.10067] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 05/29/2016] [Indexed: 01/07/2023] Open
Abstract
Although substantial studies on peroxisome proliferator-activated receptor γ (PPARγ) have focused on the mechanisms by which PPARγ regulates glucose and lipid metabolism, recent reports have suggested that PPARγ shows tumorigenic or antitumorigenic effects. The roles and mechanisms of PPARγ activation in esophageal cancer remain unclarified. EC109 and TE10 esophageal cancer cells were treated with 0, 10, 20 and 40 mM of PPARγ agonist rosiglitazone (RGZ) for 24, 48, and 72 h, and the cell viability and apoptosis were detected using methyl thiazolyl tetrazolium (MTT) assay and Flow cytometric (FCM) analysis, respectively. Moreover, the effects of inhibition of PPARγ by antagonist or specific RNA interference on cell viability, apoptosis, the Toll-like receptor 4 (TLR4) and mitogen-activated protein kinase (MAPK) pathways were evaluated. Additionally, the effect of TLR4 signaling on the MAPK pathway, cell viability and apoptosis was assessed. The results showed that RGZ suppressed proliferation and induced apoptosis of esophageal cancer cells, which could be partly restored by inactivation of PPARγ. RGZ suppressed the MAPK and TLR4 pathways, and the inhibitory effect could be counteracted by PPARγ antagonist or specific RNA interference. We also suggested that MAPK activation was regulated by the TLR4 pathway and that blocking the TLR4 and MAPK pathways significantly suppressed proliferation and induced apoptosis of esophageal cancer cells. In conclusion, our data suggested that activation of PPARγ suppressed proliferation and induced apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway.
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Affiliation(s)
- Kai Wu
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yang Yang
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Donglei Liu
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yu Qi
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Chunyang Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Jia Zhao
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Song Zhao
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
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Geng L, Zhou W, Liu B, Wang X, Chen B. DHA induces apoptosis of human malignant breast cancer tissues by the TLR-4/PPAR-α pathways. Oncol Lett 2017; 15:2967-2977. [PMID: 29435026 PMCID: PMC5778790 DOI: 10.3892/ol.2017.7702] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 09/15/2017] [Indexed: 01/16/2023] Open
Abstract
Docosahexaenoic acid (DHA) oil is an important polyunsaturated fatty acid for the human body. Evidence has demonstrated that DHA is beneficial for inhibiting mammary carcinogenesis. However, the mechanisms of DHA mediating apoptosis induction have not been fully elucidated. Thus, in the present study, the activity levels of total-superoxide dismutase (t-SOD), catalase (CAT), glutathione-peroxidase (GSH-PX) and the concentration of malondialdehyde (MDA) were determined in DHA oil-treated human malignant breast tissues. The results revealed that compared with control, DHA significantly increased the main antioxidant enzymes levels, including t-SOD, CAT, and GSH-PX, but decreased the MDA concentration in the DHA oil treated breast cancer tissues. Furthermore, DHA significantly increased the ratio of cyclic (c)AMP/cGMP levels and promoted the expression of Toll-like receptor 4 (TLR-4) and peroxisome proliferator activated receptor (PPAR)-α, thus DHA induced breast cancer cell apoptosis. We hypothesized that the levels of TLR-4 and PPAR-α are involved in the antitumorigenesis properties of DHA in breast cancer. The results of the present study hold significance for the further clinical development of DHA oil in breast cancer treatment.
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Affiliation(s)
- Lijing Geng
- Key Laboratory of Molecular Cell Biology and New Drug Development of The Educational Department of Jinzhou Province, Food Science and Engineer College, Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - Wei Zhou
- Key Laboratory of Molecular Cell Biology and New Drug Development of The Educational Department of Jinzhou Province, Food Science and Engineer College, Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - Bing Liu
- Key Laboratory of Molecular Cell Biology and New Drug Development of The Educational Department of Jinzhou Province, Food Science and Engineer College, Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - Xinyun Wang
- Key Laboratory of Molecular Cell Biology and New Drug Development of The Educational Department of Jinzhou Province, Food Science and Engineer College, Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - Bo Chen
- Key Laboratory of Molecular Cell Biology and New Drug Development of The Educational Department of Jinzhou Province, Food Science and Engineer College, Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
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38
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Jiang FM, Li XF, Cheng SQ, Cao YZ, Huang CJ, Yang JY, Lin J. Clinical significance of expression of TLR3 and TLR4 in liver tissue of patients with chronic hepatitis B. Shijie Huaren Xiaohua Zazhi 2017; 25:2879-2887. [DOI: 10.11569/wcjd.v25.i32.2879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the correlation of the expression of Toll-like receptors 3 and 4 (TLR3, TLR4) with liver inflammation and liver fibrosis degree in the liver tissue of patients with chronic hepatitis B (CHB).
