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Yang X, Zhao H, Li R, Chen Y, Xu Z, Shang Z. Stromal thrombospondin 1 suppresses angiogenesis in oral submucous fibrosis. Int J Oral Sci 2024; 16:17. [PMID: 38403794 PMCID: PMC10894862 DOI: 10.1038/s41368-024-00286-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 12/14/2023] [Accepted: 01/21/2024] [Indexed: 02/27/2024] Open
Abstract
A decline in mucosal vascularity is a histological hallmark of oral submucous fibrosis (OSF), a premalignant disease that is largely induced by betel quid chewing. However, the lack of available models has challenged studies of angiogenesis in OSF. Here, we found that the expression of thrombospondin 1 (THBS1), an endogenous angiostatic protein, was elevated in the stroma of tissues with OSF. Using a fibroblast-attached organoid (FAO) model, the overexpression of THBS1 in OSF was stably recapitulated in vitro. In the FAO model, treatment with arecoline, a major pathogenic component in areca nuts, enhanced the secretion of transforming growth factor (TGF)-β1 by epithelial cells, which then promoted the expression of THBS1 in fibroblasts. Furthermore, human umbilical vein endothelial cells (HUVECs) were incorporated into the FAO to mimic the vascularized component. Overexpression of THBS1 in fibroblasts drastically suppressed the sprouting ability of endothelial cells in vascularized FAOs (vFAOs). Consistently, treatment with arecoline reduced the expression of CD31 in vFAOs, and this effect was attenuated when the endothelial cells were preincubated with neutralizing antibody of CD36, a receptor of THBS1. Finally, in an arecoline-induced rat OSF model, THBS1 inhibition alleviated collagen deposition and the decline in vascularity in vivo. Overall, we exploited an assembled organoid model to study OSF pathogenesis and provide a rationale for targeting THBS1.
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Affiliation(s)
- Xiao Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Hui Zhao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Oral and Maxillofacial-Head and Neck Oncology, School of Stomatology-Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Rui Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yang Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Zhi Xu
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Zhengjun Shang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
- Department of Oral and Maxillofacial-Head and Neck Oncology, School of Stomatology-Hospital of Stomatology, Wuhan University, Wuhan, China.
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Yang J, Bae H. Drug conjugates for targeting regulatory T cells in the tumor microenvironment: guided missiles for cancer treatment. Exp Mol Med 2023; 55:1996-2004. [PMID: 37653036 PMCID: PMC10545761 DOI: 10.1038/s12276-023-01080-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 06/20/2023] [Accepted: 06/23/2023] [Indexed: 09/02/2023] Open
Abstract
Within the tumor microenvironment (TME), regulatory T cells (Tregs) play a key role in suppressing anticancer immune responses; therefore, various strategies targeting Tregs are becoming important for tumor therapy. To prevent the side effects of nonspecific Treg depletion, such as immunotherapy-related adverse events (irAEs), therapeutic strategies that specifically target Tregs in the TME are being investigated. Tumor-targeting drug conjugates are efficient drugs in which a cytotoxic payload is assembled into a carrier that binds Tregs via a linker. By allowing the drug to act selectively on target cells, this approach has the advantage of increasing the therapeutic effect and minimizing the side effects of immunotherapy. Antibody-drug conjugates, immunotoxins, peptide-drug conjugates, and small interfering RNA conjugates are being developed as Treg-targeting drug conjugates. In this review, we discuss key themes and recent advances in drug conjugates targeting Tregs in the TME, as well as future design strategies for successful use of drug conjugates for Treg targeting in immunotherapy.
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Affiliation(s)
- Juwon Yang
- Department of Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Hyunsu Bae
- Department of Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
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Exposito F, Redrado M, Houry M, Hastings K, Molero-Abraham M, Lozano T, Solorzano JL, Sanz-Ortega J, Adradas V, Amat R, Redin E, Leon S, Legarra N, Garcia J, Serrano D, Valencia K, Robles-Oteiza C, Foggetti G, Otegui N, Felip E, Lasarte JJ, Paz-Ares L, Zugazagoitia J, Politi K, Montuenga L, Calvo A. PTEN Loss Confers Resistance to Anti-PD-1 Therapy in Non-Small Cell Lung Cancer by Increasing Tumor Infiltration of Regulatory T Cells. Cancer Res 2023; 83:2513-2526. [PMID: 37311042 DOI: 10.1158/0008-5472.can-22-3023] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 04/11/2023] [Accepted: 06/08/2023] [Indexed: 06/15/2023]
Abstract
Immunotherapy resistance in non-small cell lung cancer (NSCLC) may be mediated by an immunosuppressive microenvironment, which can be shaped by the mutational landscape of the tumor. Here, we observed genetic alterations in the PTEN/PI3K/AKT/mTOR pathway and/or loss of PTEN expression in >25% of patients with NSCLC, with higher frequency in lung squamous carcinomas (LUSC). Patients with PTEN-low tumors had higher levels of PD-L1 and PD-L2 and showed worse progression-free survival when treated with immunotherapy. Development of a Pten-null LUSC mouse model revealed that tumors with PTEN loss were refractory to antiprogrammed cell death protein 1 (anti-PD-1), highly metastatic and fibrotic, and secreted TGFβ/CXCL10 to promote conversion of CD4+ lymphocytes into regulatory T cells (Treg). Human and mouse PTEN-low tumors were enriched in Tregs and expressed higher levels of immunosuppressive genes. Importantly, treatment of mice bearing Pten-null tumors with TLR agonists and anti-TGFβ antibody aimed to alter this immunosuppressive microenvironment and led to tumor rejection and immunologic memory in 100% of mice. These results demonstrate that lack of PTEN causes immunotherapy resistance in LUSCs by establishing an immunosuppressive tumor microenvironment that can be reversed therapeutically. SIGNIFICANCE PTEN loss leads to the development of an immunosuppressive microenvironment in lung cancer that confers resistance to anti-PD-1 therapy, which can be overcome by targeting PTEN loss-mediated immunosuppression.
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Affiliation(s)
- Francisco Exposito
- Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
- CIBERONC, ISCIII, Madrid, Spain
- IDISNA, Pamplona, Spain
- Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
| | - Miriam Redrado
- Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
- IDISNA, Pamplona, Spain
| | - Maeva Houry
- Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Katherine Hastings
- Yale Cancer Center, New Haven, Connecticut
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut
- Department of Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, Connecticut
| | - Magdalena Molero-Abraham
- Department of Medical Oncology and Tumor Microenvironment and Immunotherapy Research Group, 12 de Octubre Hospital, Madrid, Spain
| | - Teresa Lozano
- Immunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Jose Luis Solorzano
- Anatomic Pathology and Molecular Diagnostics, MD Anderson Cancer Center Madrid, Madrid, Spain
| | - Julian Sanz-Ortega
- Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Vera Adradas
- Department of Medical Oncology and Tumor Microenvironment and Immunotherapy Research Group, 12 de Octubre Hospital, Madrid, Spain
| | - Ramon Amat
- Thoracic Cancers Translational Genomics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Esther Redin
- Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
- CIBERONC, ISCIII, Madrid, Spain
- IDISNA, Pamplona, Spain
- Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
| | - Sergio Leon
- Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
- Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
| | - Naroa Legarra
- Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Javier Garcia
- Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
| | - Diego Serrano
- Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
- IDISNA, Pamplona, Spain
- Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
| | - Karmele Valencia
- Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
- CIBERONC, ISCIII, Madrid, Spain
| | | | - Giorgia Foggetti
- Yale Cancer Center, New Haven, Connecticut
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut
- Department of Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, Connecticut
| | - Nerea Otegui
- Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
- Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
| | - Enriqueta Felip
- Thoracic Cancers Translational Genomics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Juan J Lasarte
- IDISNA, Pamplona, Spain
- Immunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Luis Paz-Ares
- CIBERONC, ISCIII, Madrid, Spain
- Department of Medical Oncology and Tumor Microenvironment and Immunotherapy Research Group, 12 de Octubre Hospital, Madrid, Spain
| | - Jon Zugazagoitia
- CIBERONC, ISCIII, Madrid, Spain
- Department of Medical Oncology and Tumor Microenvironment and Immunotherapy Research Group, 12 de Octubre Hospital, Madrid, Spain
| | - Katerina Politi
- Yale Cancer Center, New Haven, Connecticut
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut
- Department of Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, Connecticut
| | - Luis Montuenga
- Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
- CIBERONC, ISCIII, Madrid, Spain
- IDISNA, Pamplona, Spain
- Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
| | - Alfonso Calvo
- Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
- CIBERONC, ISCIII, Madrid, Spain
- IDISNA, Pamplona, Spain
- Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
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Aria H, Rezaei M. Immunogenic cell death inducer peptides: A new approach for cancer therapy, current status and future perspectives. Biomed Pharmacother 2023; 161:114503. [PMID: 36921539 DOI: 10.1016/j.biopha.2023.114503] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/23/2023] [Accepted: 03/07/2023] [Indexed: 03/14/2023] Open
Abstract
Immunogenic Cell Death (ICD) is a type of cell death that kills tumor cells by stimulating the adaptive immune response against other tumor cells. ICD depends on the endoplasmic reticulum (ER) stress and the secretion of Damage-Associated Molecular Patterns (DAMP) by the dying tumor cell. DAMPs recruit innate immune cells such as Dendritic Cells (DC), triggering a cancer-specific immune response such as cytotoxic T lymphocytes (CTLs) to eliminate remaining cancer cells. ICD is accompanied by several hallmarks in dying cells, such as surface translocation of ER chaperones, calreticulin (CALR), and extracellular secretion of DAMPs such as high mobility group protein B1 (HMGB1) and adenosine triphosphate (ATP). Therapeutic peptides can kill bacteria and tumor cells thus affecting the immune system. They have high specificity and affinity for their targets, small size, appropriate cell membrane penetration, short half-life, and simple production processes. Peptides are interesting agents for immunomodulation since they may overcome the limitations of other therapeutics. Thus, the development of peptides affecting the TME and active antitumoral immunity has been actively pursued. On the other hand, several peptides have been recently identified to trigger ICD and anti-cancer responses. In the present review, we review previous studies on peptide-induced ICD, their mechanism, their targets, and markers. They include anti-microbial peptides (AMPs), cationic or mitochondrial targeting, checkpoint inhibitors, antiapoptotic inhibitors, and "don't eat me" inhibitor peptides. Also, peptides will be investigated potentially inducing ICD that is divided into ER stressors, ATPase inhibitors, and anti-microbial peptides.
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Affiliation(s)
- Hamid Aria
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Marzieh Rezaei
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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Li D, Zhang J, Yuan S, Wang C, Chang J, Tong Y, Liu R, Sang T, Li L, Li J, Ouyang Q, Chen X. TGF
‐β1 peptide‐based inhibitor
P144
ameliorates renal fibrosis after ischemia–reperfusion injury by modulating alternatively activated macrophages. Cell Prolif 2022; 55:e13299. [PMID: 35762283 PMCID: PMC9528764 DOI: 10.1111/cpr.13299] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 06/07/2022] [Accepted: 06/10/2022] [Indexed: 11/30/2022] Open
Abstract
Objectives Ischemia–reperfusion injury (IRI) is a major cause of chronic renal fibrosis. Currently, numerous therapies have shown a minimal effect on the blockade of fibrosis progression. Here, the therapeutic potential of peptide‐based TGF‐β1 inhibitor P144 in IRI‐induced renal fibrosis and the underlying mechanism were analyzed. Materials and Methods The unilateral ischemia–reperfusion injury with the contralateral nephrectomy model was established, and the P144 was administered intravenously 1d/14d after the onset of IRI. The histopathology and immunofluorescence staining were used to detect renal fibrosis and macrophage infiltration. The in vivo fluorescence imaging was used to measure the bio‐distribution of P144. The transwell assays were used to observe the migration of macrophages. RT‐qPCR and western blot were used to analyze TGF‐β1 signaling. Results P144 ameliorated the accumulation of extracellular matrix in the kidney and improved the renal function in the unilateral ischemia–reperfusion injury plus contralateral nephrectomy model. Mechanistically, P144 downregulated the TGF‐β1‐Smad3 signaling at both the transcriptional and translational levels and further reduced the TGF‐β1‐dependent infiltration of macrophages to the injured kidney. Additionally, P144 blocked the polarization of macrophages to an M2‐like phenotype induced by TGF‐β1 in vitro, but showed no effect on their proliferation. Conclusions Our study showed that the TGF‐β1 peptide‐based inhibitor P144 decreased renal fibrosis through the blockade of the TGF‐β1–Smad3 signaling pathway and the modulation of macrophage polarization, suggesting its potential therapeutic use in IRI‐induced renal fibrosis.
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Affiliation(s)
- Delun Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Kidney Disease Research Beijing China
- School of Clinical Medicine Guangdong Pharmaceutical University Guangzhou China
| | - Jian Zhang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Kidney Disease Research Beijing China
| | - Siyu Yuan
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Kidney Disease Research Beijing China
| | - Chao Wang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Kidney Disease Research Beijing China
- School of Traditional Chinese Medicine Guangdong Pharmaceutical University Guangzhou China
| | - Jiakai Chang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Kidney Disease Research Beijing China
| | - Yan Tong
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Kidney Disease Research Beijing China
| | - Ran Liu
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Kidney Disease Research Beijing China
| | - Tian Sang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Kidney Disease Research Beijing China
| | - Lili Li
- CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety National Center for Nanoscience and Technology (NCNST) Beijing China
| | - Jijun Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Kidney Disease Research Beijing China
| | - Qing Ouyang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Kidney Disease Research Beijing China
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Kidney Disease Research Beijing China
- School of Clinical Medicine Guangdong Pharmaceutical University Guangzhou China
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P144 a Transforming Growth Factor Beta Inhibitor Peptide, Generates Antifibrogenic Effects in a Radiotherapy Induced Fibrosis Model. Curr Oncol 2022; 29:2650-2661. [PMID: 35448191 PMCID: PMC9024500 DOI: 10.3390/curroncol29040217] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/06/2022] [Accepted: 04/08/2022] [Indexed: 12/04/2022] Open
Abstract
Radiation-induced fibrosis (RIF) is a severe side effect related with soft tissues sarcomas (STS) radiotherapy. RIF is a multicellular process initiated primarily by TGF-β1 that is increased in irradiated tissue, whose signaling leads to intracellular Smad2/3 phosphorylation and further induction of profibrotic target genes. P144 (Disetertide©) is a peptide inhibitor of TGF-β1 and is proposed as a candidate compound for reducing RIF associated wound healing problems and muscle fibrosis in STS. Methods: A treatment and control group of WNZ rabbits were employed to implement a brachytherapy animal model, through catheter implantation at the lower limb. Two days after implantation, animals received 20 Gy isodosis, intended to induce a high RIF grade. The treatment group received intravenous P144 administration following a brachytherapy session, repeated at 24–72 h post-radiation, while the control group received placebo. Four weeks later, affected muscular tissues underwent histological processing for collagen quantification and P-Smad2/3 immunohistochemistry through image analysis. Results: High isodosis Brachytherapy produced remarkable fibrosis in this experimental model. Results showed retained macro and microscopical morphology of muscle in the P144 treated group, with reduced extracellular matrix fibrosis, with a lower area of collagen deposition measured through Masson’s trichrome staining. Intravenous P144 also induced a significant reduction in Smad2/3 phosphorylation levels compared with the placebo group. Conclusions: P144 administration clearly reduces RIF and opens a new potential co-treatment approach to reduce complications in soft tissue sarcoma (STS) radiotherapy. Further studies are required to establish whether the dosage and timing optimization of P144 administration, in different RIF phases, might entirely avoid fibrosis associated with STS brachytherapy.