METHODS One hundred and fifty-six CHB liver tissues obtained by liver biopsy were subjected to immunohistochemical staining for TLR3 and TLR4. Ten normal liver tissues served as controls. Then, immunohistochemical staining was quantified, and its correlation liver inflammatory activity and liver fibrosis degree was analyzed statistically.
RESULTS TLR3 was strongly expressed in liver tissue of patients with CHB, mainly in the cytoplasm of liver cells and occasionally in the nucleus. The expression of TLR3 in liver tissue had a significant positive correlation with inflammation grade (rs = 0.528, P < 0.01), and there was a significant linear relationship between them (χ2 = 16.679, P < 0.01). The expression of TLR3 was also correlated with liver fibrosis degree (rs = 0.510, P < 0.01), and there was a significant linear relationship between them (χ2 = 16.654, P < 0.01). TLR4 was obviously expressed in liver cells, mainly in the cytoplasm and occasionally on cell membrane The expression of TLR4 had a significant positive correlation of liver fibrosis degree (rs = 0.354, P < 0.01), and there was a significant linear relationship between them (χ2 = 10.124, P < 0.05).
CONCLUSION High expression of TLR3 and TRL4 is positively correlated with liver inflammation and liver fibrosis degree in CHB patients, suggesting that they might participate in the pathogenesis of CHB.
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Affiliation(s)
- Fu-Ming Jiang
- Department of Liver Disease, the Third People's Hospital of Guilin, Guilin 541002, Guangxi Zhuang Autonomous Region, China
| | - Xiu-Fen Li
- Zhengzhou Shuqing Medical College, Zhengzhou 450064, He'nan Province, China
| | - Shu-Quan Cheng
- Department of Liver Disease, the Third People's Hospital of Guilin, Guilin 541002, Guangxi Zhuang Autonomous Region, China
| | - Ya-Zhao Cao
- Guilin Medical University, Guilin 541004, Guangxi Zhuang Autonomous Region, China
| | - Cheng-Jun Huang
- Department of Liver Disease, the Third People's Hospital of Guilin, Guilin 541002, Guangxi Zhuang Autonomous Region, China
| | - Jing-Yi Yang
- Department of Liver Disease, the Third People's Hospital of Guilin, Guilin 541002, Guangxi Zhuang Autonomous Region, China
| | - Jun Lin
- Guilin Medical University, Guilin 541004, Guangxi Zhuang Autonomous Region, China
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Zuliani-Alvarez L, Marzeda AM, Deligne C, Schwenzer A, McCann FE, Marsden BD, Piccinini AM, Midwood KS. Mapping tenascin-C interaction with toll-like receptor 4 reveals a new subset of endogenous inflammatory triggers. Nat Commun 2017; 8:1595. [PMID: 29150600 PMCID: PMC5693923 DOI: 10.1038/s41467-017-01718-7] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 10/05/2017] [Indexed: 02/08/2023] Open
Abstract
Pattern recognition underpins innate immunity; the accurate identification of danger, including infection, injury, or tumor, is key to an appropriately targeted immune response. Pathogen detection is increasingly well defined mechanistically, but the discrimination of endogenous inflammatory triggers remains unclear. Tenascin-C, a matrix protein induced upon tissue damage and expressed by tumors, activates toll-like receptor 4 (TLR4)-mediated sterile inflammation. Here we map three sites within tenascin-C that directly and cooperatively interact with TLR4. We also identify a conserved inflammatory epitope in related proteins from diverse families, and demonstrate that its presence targets molecules for TLR detection, while its absence enables escape of innate immune surveillance. These data reveal a unique molecular code that defines endogenous proteins as inflammatory stimuli by marking them for recognition by TLRs.
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Affiliation(s)
- Lorena Zuliani-Alvarez
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK
| | - Anna M Marzeda
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK
| | - Claire Deligne
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK
| | - Anja Schwenzer
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK
| | - Fiona E McCann
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK
| | - Brian D Marsden
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK.,Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7DQ, UK
| | - Anna M Piccinini
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK.,School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK
| | - Kim S Midwood
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK.