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Multiple Faces of the Glioblastoma Microenvironment. Int J Mol Sci 2022; 23:ijms23020595. [PMID: 35054779 PMCID: PMC8775531 DOI: 10.3390/ijms23020595] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 12/31/2021] [Accepted: 01/03/2022] [Indexed: 12/23/2022] Open
Abstract
The tumor microenvironment is a highly dynamic accumulation of resident and infiltrating tumor cells, responsible for growth and invasion. The authors focused on the leading-edge concepts regarding the glioblastoma microenvironment. Due to the fact that the modern trend in the research and treatment of glioblastoma is represented by multiple approaches that target not only the primary tumor but also the neighboring tissue, the study of the microenvironment in the peritumoral tissue is an appealing direction for current and future therapies.
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Lv X, Xu G. Regulatory role of the transforming growth factor-β signaling pathway in the drug resistance of gastrointestinal cancers. World J Gastrointest Oncol 2021; 13:1648-1667. [PMID: 34853641 PMCID: PMC8603464 DOI: 10.4251/wjgo.v13.i11.1648] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/28/2021] [Accepted: 08/18/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancer, including esophageal, gastric, and colorectal cancer, is one of the most prevalent types of malignant carcinoma and the leading cause of cancer-related deaths. Despite significant advances in therapeutic strategies for GI cancers in recent decades, drug resistance with various mechanisms remains the prevailing cause of therapy failure in GI cancers. Accumulating evidence has demonstrated that the transforming growth factor (TGF)-β signaling pathway has crucial, complex roles in many cellular functions related to drug resistance. This review summarizes current knowledge regarding the role of the TGF-β signaling pathway in the resistance of GI cancers to conventional chemotherapy, targeted therapy, immunotherapy, and traditional medicine. Various processes, including epithelial-mesenchymal transition, cancer stem cell development, tumor microenvironment alteration, and microRNA biogenesis, are proposed as the main mechanisms of TGF-β-mediated drug resistance in GI cancers. Several studies have already indicated the benefit of combining antitumor drugs with agents that suppress the TGF-β signaling pathway, but this approach needs to be verified in additional clinical studies. Moreover, the identification of potential biological markers that can be used to predict the response to TGF-β signaling pathway inhibitors during anticancer treatments will have important clinical implications in the future.
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Affiliation(s)
- Xiaoqun Lv
- Department of Pharmacy, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Guoxiong Xu
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Arce C, Rodríguez-Rovira I, De Rycke K, Durán K, Campuzano V, Fabregat I, Jiménez-Altayó F, Berraondo P, Egea G. Anti-TGFβ (Transforming Growth Factor β) Therapy With Betaglycan-Derived P144 Peptide Gene Delivery Prevents the Formation of Aortic Aneurysm in a Mouse Model of Marfan Syndrome. Arterioscler Thromb Vasc Biol 2021; 41:e440-e452. [PMID: 34162229 DOI: 10.1161/atvbaha.121.316496] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Objective We investigated the effect of a potent TGFβ (transforming growth factor β) inhibitor peptide (P144) from the betaglycan/TGFβ receptor III on aortic aneurysm development in a Marfan syndrome mouse model. Approach and Results We used a chimeric gene encoding the P144 peptide linked to apolipoprotein A-I via a flexible linker expressed by a hepatotropic adeno-associated vector. Two experimental approaches were performed: (1) a preventive treatment where the vector was injected before the onset of the aortic aneurysm (aged 4 weeks) and followed-up for 4 and 20 weeks and (2) a palliative treatment where the vector was injected once the aneurysm was formed (8 weeks old) and followed-up for 16 weeks. We evaluated the aortic root diameter by echocardiography, the aortic wall architecture and TGFβ signaling downstream effector expression of pSMAD2 and pERK1/2 by immunohistomorphometry, and Tgfβ1 and Tgfβ2 mRNA expression levels by real-time polymerase chain reaction. Marfan syndrome mice subjected to the preventive approach showed no aortic dilation in contrast to untreated Marfan syndrome mice, which at the same end point age already presented the aneurysm. In contrast, the palliative treatment with P144 did not halt aneurysm progression. In all cases, P144 improved elastic fiber morphology and normalized pERK1/2-mediated TGFβ signaling. Unlike the palliative treatment, the preventive treatment reduced Tgfβ1 and Tgfβ2 mRNA levels. Conclusions P144 prevents the onset of aortic aneurysm but not its progression. Results indicate the importance of reducing the excess of active TGFβ signaling during the early stages of aortic disease progression.
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Affiliation(s)
- Cristina Arce
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, Spain (C.A., I.R.-R., K.D.R., V.C., G.E.)
| | - Isaac Rodríguez-Rovira
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, Spain (C.A., I.R.-R., K.D.R., V.C., G.E.)
| | - Karo De Rycke
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, Spain (C.A., I.R.-R., K.D.R., V.C., G.E.)
| | - Karina Durán
- Department of Cardiology, Hospital Clínic y Provincial de Barcelona, Spain (K.D.)
| | - Victoria Campuzano
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, Spain (C.A., I.R.-R., K.D.R., V.C., G.E.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Spain (V.C.)
| | - Isabel Fabregat
- Bellvitge Biomedical Research Institute (IDIBELL) and Centro de Investigación Biomédica en Red de Enfermedades Hepático-Digestivas (CIBEREHD), ISCIII, Spain (I.F.)
| | - Francesc Jiménez-Altayó
- Department of Therapeutic Pharmacology and Toxicology, School of Medicine, Neuroscience Institute, Autonomous University of Barcelona, Bellaterra, Spain (F.J.-A.)
| | - Pedro Berraondo
- Program of Immunology and Immunotherapy, CIMA University of Navarra, Pamplona, Spain (P.B.)
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain (P.B.)
| | - Gustavo Egea
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, Spain (C.A., I.R.-R., K.D.R., V.C., G.E.)
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain (G.E.)
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10
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Listik E, Horst B, Choi AS, Lee NY, Győrffy B, Mythreye K. A bioinformatic analysis of the inhibin-betaglycan-endoglin/CD105 network reveals prognostic value in multiple solid tumors. PLoS One 2021; 16:e0249558. [PMID: 33819300 PMCID: PMC8021191 DOI: 10.1371/journal.pone.0249558] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 03/21/2021] [Indexed: 12/13/2022] Open
Abstract
Inhibins and activins are dimeric ligands belonging to the TGFβ superfamily with emergent roles in cancer. Inhibins contain an α-subunit (INHA) and a β-subunit (either INHBA or INHBB), while activins are mainly homodimers of either βA (INHBA) or βB (INHBB) subunits. Inhibins are biomarkers in a subset of cancers and utilize the coreceptors betaglycan (TGFBR3) and endoglin (ENG) for physiological or pathological outcomes. Given the array of prior reports on inhibin, activin and the coreceptors in cancer, this study aims to provide a comprehensive analysis, assessing their functional prognostic potential in cancer using a bioinformatics approach. We identify cancer cell lines and cancer types most dependent and impacted, which included p53 mutated breast and ovarian cancers and lung adenocarcinomas. Moreover, INHA itself was dependent on TGFBR3 and ENG/CD105 in multiple cancer types. INHA, INHBA, TGFBR3, and ENG also predicted patients' response to anthracycline and taxane therapy in luminal A breast cancers. We also obtained a gene signature model that could accurately classify 96.7% of the cases based on outcomes. Lastly, we cross-compared gene correlations revealing INHA dependency to TGFBR3 or ENG influencing different pathways themselves. These results suggest that inhibins are particularly important in a subset of cancers depending on the coreceptor TGFBR3 and ENG and are of substantial prognostic value, thereby warranting further investigation.
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Affiliation(s)
- Eduardo Listik
- Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Ben Horst
- Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina, United States of America
| | - Alex Seok Choi
- Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Nam. Y. Lee
- Division of Pharmacology, Chemistry and Biochemistry, College of Medicine, University of Arizona, Tucson, Arizona, United States of America
| | - Balázs Győrffy
- TTK Cancer Biomarker Research Group, Institute of Enzymology, and Semmelweis University Department of Bioinformatics and 2nd Department of Pediatrics, Budapest, Hungary
| | - Karthikeyan Mythreye
- Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
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11
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Zefferino R, Piccoli C, Di Gioia S, Capitanio N, Conese M. How Cells Communicate with Each Other in the Tumor Microenvironment: Suggestions to Design Novel Therapeutic Strategies in Cancer Disease. Int J Mol Sci 2021; 22:ijms22052550. [PMID: 33806300 PMCID: PMC7961918 DOI: 10.3390/ijms22052550] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/25/2021] [Accepted: 02/26/2021] [Indexed: 02/06/2023] Open
Abstract
Connexin- and pannexin (Panx)-formed hemichannels (HCs) and gap junctions (GJs) operate an interaction with the extracellular matrix and GJ intercellular communication (GJIC), and on account of this they are involved in cancer onset and progression towards invasiveness and metastatization. When we deal with cancer, it is not correct to omit the immune system, as well as neglecting its role in resisting or succumbing to formation and progression of incipient neoplasia until the formation of micrometastasis, nevertheless what really occurs in the tumor microenvironment (TME), which are the main players and which are the tumor or body allies, is still unclear. The goal of this article is to discuss how the pivotal players act, which can enhance or contrast cancer progression during two important process: "Activating Invasion and Metastasis" and the "Avoiding Immune Destruction", with a particular emphasis on the interplay among GJIC, Panx-HCs, and the purinergic system in the TME without disregarding the inflammasome and cytokines thereof derived. In particular, the complex and contrasting roles of Panx1/P2X7R signalosome in tumor facilitation and/or inhibition is discussed in regard to the early/late phases of the carcinogenesis. Finally, considering this complex interplay in the TME between cancer cells, stromal cells, immune cells, and focusing on their means of communication, we should be capable of revealing harmful messages that help the cancer growth and transform them in body allies, thus designing novel therapeutic strategies to fight cancer in a personalized manner.
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Affiliation(s)
- Roberto Zefferino
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (S.D.G.); (M.C.)
- Correspondence: ; Tel.: +39-0881-884673
| | - Claudia Piccoli
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; (C.P.); (N.C.)
| | - Sante Di Gioia
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (S.D.G.); (M.C.)
| | - Nazzareno Capitanio
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; (C.P.); (N.C.)
| | - Massimo Conese
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (S.D.G.); (M.C.)
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12
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Bielecki PA, Lorkowski ME, Becicka WM, Atukorale PU, Moon TJ, Zhang Y, Wiese M, Covarrubias G, Ravichandran S, Karathanasis E. Immunostimulatory silica nanoparticle boosts innate immunity in brain tumors. NANOSCALE HORIZONS 2021; 6:156-167. [PMID: 33400743 PMCID: PMC7878432 DOI: 10.1039/d0nh00446d] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
The high mortality associated with glioblastoma multiforme (GBM) is attributed to its invasive nature, hypoxic core, resistant cell subpopulations and a highly immunosuppressive tumor microenvironment (TME). To support adaptive immune function and establish a more robust antitumor immune response, we boosted the local innate immune compartment of GBM using an immunostimulatory mesoporous silica nanoparticle, termed immuno-MSN. The immuno-MSN was specifically designed for systemic and proficient delivery of a potent innate immune agonist to dysfunctional antigen-presenting cells (APCs) in the brain TME. The cargo of the immuno-MSN was cyclic diguanylate monophosphate (cdGMP), a Stimulator of Interferon Gene (STING) agonist. Studies showed the immuno-MSN promoted the uptake of STING agonist by APCs in vitro and the subsequent release of the pro-inflammatory cytokine interferon β, 6-fold greater than free agonist. In an orthotopic GBM mouse model, systemically administered immuno-MSN particles were taken up by APCs in the near-perivascular regions of the brain tumor with striking efficiency. The immuno-MSNs facilitated the recruitment of dendritic cells and macrophages to the TME while sparing healthy brain tissue and peripheral organs, resulting in elevated circulating CD8+ T cell activity (2.5-fold) and delayed GBM tumor growth. We show that an engineered immunostimulatory nanoparticle can support pro-inflammatory innate immune function in GBM and subsequently augment current immunotherapeutic interventions and improve their therapeutic outcome.
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Affiliation(s)
- Peter A Bielecki
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA.
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13
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Gómez-Gil V. Therapeutic Implications of TGFβ in Cancer Treatment: A Systematic Review. Cancers (Basel) 2021; 13:379. [PMID: 33498521 PMCID: PMC7864190 DOI: 10.3390/cancers13030379] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 12/24/2022] Open
Abstract
Transforming growth factor β (TGFβ) is a pleiotropic cytokine that participates in a wide range of biological functions. The alterations in the expression levels of this factor, or the deregulation of its signaling cascade, can lead to different pathologies, including cancer. A great variety of therapeutic strategies targeting TGFβ, or the members included in its signaling pathway, are currently being researched in cancer treatment. However, the dual role of TGFβ, as a tumor suppressor or a tumor-promoter, together with its crosstalk with other signaling pathways, has hampered the development of safe and effective treatments aimed at halting the cancer progression. This systematic literature review aims to provide insight into the different approaches available to regulate TGFβ and/or the molecules involved in its synthesis, activation, or signaling, as a cancer treatment. The therapeutic strategies most commonly investigated include antisense oligonucleotides, which prevent TGFβ synthesis, to molecules that block the interaction between TGFβ and its signaling receptors, together with inhibitors of the TGFβ signaling cascade-effectors. The effectiveness and possible complications of the different potential therapies available are also discussed.
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Affiliation(s)
- Verónica Gómez-Gil
- Department of Biomedical Sciences (Area of Pharmacology), School of Medicine and Health Sciences, University of Alcalá, 28805 Alcalá de Henares, Madrid, Spain
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14
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Furukawa N, Popel AS. Peptides that immunoactivate the tumor microenvironment. Biochim Biophys Acta Rev Cancer 2021; 1875:188486. [PMID: 33276025 PMCID: PMC8369429 DOI: 10.1016/j.bbcan.2020.188486] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 11/04/2020] [Accepted: 11/21/2020] [Indexed: 02/07/2023]
Abstract
Cancer immunotherapy has achieved positive clinical outcomes and is revolutionizing cancer treatment. However, cancer immunotherapy has thus far failed to improve outcomes for most "cold tumors", which are characterized by low infiltration of immune cells and immunosuppressive tumor microenvironment. Enhancing the responsiveness of cold tumors to cancer immunotherapy by stimulating the components of the tumor microenvironment is a strategy pursued in the last decade. Currently, most of the agents used to modify the tumor microenvironment are small molecules or antibodies. Small molecules exhibit low affinity and specificity towards the target and antibodies have shortcomings such as poor tissue penetration and high production cost. Peptides may overcome these drawbacks and therefore are promising materials for immunomodulating agents. Here we systematically summarize the currently developed immunoactivating peptides and discuss the potential of peptide therapeutics in cancer immunology.
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Affiliation(s)
- Natsuki Furukawa
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, USA.
| | - Aleksander S Popel
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
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15
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Hanafy NAN, Fabregat I, Leporatti S, El Kemary M. Encapsulating TGF-β1 Inhibitory Peptides P17 and P144 as a Promising Strategy to Facilitate Their Dissolution and to Improve Their Functionalization. Pharmaceutics 2020; 12:E421. [PMID: 32370293 PMCID: PMC7284799 DOI: 10.3390/pharmaceutics12050421] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 04/28/2020] [Accepted: 04/29/2020] [Indexed: 12/13/2022] Open
Abstract
: Transforming growth factor-beta (TGFβ1) is considered as a master regulator for many intracellular signaling pathways, including proliferation, differentiation and death, both in health and disease. It further represents an oncogenic factor in advanced tumors allowing cancer cells to be more invasive and prone to move into the metastatic process. This finding has received great attention for discovering new therapeutic molecules against the TGFβ1 pathway. Among many TGFβ1 inhibitors, peptides (P17 and P144) were designed to block the TGFβ1 pathway. However, their therapeutic applications have limited use, due to lack of selection for their targets and their possible recognition by the immune system and further due to their potential cytotoxicity on healthy cells. Besides that, P144 is a highly hydrophobic molecule with less dissolution even in organic solution. Here, we aimed to overcome the dissolution of P144, as well as design nano-delivery strategies to protect normal cells, to increase cellular penetration and to raise the targeted therapy of both P17 and P144. Peptides were encapsulated in moieties of polymer hybrid protein. Their assembly was investigated by TEM, microplate spectrum analysis and fluorescence microscopy. SMAD phosphorylation was analyzed by Western blot as a hallmark of their biological efficiency. The results showed that the encapsulation of P17 and P144 might improve their potential therapeutic applications.