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40
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Chang H, Wang Y, Yin X, Liu X, Xuan H. Ethanol extract of propolis and its constituent caffeic acid phenethyl ester inhibit breast cancer cells proliferation in inflammatory microenvironment by inhibiting TLR4 signal pathway and inducing apoptosis and autophagy. Altern Ther Health Med 2017; 17:471. [PMID: 28950845 PMCID: PMC5615448 DOI: 10.1186/s12906-017-1984-9] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 09/22/2017] [Indexed: 12/19/2022]
Abstract
Background Propolis and its major constituent – caffeic acid phenethyl ester (CAPE) have good abilities on antitumor and anti-inflammation. However, little is known about the actions of propolis and CAPE on tumor in inflammatory microenvironment, and inflammatory responses play decisive roles at different stages of tumor development. To understand the effects and mechanisms of ethanol-extracted Chinese propolis (EECP) and its major constituent - CAPE in inflammation-stimulated tumor, we investigated their effects on Toll-like receptor 4 (TLR4) signaling pathway which plays a crucial role in breast cancer MDA-MB-231 cell line. Methods 80% confluent breast cancer MDA-MB-231 cells were stimulated with 1 μg/mL lipopolysaccaride (LPS). Then the cells were divided for treatment by CAPE (25 μg/mL) and EECP (25, 50 and 100 μg/mL), respectively. Cell viability, nitric oxide (NO) production and cell migration were measured by sulforhodamine B assay, chemical method and scratch assay. The levels of TLR4, MyD88, IRAK4, TRIF, caspase 3, PARP, LC3B and p62 were investigated through western blotting. The expression of TLR4, LC3B and nuclear factor-κB p65 (NF-κB p65) were tested by immunofluorescence microscopy assay. Results Treatment of different concentrations of EECP (25, 50 and 100 μg/mL) and CAPE (25 μg/mL) significantly inhibited LPS-stimulated MDA-MB-231 cell line proliferation, migration and NO production. Furthermore, EECP and CAPE activated caspase3 and PARP to induce cell apoptosis, and also upregulated LC3-II and decreased p62 level to induce autophagy during the process. TLR4 signaling pathway molecules such as TLR4, MyD88, IRAK4, TRIF and NF-κB p65 were all down-regulated after EECP and CAPE treatment in LPS-stimulated MDA-MB-231 cells. Conclusions These findings indicated that EECP and its major constituent - CAPE inhibited breast cancer MDA-MB-231 cells proliferation in inflammatory microenvironment through activating apoptosis, autophagy and inhibiting TLR4 signaling pathway. EECP and CAPE may hold promising prospects in treating inflammation-induced tumor.
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Beyer K, Partecke LI, Roetz F, Fluhr H, Weiss FU, Heidecke CD, von Bernstorff W. LPS promotes resistance to TRAIL-induced apoptosis in pancreatic cancer. Infect Agent Cancer 2017; 12:30. [PMID: 28572836 PMCID: PMC5450120 DOI: 10.1186/s13027-017-0139-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Accepted: 05/16/2017] [Indexed: 12/29/2022] Open
Abstract
Background Though TRAIL has been hailed as a promising drug for tumour treatment, it has been observed that many tumour cells have developed escape mechanisms against TRAIL-induced apoptosis. As a receptor of LPS, TLR 4, which is expressed on a variety of cancer cells, can be associated with TRAIL-resistance of tumour cells and tumour progression as well as with the generation of an anti-tumour immune response. Methods In this study, the sensitivity to TRAIL-induced apoptosis as well as the influence of LPS-co-stimulation on the cell viability of the pancreatic cancer cell lines PANC-1, BxPC-3 and COLO 357 was examined by FACS analyses and a cell viability assay. Subsequently, the expression of TRAIL-receptors was detected via FACS analyses. Levels of osteoprotegerin (OPG) were also determined using an enzyme-linked immunosorbent assay. Results PANC-1 cells were shown to be resistant to TRAIL-induced apoptosis. This was accompanied by significantly increased osteoprotegerin levels and a significantly decreased expression of DR4. In contrast, TRAIL significantly induced apoptosis in COLO 357 cells and to a lesser degree in BxPC-3 cells. Co-stimulation of COLO 357 as well as BxPC-3 cells combining TRAIL and LPS resulted in a significant decrease in TRAIL-induced apoptosis. In COLO 357 cells TRAIL-stimulation decreased the levels of OPG thereby not altering the expression of the TRAIL-receptors 1–4 resulting in a high susceptibility to TRAIL-induced apoptosis. Co-stimulation with LPS and TRAIL completely reversed the effect of TRAIL on OPG levels reaching a 2-fold increase beyond the level of non-stimulated cells resulting in a lower susceptibility to apoptosis. In BxPC-3, TRAIL stimulation decreased the expression of DR4 and significantly increased the decoy receptors TRAIL-R3 and TRAIL-R4 leading to a decrease in TRAIL-induced apoptosis. OPG levels remained unchanged. Co-stimulation with TRAIL and LPS further enhanced the changes in TRAIL-receptor-expression promoting apoptosis resistance. Conclusions Here it has been shown that TRAIL-resistance in pancreatic cancer cells can be mediated by the inflammatory molecule LPS as well as by different expression patterns of functional and non-functional TRAIL-receptors.
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Affiliation(s)
- Katharina Beyer
- Department of General, Visceral, Thoracic and Vascular Surgery, Universitätsmedizin Greifswald, Greifswald, Germany.,Department of General, Visceral and Vascular Surgery, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Lars Ivo Partecke
- Department of General, Visceral, Thoracic and Vascular Surgery, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Felicitas Roetz
- Department of General, Visceral, Thoracic and Vascular Surgery, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Herbert Fluhr
- Department of Medicine A, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Frank Ulrich Weiss
- Department of Obstetrics and Gynaecology, Universitätsklinikum Heidelberg, Heidelberg, Germany
| | - Claus-Dieter Heidecke
- Department of General, Visceral, Thoracic and Vascular Surgery, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Wolfram von Bernstorff
- Department of General, Visceral, Thoracic and Vascular Surgery, Universitätsmedizin Greifswald, Greifswald, Germany
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Dysregulation of signaling pathways associated with innate antibacterial immunity in patients with pancreatic cancer. Cent Eur J Immunol 2017; 41:404-418. [PMID: 28450804 PMCID: PMC5382886 DOI: 10.5114/ceji.2016.65140] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2016] [Accepted: 09/16/2016] [Indexed: 02/07/2023] Open
Abstract
Disorders of innate antibacterial response are of fundamental importance in the development of gastrointestinal cancers, including pancreatic cancer. Multi-regulatory properties of the Toll-like receptors (TLRs) (e.g., regulation of proliferation, the activity of NF-κB, gene transcription of apoptosis proteins, regulation of angiogenesis, HIF-1α protein expression) are used in experimental studies to better understand the pathogenesis of pancreatic cancer, for early diagnosis, and for more effective therapeutic intervention. There are known numerous examples of TLR agonists (e.g., TLR2/5 ligands, TLR6, TLR9) of antitumor effect. The direction of these studies is promising, but a small number of them does not allow for an accurate assessment of the impact of TLR expression disorders, proteins of these signaling pathways, or attempts to block or stimulate them, on the results of treatment of pancreatic cancer patients. It is known, however, that the expression disorders of proteins of innate antibacterial response signaling pathways occur not only in tumor tissue but also in peripheral blood leukocytes of pancreatic cancer patients (e.g., increased expression of TLR4, NOD1, TRAF6), which is one of the most important factors facilitating further tumor development. This review mainly focuses on the genetic aspects of signaling pathway disorders associated with innate antibacterial response in the pathogenesis and diagnosis of pancreatic cancer.
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Grimmig T, Moench R, Kreckel J, Haack S, Rueckert F, Rehder R, Tripathi S, Ribas C, Chandraker A, Germer CT, Gasser M, Waaga-Gasser AM. Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer. Int J Mol Sci 2016; 17:ijms17122060. [PMID: 27941651 PMCID: PMC5187860 DOI: 10.3390/ijms17122060] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/23/2016] [Accepted: 12/02/2016] [Indexed: 02/07/2023] Open
Abstract
Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers. TLR-stimulated pancreatic cancer cells were specifically investigated for activated signaling pathways of VEGF/PDGF and anti-apoptotic Bcl-xL expression as well as tumor cell growth. The primary pancreatic cancers and cell lines expressed TLR2, -4, and -9. TLR-specific stimulation resulted in activated MAP-kinase signaling, most likely via autoregulative stimulation of demonstrated TLR-induced VEGF and PDGF expression. Moreover, TLR activation prompted the expression of Bcl-xL and has been demonstrated for the first time to induce tumor cell proliferation in pancreatic cancer. These findings strongly suggest that pancreatic cancer cells use specific Toll like receptor signaling to promote tumor cell proliferation and emphasize the particular role of TLR2, -4, and -9 in this autoregulative process of tumor cell activation and proliferation in pancreatic cancer.