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Affiliation(s)
- Nemany A. N. Hanafy
- Nanomedicine Department, Institute of Nanoscience and Nanotechnology, Kafrelsheikh University, Kafrelsheikh 33516, Egypt;
| | - Isabel Fabregat
- Bellvitge Biomedical Research Institute (IDIBELL), University of Barcelona (UB) and CIBEREHD, Gran Via de l’Hospitalet, 199, Hospitalet de Llobregat, 08908 Barcelona, Spain;
| | - Stefano Leporatti
- CNR NANOTEC-Istituto di Nanotecnologia, Via Monteroni, 73100 Lecce, Italy
| | - Maged El Kemary
- Nanomedicine Department, Institute of Nanoscience and Nanotechnology, Kafrelsheikh University, Kafrelsheikh 33516, Egypt;
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16
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Sharifi H, Shafiee A, Molavi G, Razi E, Mousavi N, Sarvizadeh M, Taghizadeh M. Leukemia-derived exosomes: Bringing oncogenic signals to blood cells. J Cell Biochem 2019; 120:16307-16315. [PMID: 31127656 DOI: 10.1002/jcb.29018] [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: 01/24/2019] [Revised: 04/11/2019] [Accepted: 04/18/2019] [Indexed: 12/26/2022]
Abstract
Leukemia is a cancer, which is derived from leukocytes and precursors of leukocytes in the bone marrow. A large number of pivotal biological processes are linked to leukemia pathogenesis. More insights into these mechanisms can provide a better developing pharmacological platform for patients with leukemia. Among the different players in leukemia pathogenesis, exosomes have appeared as a new biological vehicle, which can transfer oncogenic signals to blood cells. Exosomes are nano-carriers, which enable transferring numerous cargos such as DNA fragments, RNAs, messenger RNAs, microRNAs, long noncoding RNA, and proteins. Targeting the contents of exosomes leads to the alteration of host cell behavior. Increasing evidence has indicated that leukemia-derived exosomes could be utilized as prognostic, diagnostic, and therapeutic biomarkers for individuals suffering from leukemia. In this regard, the importance of exosomes in terms of initiation and progression of leukemia was underlined in this study.
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Affiliation(s)
- Hossein Sharifi
- The Advocate Center for Clinical Research, Ayatollah Yasrebi Hospital, Kashan, Iran
| | - Alimohammad Shafiee
- Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Ghader Molavi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ebrahim Razi
- The Advocate Center for Clinical Research, Ayatollah Yasrebi Hospital, Kashan, Iran
| | - Nousin Mousavi
- Department of Surgery, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mostafa Sarvizadeh
- The Advocate Center for Clinical Research, Ayatollah Yasrebi Hospital, Kashan, Iran
| | - Mohsen Taghizadeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
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17
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Huang JJ, Corona AL, Dunn BP, Cai EM, Prakken JN, Blobe GC. Increased type III TGF-β receptor shedding decreases tumorigenesis through induction of epithelial-to-mesenchymal transition. Oncogene 2019; 38:3402-3414. [PMID: 30643193 PMCID: PMC6586422 DOI: 10.1038/s41388-018-0672-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 12/17/2018] [Accepted: 12/18/2018] [Indexed: 12/16/2022]
Abstract
The type III TGF-β receptor (TβRIII) is a TGF-β co-receptor that presents ligand to the type II TGF-β receptor to initiate signaling. TβRIII also undergoes ectodomain shedding to release a soluble form (sTβRIII) that can bind ligand, sequestering it away from cell surface receptors. We have previously identified a TβRIII extracellular mutant that has enhanced ectodomain shedding ("super shedding (SS)"-TβRIII-SS). Here, we utilize TβRIII-SS to study the balance of cell surface and soluble TβRIII in the context of lung cancer. We demonstrate that expressing TβRIII-SS in lung cancer cell models induces epithelial-to-mesenchymal transition (EMT) and that these TβRIII-SS (EMT) cells are less migratory, invasive and adhesive and more resistant to gemcitabine. Moreover, TβRIII-SS (EMT) cells exhibit decreased tumorigenicity but increased growth rate in vitro and in vivo. These studies suggest that the balance of cell surface and soluble TβRIII may regulate a dichotomous role for TβRIII during cancer progression.
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Affiliation(s)
- Jennifer J Huang
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA
| | - Armando L Corona
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA
| | - Brian P Dunn
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Elise M Cai
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Jesse N Prakken
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Gerard C Blobe
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA. .,Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
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18
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Fabregat I, Caballero-Díaz D. Transforming Growth Factor-β-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis. Front Oncol 2018; 8:357. [PMID: 30250825 PMCID: PMC6139328 DOI: 10.3389/fonc.2018.00357] [Citation(s) in RCA: 241] [Impact Index Per Article: 34.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 08/13/2018] [Indexed: 12/11/2022] Open
Abstract
The Transforming Growth Factor-beta (TGF-β) family plays relevant roles in the regulation of different cellular processes that are essential for tissue and organ homeostasis. In the case of the liver, TGF-β signaling participates in different stages of disease progression, from initial liver injury toward fibrosis, cirrhosis and cancer. When a chronic injury takes place, mobilization of lymphocytes and other inflammatory cells occur, thus setting the stage for persistence of an inflammatory response. Macrophages produce profibrotic mediators, among them, TGF-β, which is responsible for activation -transdifferentiation- of quiescent hepatic stellate cells (HSC) to a myofibroblast (MFB) phenotype. MFBs are the principal source of extracellular matrix protein (ECM) accumulation and prominent mediators of fibrogenesis. TGF-β also mediates an epithelial-mesenchymal transition (EMT) process in hepatocytes that may contribute, directly or indirectly, to increase the MFB population. In hepatocarcinogenesis, TGF-β plays a dual role, behaving as a suppressor factor at early stages, but contributing to later tumor progression, once cells escape from its cytostatic effects. As part of its potential pro-tumorigenic actions, TGF-β induces EMT in liver tumor cells, which increases its pro-migratory and invasive potential. In parallel, TGF-β also induces changes in tumor cell plasticity, conferring properties of a migratory tumor initiating cell (TIC). The main aim of this review is to shed light about the pleiotropic actions of TGF-β that explain its effects on the different liver cell populations. The cross-talk with other signaling pathways that contribute to TGF-β effects, in particular the Epidermal Growth Factor Receptor (EGFR), will be presented. Finally, we will discuss the rationale for targeting the TGF-β pathway in liver pathologies.
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Affiliation(s)
- Isabel Fabregat
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute, Barcelona, Spain.,Department of Physiological Sciences, School of Medicine, University of Barcelona, Barcelona, Spain.,Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Barcelona, Spain
| | - Daniel Caballero-Díaz
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute, Barcelona, Spain.,Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Barcelona, Spain
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19
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March JT, Golshirazi G, Cernisova V, Carr H, Leong Y, Lu-Nguyen N, Popplewell LJ. Targeting TGFβ Signaling to Address Fibrosis Using Antisense Oligonucleotides. Biomedicines 2018; 6:biomedicines6030074. [PMID: 29941814 PMCID: PMC6164894 DOI: 10.3390/biomedicines6030074] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 06/13/2018] [Accepted: 06/14/2018] [Indexed: 12/29/2022] Open
Abstract
Fibrosis results from the excessive accumulation of extracellular matrix in chronically injured tissue. The fibrotic process is governed by crosstalk between many signaling pathways. The search for an effective treatment is further complicated by the fact that there is a degree of tissue-specificity in the pathways involved, although the process is not completely understood for all tissues. A plethora of drugs have shown promise in pre-clinical models, which is not always borne out translationally in clinical trial. With the recent approvals of two antisense oligonucleotides for the treatment of the genetic diseases Duchenne muscular dystrophy and spinal muscular atrophy, we explore here the potential of antisense oligonucleotides to knockdown the expression of pro-fibrotic proteins. We give an overview of the generalized fibrotic process, concentrating on key players and highlight where antisense oligonucleotides have been used effectively in cellular and animal models of different fibrotic conditions. Consideration is given to the advantages antisense oligonucleotides would have as an anti-fibrotic therapy alongside factors that would need to be addressed to improve efficacy. A prospective outlook for the development of antisense oligonucleotides to target fibrosis is outlined.