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Affiliation(s)
- Tanja Grimmig
- Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, 97080 Wuerzburg, Germany.
| | - Romana Moench
- Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, 97080 Wuerzburg, Germany.
| | - Jennifer Kreckel
- Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, 97080 Wuerzburg, Germany.
| | - Stephanie Haack
- Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, 97080 Wuerzburg, Germany.
| | - Felix Rueckert
- Surgical Clinic Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
| | - Roberta Rehder
- Medical School, Evangelic Faculty of Paraná, 80730-000 Curitiba, Brazil.
| | - Sudipta Tripathi
- Brigham and Women's Hospital, Transplant Research Center, Harvard Medical School, Boston, MA 02115, USA.
| | - Carmen Ribas
- Medical School, Evangelic Faculty of Paraná, 80730-000 Curitiba, Brazil.
| | - Anil Chandraker
- Brigham and Women's Hospital, Transplant Research Center, Harvard Medical School, Boston, MA 02115, USA.
| | - Christoph T Germer
- Department of Surgery I, University of Wuerzburg, 97080 Wuerzburg, Germany.
| | - Martin Gasser
- Department of Surgery I, University of Wuerzburg, 97080 Wuerzburg, Germany.
| | - Ana Maria Waaga-Gasser
- Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, 97080 Wuerzburg, Germany.
- Brigham and Women's Hospital, Transplant Research Center, Harvard Medical School, Boston, MA 02115, USA.
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Janda J, Burkett NB, Blohm-Mangone K, Huang V, Curiel-Lewandrowski C, Alberts DS, Petricoin EF, Calvert VS, Einspahr J, Dong Z, Bode AM, Wondrak GT, Dickinson SE. Resatorvid-based Pharmacological Antagonism of Cutaneous TLR4 Blocks UV-induced NF-κB and AP-1 Signaling in Keratinocytes and Mouse Skin. Photochem Photobiol 2016; 92:816-825. [PMID: 27859308 DOI: 10.1111/php.12659] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 11/03/2016] [Indexed: 12/21/2022]
Abstract
Cutaneous exposure to solar ultraviolet (UV) radiation is a major causative factor in skin carcinogenesis, and improved molecular strategies for efficacious chemoprevention of nonmelanoma skin cancer (NMSC) are urgently needed. Toll-like receptor 4 (TLR4) signaling has been shown to drive skin inflammation, photoimmunosuppression, and chemical carcinogenesis. Here we have examined the feasibility of genetic and pharmacological antagonism targeting cutaneous TLR4 for the suppression of UV-induced NF-κB and AP-1 signaling in keratinocytes and mouse skin. Using immunohistochemical and proteomic microarray analysis of human skin, we demonstrate for the first time that a significant increase in expression of TLR4 occurs in keratinocytes during the progression from normal skin to actinic keratosis, also detectible during further progression to squamous cell carcinoma. Next, we demonstrate that siRNA-based genetic TLR4 inhibition blocks UV-induced stress signaling in cultured keratinocytes. Importantly, we observed that resatorvid (TAK-242), a molecularly targeted clinical TLR4 antagonist, blocks UV-induced NF-κB and MAP kinase/AP-1 activity and cytokine expression (Il-6, Il-8, and Il-10) in cultured keratinocytes and in topically treated murine skin. Taken together, our data reveal that pharmacological TLR4 antagonism can suppress UV-induced cutaneous signaling, and future experiments will explore the potential of TLR4-directed strategies for prevention of NMSC.
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Affiliation(s)
| | | | | | - Vivian Huang
- The University of Arizona Cancer Center, Tucson, AZ
| | - Clara Curiel-Lewandrowski
- The University of Arizona Cancer Center, Tucson, AZ.,Department of Medicine, The University of Arizona, Tucson, AZ
| | - David S Alberts
- The University of Arizona Cancer Center, Tucson, AZ.,Department of Medicine, The University of Arizona, Tucson, AZ
| | - Emanuel F Petricoin
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA
| | - Valerie S Calvert
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA
| | - Janine Einspahr
- The University of Arizona Cancer Center, Tucson, AZ.,Department of Medicine, The University of Arizona, Tucson, AZ
| | - Zigang Dong
- Department of Molecular Medicine and Biopharmaceutical Sciences, The Hormel Institute, The University of Minnesota, Austin, MN
| | - Ann M Bode
- Department of Molecular Medicine and Biopharmaceutical Sciences, The Hormel Institute, The University of Minnesota, Austin, MN
| | - Georg T Wondrak
- The University of Arizona Cancer Center, Tucson, AZ.,Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ
| | - Sally E Dickinson
- The University of Arizona Cancer Center, Tucson, AZ.,Department of Pharmacology, The University of Arizona, Tucson, AZ
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Mai CW, Yap KSI, Kho MT, Ismail NH, Yusoff K, Shaari K, Chin SY, Lim ESH. Mechanisms Underlying the Anti-Inflammatory Effects of Clinacanthus nutans Lindau Extracts: Inhibition of Cytokine Production and Toll-Like Receptor-4 Activation. Front Pharmacol 2016; 7:7. [PMID: 26869924 PMCID: PMC4735445 DOI: 10.3389/fphar.2016.00007] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 01/11/2016] [Indexed: 02/05/2023] Open
Abstract
Clinacanthus nutans has had a long history of use in folk medicine in Malaysia and Southeast Asia; mostly in the relief of inflammatory conditions. In this study, we investigated the effects of different extracts of C. nutans upon lipopolysaccharide (LPS) induced inflammation in order to identify its mechanism of action. Extracts of leaves and stem bark of C. nutans were prepared using polar and non-polar solvents to produce four extracts, namely polar leaf extract (LP), non-polar leaf extract (LN), polar stem extract (SP), and non-polar stem extracts (SN). The extracts were standardized by determining its total phenolic and total flavonoid contents. Its anti-inflammatory effects were assessed on LPS induced nitrite release in RAW264.7 macrophages and Toll-like receptor (TLR-4) activation in TLR-4 transfected human embryonic kidney cells (HEK-Blue(TM)-hTLR4 cells). The levels of inflammatory cytokines (TNF-α, IFN-γ, IL-1β, IL-6, IL-12p40, and IL-17) in treated RAW264.7 macrophages were quantified to verify its anti-inflammatory effects. Western blotting was used to investigate the effect of the most potent extract (LP) on TLR-4 related inflammatory proteins (p65, p38, ERK, JNK, IRF3) in RAW264.7 macrophages. All four extracts produced a significant, concentration-dependent reduction in LPS-stimulated nitric oxide, LPS-induced TLR-4 activation in HEK-Blue(TM)-hTLR4 cells and LPS-stimulated cytokines production in RAW264.7 macrophages. The most potent extract, LP, also inhibited all LPS-induced TLR-4 inflammatory proteins. These results provide a basis for understanding the mechanisms underlying the previously demonstrated anti-inflammatory activity of C. nutans extracts.
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Affiliation(s)
- Chun W. Mai
- Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical UniversityBukit Jalil, Malaysia
| | - Kok S. I. Yap
- Department of Life Sciences, School of Pharmacy, International Medical UniversityBukit Jalil, Malaysia
| | - Mee T. Kho
- School of Postgraduate Studies and Research, International Medical UniversityBukit Jalil, Malaysia
| | - Nor H. Ismail
- Atta-ur-Rahman Institute for Natural Products Discovery, Universiti Teknologi MARAShah Alam, Malaysia
| | - Khatijah Yusoff
- Institute of Bioscience, Universiti Putra MalaysiaSerdang, Malaysia
- Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra MalaysiaSerdang, Malaysia
| | - Khozirah Shaari
- Institute of Bioscience, Universiti Putra MalaysiaSerdang, Malaysia
| | - Swee Y. Chin
- Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical UniversityBukit Jalil, Malaysia
| | - Erin S. H. Lim
- Perdana University-Royal College of Surgeons Ireland, Perdana UniversitySerdang, Malaysia
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Piktel E, Niemirowicz K, Wnorowska U, Wątek M, Wollny T, Głuszek K, Góźdź S, Levental I, Bucki R. The Role of Cathelicidin LL-37 in Cancer Development. Arch Immunol Ther Exp (Warsz) 2015; 64:33-46. [PMID: 26395996 PMCID: PMC4713713 DOI: 10.1007/s00005-015-0359-5] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 05/29/2015] [Indexed: 01/04/2023]
Abstract
LL-37 is a C-terminal peptide proteolytically released from 18 kDa human cathelicidin protein (hCAP18). Chronic infections, inflammation, tissue injury and tissue regeneration are all linked with neoplastic growth, and involve LL-37 antibacterial and immunomodulatory functions. Such a link points to the possible involvement of LL-37 peptide in carcinogenesis. An increasing amount of evidence suggests that LL-37 can have two different and contradictory effects--promotion or inhibition of tumor growth. The mechanisms are tissue-specific, complex, and depend mostly on the ability of LL-37 to act as a ligand for different membrane receptors whose expression varies on different cancer cells. Overexpression of LL-37 was found to promote development and progression of ovarian, lung and breast cancers, and to suppress tumorigenesis in colon and gastric cancer. This review explores and summarizes the current views on how LL-37 contributes to immunity, pathophysiology and cell signaling involved in malignant tumor growth.