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Affiliation(s)
- James T March
- Centre for Gene and Cell Therapy, School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey TW20 0EX, UK.
| | - Golnoush Golshirazi
- Centre for Gene and Cell Therapy, School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey TW20 0EX, UK.
| | - Viktorija Cernisova
- Centre for Gene and Cell Therapy, School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey TW20 0EX, UK.
| | - Heidi Carr
- Centre for Gene and Cell Therapy, School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey TW20 0EX, UK.
| | - Yee Leong
- Centre for Gene and Cell Therapy, School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey TW20 0EX, UK.
| | - Ngoc Lu-Nguyen
- Centre for Gene and Cell Therapy, School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey TW20 0EX, UK.
| | - Linda J Popplewell
- Centre for Gene and Cell Therapy, School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey TW20 0EX, UK.
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20
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Kodet O, Dvořánková B, Bendlová B, Sýkorová V, Krajsová I, Štork J, Kučera J, Szabo P, Strnad H, Kolář M, Vlček Č, Smetana K, Lacina L. Microenvironment‑driven resistance to B‑Raf inhibition in a melanoma patient is accompanied by broad changes of gene methylation and expression in distal fibroblasts. Int J Mol Med 2018; 41:2687-2703. [PMID: 29393387 PMCID: PMC5846633 DOI: 10.3892/ijmm.2018.3448] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 01/18/2018] [Indexed: 12/25/2022] Open
Abstract
The incidence of malignant melanoma is rapidly increasing and current medicine is offering only limited options for treatment of the advanced disease. For B‑Raf mutated melanomas, treatment with mutation‑specific drug inhibitors may be used. Unfortunately, tumors frequently acquire resistance to the treatment. Tumor microenvironment, namely cancer‑associated fibroblasts, largely influence this acquired resistance. In the present study, fibroblasts were isolated from a patient suffering from acrolentiginous melanoma (Breslow, 4.0 mm; Clark, IV; B‑Raf V600E mutated). The present study focused on the expression of structural and functional markers of fibroblast activation in melanoma‑associated fibroblasts (MAFs; isolated prior to therapy initiation) as well as in autologous control fibroblasts (ACFs) of the same patient isolated during B‑Raf inhibitor therapy, yet before clinical progression of the disease. Analysis of gene transcription was also performed, as well as DNA methylation status analysis at the genomic scale of both isolates. MAFs were positive for smooth muscle actin (SMA), which is a marker of myofibroblasts and the hallmark of cancer stoma. Surprisingly, ACF isolated from the distant uninvolved skin of the same patient also exhibited strong SMA expression. A similar phenotype was also observed in control dermal fibroblasts (CDFs; from different donors) exclusively following stimulation by transforming growth factor (TGF)‑β1. Immunohistochemistry confirmed that melanoma cells potently produce TGF‑β1. Significant differences were also identified in gene transcription and in DNA methylation status at the genomic scale. Upregulation of SMA was observed in ACF cells at the protein and transcriptional levels. The present results support recent experimental findings that tumor microenvironment is driving resistance to B‑Raf inhibition in patients with melanoma. Such an activated microenvironment may be viable for the growth of circulating melanoma cells.
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Affiliation(s)
- Ondřej Kodet
- Institute of Anatomy
- Department of Dermatology and Venereology, First Faculty of Medicine, Charles University, 12808 Prague
- BIOCEV, Biotechnology and Biomedicine Center of The Academy of Sciences and Charles University in Vestec, 25250 Vestec
- Department of Dermatology and Venereology, General University Hospital, 12808 Prague
| | - Barbora Dvořánková
- Institute of Anatomy
- BIOCEV, Biotechnology and Biomedicine Center of The Academy of Sciences and Charles University in Vestec, 25250 Vestec
| | | | | | - Ivana Krajsová
- Department of Dermatology and Venereology, General University Hospital, 12808 Prague
| | - Jiří Štork
- Department of Dermatology and Venereology, First Faculty of Medicine, Charles University, 12808 Prague
- Department of Dermatology and Venereology, General University Hospital, 12808 Prague
| | - Jan Kučera
- Institute of Anatomy
- Department of Dermatology and Venereology, First Faculty of Medicine, Charles University, 12808 Prague
- Department of Dermatology and Venereology, General University Hospital, 12808 Prague
| | - Pavol Szabo
- Institute of Anatomy
- BIOCEV, Biotechnology and Biomedicine Center of The Academy of Sciences and Charles University in Vestec, 25250 Vestec
| | - Hynek Strnad
- Institute of Molecular Genetics, Academy of Sciences of The Czech Republic, 14220 Prague, Czech Republic
| | - Michal Kolář
- Institute of Molecular Genetics, Academy of Sciences of The Czech Republic, 14220 Prague, Czech Republic
| | - Čestmír Vlček
- Institute of Molecular Genetics, Academy of Sciences of The Czech Republic, 14220 Prague, Czech Republic
| | - Karel Smetana
- Institute of Anatomy
- BIOCEV, Biotechnology and Biomedicine Center of The Academy of Sciences and Charles University in Vestec, 25250 Vestec
| | - Lukáš Lacina
- Institute of Anatomy
- Department of Dermatology and Venereology, First Faculty of Medicine, Charles University, 12808 Prague
- BIOCEV, Biotechnology and Biomedicine Center of The Academy of Sciences and Charles University in Vestec, 25250 Vestec
- Department of Dermatology and Venereology, General University Hospital, 12808 Prague
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21
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Xu X, Zheng L, Yuan Q, Zhen G, Crane JL, Zhou X, Cao X. Transforming growth factor-β in stem cells and tissue homeostasis. Bone Res 2018; 6:2. [PMID: 29423331 PMCID: PMC5802812 DOI: 10.1038/s41413-017-0005-4] [Citation(s) in RCA: 289] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 11/12/2017] [Accepted: 11/15/2017] [Indexed: 02/05/2023] Open
Abstract
TGF-β 1-3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix (ECM). The biological functions of TGF-β in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-β in maintaining stem cells and tissue homeostasis have not been well-documented until recent advances, which delineate their functions in a given context. Our recent findings, along with data reported by others, have clearly shown that temporal and spatial activation of TGF-β is involved in the recruitment of stem/progenitor cell participation in tissue regeneration/remodeling process, whereas sustained abnormalities in TGF-β ligand activation, regardless of genetic or environmental origin, will inevitably disrupt the normal physiology and lead to pathobiology of major diseases. Modulation of TGF-β signaling with different approaches has proven effective pre-clinically in the treatment of multiple pathologies such as sclerosis/fibrosis, tumor metastasis, osteoarthritis, and immune disorders. Thus, further elucidation of the mechanisms by which TGF-β is activated in different tissues/organs and how targeted cells respond in a context-dependent way can likely be translated with clinical benefits in the management of a broad range of diseases with the involvement of TGF-β.