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Affiliation(s)
- Ewelina Piktel
- Department of Microbiological and Nanobiomedical Engineering, Medical University of Białystok, Mickiewicza 2c, 15-222, Białystok, Poland
| | - Katarzyna Niemirowicz
- Department of Microbiological and Nanobiomedical Engineering, Medical University of Białystok, Mickiewicza 2c, 15-222, Białystok, Poland
| | - Urszula Wnorowska
- Department of Microbiological and Nanobiomedical Engineering, Medical University of Białystok, Mickiewicza 2c, 15-222, Białystok, Poland
| | - Marzena Wątek
- Holy Cross Oncology Center of Kielce, Kielce, Poland
| | - Tomasz Wollny
- Holy Cross Oncology Center of Kielce, Kielce, Poland
| | | | - Stanisław Góźdź
- The Faculty of Health Sciences of The Jan Kochanowski University in Kielce, Kielce, Poland
| | - Ilya Levental
- Department of Integrative Biology and Pharmacology, The University of Texas Medical School, Houston, TX, USA
| | - Robert Bucki
- Department of Microbiological and Nanobiomedical Engineering, Medical University of Białystok, Mickiewicza 2c, 15-222, Białystok, Poland.
- Department of Physiology, Pathophysiology and Microbiology of Infections, Faculty of Health Sciences of The Jan Kochanowski University in Kielce, Kielce, Poland.
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Yang J, Li M, Zheng QC. Emerging role of Toll-like receptor 4 in hepatocellular carcinoma. J Hepatocell Carcinoma 2015; 2:11-7. [PMID: 27508190 PMCID: PMC4918281 DOI: 10.2147/jhc.s44515] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Toll-like receptor (TLR) signaling has been implicated in inflammatory-related cancers. The upregulation of TLR signaling in hepatocellular carcinoma (HCC) suggests that it may play an essential role in the prognosis of chronic and inflammatory diseases that ultimately culminate in HCC. Here, we provide evidence about the involvement of the TLR pathway in the initiation, progression, and metastasis of HCC. The differential expression of TLR in epithelial cells has also been discussed. In particular, we emphasize the physiological role of TLR4 in the development and pathogenesis of HCC and propose novel and promising approaches for HCC therapeutics with the aid of TLR ligands.
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Affiliation(s)
- Jing Yang
- Department of First General Surgery, Gansu Provincial Hospital, Lanzhou, People's Republic of China
| | - Min Li
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Qi Chang Zheng
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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Effects of Alcohol on Tumor Growth, Metastasis, Immune Response, and Host Survival. Alcohol Res 2015; 37:311-22. [PMID: 26695753 PMCID: PMC4590626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Most research involving alcohol and cancer concerns the relationship between alcohol consumption and cancer risk and the mechanisms of carcinogenesis. This review relates the amount and duration of alcohol intake in humans and in animal models of cancer to tumor growth, angiogenesis, invasion, metastasis, immune response, and host survival in specific types and subtypes of cancer. Research on the influence of alcohol drinking on human cancer patients is limited. Although there is more information in animal models of cancer, many aspects still are ill defined. More research is needed to define the mechanisms that underlie the role of alcohol on cancer progression in both animals and humans. Activation of the immune system can play a positive role in keeping cancer under control, but this also can facilitate cancer progression. Additionally, a functional immune system is required for cancer patients to achieve an optimal response to conventional chemotherapy. Insight into the underlying mechanisms of these interactions could lead to effective immunotherapeutic approaches to treat alcoholics with cancer. Defining the epigenetic mechanisms that modulate cancer progression also has great potential for the development of new treatment options not only for treating alcoholics with cancer but also for treating other alcohol-induced diseases.
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Li TT, Ogino S, Qian ZR. Toll-like receptor signaling in colorectal cancer: Carcinogenesis to cancer therapy. World J Gastroenterol 2014; 20:17699-17708. [PMID: 25548469 PMCID: PMC4273121 DOI: 10.3748/wjg.v20.i47.17699] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 08/27/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins, and signal expression of major histocompatibility complex proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These protein receptors are characterized by their ability to respond to invading pathogens promptly by recognizing particular TLR ligands, including flagellin and lipopolysaccharide of bacteria, nucleic acids derived from viruses, and zymosan of fungi. There are 2 major TLR pathways; one is mediated by myeloid differentiation factor 88 (MYD88) adaptor proteins, and the other is independent of MYD88. The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1) and all the TLRs, except TLR3, have been shown to activate this pathway. TLR3 and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling. TLRs play a vital role in activating immune responses. TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis, and are highly likely to be involved in the activation of a number of pathways following cancer therapy. Colorectal cancer (CRC) is one of the most common cancers, and accounts for almost half a million deaths annually worldwide. Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum. The key molecules involved in inflammation-driven carcinogenesis include TLRs. As sensors of cell death and tissue remodeling, TLRs may have a universal role in cancer; stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years. TLRs 3/4/7/8/9 are all validated targets for cancer therapy, and a number of companies are developing agonists and vaccine adjuvants. On the other hand, antagonists may favor inhibition of signaling responsible for autoimmune responses. In this paper, we review TLR signaling in CRC from carcinogenesis to cancer therapy.
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Slattery ML, Lundgreen A, Torres-Mejia G, Wolff RK, Hines L, Baumgartner K, John EM. Diet and lifestyle factors modify immune/inflammation response genes to alter breast cancer risk and prognosis: the Breast Cancer Health Disparities Study. Mutat Res 2014; 770:19-28. [PMID: 25332681 PMCID: PMC4201121 DOI: 10.1016/j.mrfmmm.2014.08.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Tumor necrosis factor-α (TNF) and toll-like receptors (TLR) are important mediators of inflammation. We examined 10 of these genes with respect to breast cancer risk and mortality in a genetically admixed population of Hispanic/Native American (NA) (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1585 controls) women. Additionally, we explored if diet and lifestyle factors modified associations with these genes. Overall, these genes (collectively) were associated with breast cancer risk among women with >70% NA ancestry (P(ARTP) = 0.0008), with TLR1 rs7696175 being the primary risk contributor (OR 1.77, 95% CI 1.25, 2.51). Overall, TLR1 rs7696175 (HR 1.40, 95% CI 1.03, 1.91; P(adj) = 0.032), TLR4 rs5030728 (HR 1.96, 95% CI 1.30, 2.95; P(adj) = 0.014), and TNFRSF1A rs4149578 (HR 2.71, 95% CI 1.28, 5.76; P(adj) = 0.029) were associated with increased breast cancer mortality. We observed several statistically significant interactions after adjustment for multiple comparisons, including interactions between our dietary oxidative balance score and CD40LG and TNFSF1A; between cigarette smoking and TLR1, TLR4, and TNF; between body mass index (BMI) among pre-menopausal women and TRAF2; and between regular use of aspirin/non-steroidal anti-inflammatory drugs and TLR3 and TRA2. In conclusion, our findings support a contributing role of certain TNF-α and TLR genes in both breast cancer risk and survival, particularly among women with higher NA ancestry. Diet and lifestyle factors appear to be important mediators of the breast cancer risk associated with these genes.
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Affiliation(s)
- Martha L. Slattery
- University of Utah, Department of Medicine, 383 Colorow, Salt Lake City, UT 84108. 801-585-6955
| | - Abbie Lundgreen
- University of Utah, Department of Medicine, 383 Colorow, Salt Lake City, UT 84108. 801-585-6955
| | - Gabriela Torres-Mejia
- Instituto Nacional de Salud Pública, Centro de Investigación en Salud Poblacional, Av. Universidad No. 655, Col. Sta. Ma. Ahuacatitlán, Cuernavaca Morelos CP 62100, México
| | - Roger K. Wolff
- University of Utah, Department of Medicine, 383 Colorow, Salt Lake City, UT 84108. 801-585-6955
| | - Lisa Hines
- University of Colorado at Colorado Springs, Department of Biology, Colorado Springs, CO 80918
| | - Kathy Baumgartner
- Department of Epidemiology and Population Health, School of Public Health & Information Sciences, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40292
| | - Esther M. John
- Cancer Prevention Institute of California, Fremont, CA 94538, and Division of Epidemiology, Department of Health Research and Policy and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305
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