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Affiliation(s)
- Xin Xu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Liwei Zheng
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Quan Yuan
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Gehua Zhen
- Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Janet L. Crane
- Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD USA
- Department of Pediatrics, Johns Hopkins University, Baltimore, MD USA
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xu Cao
- Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD USA
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22
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Szaryńska M, Olejniczak A, Kobiela J, Spychalski P, Kmieć Z. Therapeutic strategies against cancer stem cells in human colorectal cancer. Oncol Lett 2017; 14:7653-7668. [PMID: 29250169 PMCID: PMC5727596 DOI: 10.3892/ol.2017.7261] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 09/01/2017] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is the third most frequent malignancy and represents the fourth most common cause of cancer-associated mortalities in the world. Despite many advances in the treatment of CRC, the 5-year survival rate of patients with CRC remains unsatisfactory due to tumor recurrence and metastases. Recently, cancer stem cells (CSCs), have been suggested to be responsible for the initiation and relapse of the disease, and have been identified in CRC. Due to their basic biological features, which include self-renewal and pluripotency, CSCs may be novel therapeutic targets for CRC and other cancer types. Conventional therapeutics only act on proliferating and mature cancer cells, while quiescent CSCs survive and often become resistant to chemotherapy. In this review, markers of CRC-CSCs are evaluated and the recently introduced experimental therapies that specifically target these cells by inducing CSC proliferation, differentiation and sensitization to apoptotic signals via molecules including Dickkopf-1, bone morphogenetic protein 4, Kindlin-1, tankyrases, and p21-activated kinase 1, are discussed. In addition, novel strategies aimed at inhibiting some crucial processes engaged in cancer progression regulated by the Wnt, transforming growth factor β and Notch signaling pathways (pyrvinium pamoate, silibinin, PRI-724, P17, and P144 peptides) are also evaluated. Although the metabolic alterations in cancer were first described decades ago, it is only recently that the concept of targeting key regulatory molecules of cell metabolism, such as sirtuin 1 (miR-34a) and AMPK (metformin), has emerged. In conclusion, the discovery of CSCs has resulted in the definition of novel therapeutic targets and the development of novel experimental therapies for CRC. However, further investigations are required in order to apply these novel drugs in human CRC.
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Affiliation(s)
- Magdalena Szaryńska
- Department of Histology, Medical University of Gdańsk, 80-210 Gdańsk; Gdańsk, Poland
| | - Agata Olejniczak
- Department of Histology, Medical University of Gdańsk, 80-210 Gdańsk; Gdańsk, Poland
| | - Jarosław Kobiela
- Department of General, Endocrine and Transplant Surgery, Invasive Medicine Center, Medical University of Gdańsk, 80-214 Gdańsk, Poland
| | - Piotr Spychalski
- Department of General, Endocrine and Transplant Surgery, Invasive Medicine Center, Medical University of Gdańsk, 80-214 Gdańsk, Poland
| | - Zbigniew Kmieć
- Department of Histology, Medical University of Gdańsk, 80-210 Gdańsk; Gdańsk, Poland
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23
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Walton KL, Johnson KE, Harrison CA. Targeting TGF-β Mediated SMAD Signaling for the Prevention of Fibrosis. Front Pharmacol 2017; 8:461. [PMID: 28769795 PMCID: PMC5509761 DOI: 10.3389/fphar.2017.00461] [Citation(s) in RCA: 421] [Impact Index Per Article: 52.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 06/27/2017] [Indexed: 01/18/2023] Open
Abstract
Fibrosis occurs when there is an imbalance in extracellular matrix (ECM) deposition and degradation. Excessive ECM deposition results in scarring and thickening of the affected tissue, and interferes with tissue and organ homeostasis – mimicking an exaggerated “wound healing” response. Many transforming growth factor-β (TGF-β) ligands are potent drivers of ECM deposition, and additionally, have a natural affinity for the ECM, creating a concentrated pool of pro-fibrotic factors at the site of injury. Consequently, TGF-β ligands are upregulated in many human fibrotic conditions and, as such, are attractive targets for fibrosis therapy. Here, we will discuss the contribution of TGF-β proteins in the pathogenesis of fibrosis, and promising anti-fibrotic approaches that target TGF-β ligands.
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Affiliation(s)
- Kelly L Walton
- Growth Factor Therapeutics Laboratory, Department of Physiology, Monash University, ClaytonVIC, Australia
| | - Katharine E Johnson
- Growth Factor Therapeutics Laboratory, Department of Physiology, Monash University, ClaytonVIC, Australia
| | - Craig A Harrison
- Growth Factor Therapeutics Laboratory, Department of Physiology, Monash University, ClaytonVIC, Australia
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24
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Rossowska J, Anger N, Szczygieł A, Mierzejewska J, Pajtasz-Piasecka E. Intratumoral Lentivector-Mediated TGF-β1 Gene Downregulation As a Potent Strategy for Enhancing the Antitumor Effect of Therapy Composed of Cyclophosphamide and Dendritic Cells. Front Immunol 2017; 8:713. [PMID: 28713366 PMCID: PMC5492852 DOI: 10.3389/fimmu.2017.00713] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 06/01/2017] [Indexed: 12/27/2022] Open
Abstract
Vaccination with dendritic cells (DCs) stimulated with tumor antigens can induce specific cellular immune response that recognizes a high spectrum of tumor antigens. However, the ability of cancer cells to produce immunosuppressive factors drastically decreases the antitumor activity of DCs. The main purpose of the study was to improve the effectiveness of DC-based immunotherapy or chemoimmunotherapy composed of cyclophosphamide (CY) and DCs by application of lentivectors (LVs)-encoding short hairpin RNA specific for TGF-β1 (shTGFβ1 LVs). We observed that s.c. inoculation of both MC38 cells with silenced expression of TGF-β1 (MC38/shTGF-β1) and direct intratumoral application of shTGFβ1 LVs contributed to reduction of suppressor activity of myeloid cells and Tregs in tumor. Contrary to expectations, in mice bearing wild tumor, the application of shTGFβ1 LVs prior to vaccination with bone marrow-derived DC stimulated with tumor antigens (BMDC/TAg) did not influence myeloid-derived suppressor cell (MDSC) infiltration into tumor. As a result, we observed only minor MC38 tumor growth inhibition (TGI) accompanied by systemic antitumor response activation comparable to that obtained for negative control (shN). However, when the proposed scheme was complemented by pretreatment with a low dose of CY, we noticed high MC38 TGI together with decreased number of MDSCs in tumor and induction of Th1-type response. Moreover, in both schemes of treatment, LVs (shTGFβ1 as well as shN) induced high influx of CTLs into tumor associated probably with the viral antigen introduction into tumor microenvironment. Concluding, the application of shTGFβ1 LVs alone or in combination with DC-based vaccines is not sufficient for long-lasting elimination of suppression in tumor. However, simultaneous reduction of TGF-β1 in tumor microenvironment and its remodeling by pretreatment with a low dose of CY facilitates the settlement of peritumorally inoculated DCs and supports them in restoration and activation of a potent antitumor response.
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Affiliation(s)
- Joanna Rossowska
- Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Natalia Anger
- Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Agnieszka Szczygieł
- Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Jagoda Mierzejewska
- Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Elżbieta Pajtasz-Piasecka
- Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
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25
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The Process and Regulatory Components of Inflammation in Brain Oncogenesis. Biomolecules 2017; 7:biom7020034. [PMID: 28346397 PMCID: PMC5485723 DOI: 10.3390/biom7020034] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 03/09/2017] [Accepted: 03/22/2017] [Indexed: 12/17/2022] Open
Abstract
Central nervous system tumors comprising the primary cancers and brain metastases remain the most lethal neoplasms and challenging to treat. Substantial evidence points to a paramount role for inflammation in the pathology leading to gliomagenesis, malignant progression and tumor aggressiveness in the central nervous system (CNS) microenvironment. This review summarizes the salient contributions of oxidative stress, interleukins, tumor necrosis factor-α(TNF-α), cyclooxygenases, and transcription factors such as signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and the associated cross-talks to the inflammatory signaling in CNS cancers. The roles of reactive astrocytes, tumor associated microglia and macrophages, metabolic alterations, microsatellite instability, O6-methylguanine DNA methyltransferase (MGMT) DNA repair and epigenetic alterations mediated by the isocitrate dehydrogenase 1 (IDH1) mutations have been discussed. The inflammatory pathways with relevance to the brain cancer treatments have been highlighted.
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26
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Gallo-Oller G, Vollmann-Zwerenz A, Meléndez B, Rey JA, Hau P, Dotor J, Castresana JS. P144, a Transforming Growth Factor beta inhibitor peptide, generates antitumoral effects and modifies SMAD7 and SKI levels in human glioblastoma cell lines. Cancer Lett 2016; 381:67-75. [PMID: 27473823 DOI: 10.1016/j.canlet.2016.07.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 07/20/2016] [Accepted: 07/21/2016] [Indexed: 12/22/2022]
Abstract
Glioblastoma (GBM) is the most prevalent malignant primary brain tumor, accounting for 60-70% of all gliomas. Current median patient survival time is 14-16 months after diagnosis. Numerous efforts in therapy have not significantly altered the nearly uniform lethality of this malignancy. The Transforming Growth Factor beta (TGF-β) signaling pathway plays a key role in GBM and is implicated in proliferation, invasion and therapy resistance. Several inhibitors of the TGF-β pathway have entered clinical trials or are under development. In this work, the therapeutic potential of P144, a TGF-β inhibitor peptide, was analyzed. P144 decreased proliferation, migration, invasiveness, and tumorigenicity in vitro, whereas apoptosis and anoikis were significantly increased for GBM cell lines. SMAD2 phosphorylation was reduced, together with a downregulation of SKI and an upregulation of SMAD7 at both transcriptional and translational levels. Additionally, P144 was able to impair tumor growth and increase survival in an in vivo flank model. Our findings suggest a potential effect of P144 in vitro and in vivo that is mediated by regulation of transcriptional target genes of the TGF-β pathway, suggesting a therapeutic potential of P144 for GBM treatment.
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Affiliation(s)
- Gabriel Gallo-Oller
- Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain
| | - Arabel Vollmann-Zwerenz
- Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg, Regensburg, Germany
| | - Bárbara Meléndez
- Molecular Pathology Research Unit, Department of Pathology, Virgen de la Salud Hospital, Toledo, Spain
| | - Juan A Rey
- IdiPaz Research Unit, La Paz University Hospital, Madrid, Spain
| | - Peter Hau
- Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg, Regensburg, Germany
| | | | - Javier S Castresana
- Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain.
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27
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Malek E, de Lima M, Letterio JJ, Kim BG, Finke JH, Driscoll JJ, Giralt SA. Myeloid-derived suppressor cells: The green light for myeloma immune escape. Blood Rev 2016; 30:341-8. [PMID: 27132116 DOI: 10.1016/j.blre.2016.04.002] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 03/28/2016] [Accepted: 04/01/2016] [Indexed: 01/04/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous, immature myeloid cell population with the ability to suppress innate and adaptive immune responses that promote tumor growth. MDSCs are increased in patients with multiple myeloma (MM) and have bidirectional interaction with tumors within the MM microenvironment. MM-MDSCs promote MM tumor growth and induce immune suppression; conversely, MM cells induce MDSC development and survival. Although the role of MDSCs in infections, inflammatory diseases and solid tumors has been extensively characterized, their tumor-promoting and immune-suppressive role in MM and the MM microenvironment is only beginning to emerge. The presence and activation of MDSCs in MM patients has been well documented; however, the direct actions and functional consequences of MDSCs on cancer cells is poorly defined. Immunosuppressive MDSCs play an important role in tumor progression primarily because of their capability to promote immune-escape, angiogenesis, drug resistance and metastasis. However, their role in the bone marrow (BM), the primary MM site, is poorly understood. MM remains an incurable malignancy, and it is likely that the BM microenvironment protects MM against chemotherapy agents and the host immune system. A growing body of evidence suggests that host immune cells with a suppressive phenotype contribute to a myeloma immunosuppressive network. Among the known suppressor cells, MDSCs and T regulatory cells (Tregs) have been found to be significantly increased in myeloma patients and their levels correlate with disease stage and clinical outcome. Furthermore, it has been shown that MDSC can mediate suppression of myeloma-specific T-cell responses through the induction of T-cell anergy and Treg development in the MM microenvironment. Here, we review clinical correlations and the preclinical proof-of-principle data on the role of MDSCs in myeloma immunotolerance and highlight the mechanistically relevant MDSC-targeted compounds and their potential utility in a new approach for anti-myeloma therapy.
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Affiliation(s)
- Ehsan Malek
- University Hospitals Case Medical Center, Seidman Cancer Center, Cleveland, OH, USA.
| | - Marcos de Lima
- University Hospitals Case Medical Center, Seidman Cancer Center, Cleveland, OH, USA
| | - John J Letterio
- Department of Pediatrics, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA; The Angie Fowler Adolescent & Young Adult Cancer Institute, Rainbow Babies & Children's Hospital, University Hospitals, Cleveland, OH, USA
| | - Byung-Gyu Kim
- Department of Pediatrics, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA; The Angie Fowler Adolescent & Young Adult Cancer Institute, Rainbow Babies & Children's Hospital, University Hospitals, Cleveland, OH, USA
| | - James H Finke
- Taussig Cancer Institute, Glickman Urological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - James J Driscoll
- Division of Hematology and Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA; The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Sergio A Giralt
- Adult Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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28
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Cui C, Feng H, Shi X, Wang Y, Feng Z, Liu J, Han Z, Fu J, Fu Z, Tong H. Artesunate down-regulates immunosuppression from colorectal cancer Colon26 and RKO cells in vitro by decreasing transforming growth factor β1 and interleukin-10. Int Immunopharmacol 2015; 27:110-21. [DOI: 10.1016/j.intimp.2015.05.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 04/28/2015] [Accepted: 05/03/2015] [Indexed: 11/30/2022]
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Medina-Echeverz J, Vasquez M, Gomar C, Ardaiz N, Berraondo P. Overexpression of apolipoprotein A-I fused to an anti-transforming growth factor beta peptide modulates the tumorigenicity and immunogenicity of mouse colon cancer cells. Cancer Immunol Immunother 2015; 64:717-25. [PMID: 25795134 PMCID: PMC11028610 DOI: 10.1007/s00262-015-1681-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 03/06/2015] [Indexed: 02/01/2023]
Abstract
Transforming growth factor beta (TGF-β) promotes tumor growth, invasion and metastasis in established tumors. In this study, we analyzed the effect of overexpressing an anti-TGF-β peptide fused to apolipoprotein A-I (ApoA-I) as a scaffold molecule. We generated and characterized stable MC38 colon carcinoma clones expressing ApoA-I fused to the anti-TGF-β peptide P144 and ApoA-I as control cells. We evaluated in vitro the gene expression profile, cell cycle and anchorage-independent growth. The in vivo tumorigenic potential and immunogenicity were analyzed inoculating the MC38 clones into C57BL/6 mice, recombination-activating gene 1 knockout mice or mice deficient in NK cells either subcutaneously or intrasplenically to generate hepatic metastases. While overexpression of ApoA-I had no effect on the parameters analyzed, ApoA-I fused to P144 markedly diminished the tumorigenic capacity and metastatic potential of MC38 in vitro and in vivo, thus generating a highly immunogenic cell line. MC38 cells transfected with ApoA-I fused to P144 triggered memory T cell responses able to eliminate the parental cell line upon re-challenge. In summary, expression of ApoA-I fused to P144 is a novel strategy to modulate TGF-β in tumor cells. These results highlight the potential of TGF-β as a target in the development of new antitumor treatments.
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Affiliation(s)
- José Medina-Echeverz
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Avda. Pio XII 55, 31008 Pamplona, Spain
| | - Marcos Vasquez
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Avda. Pio XII 55, 31008 Pamplona, Spain
| | - Celia Gomar
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Avda. Pio XII 55, 31008 Pamplona, Spain
| | - Nuria Ardaiz
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Avda. Pio XII 55, 31008 Pamplona, Spain
| | - Pedro Berraondo
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Avda. Pio XII 55, 31008 Pamplona, Spain
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30
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Workenhe ST, Verschoor ML, Mossman KL. The role of oncolytic virus immunotherapies to subvert cancer immune evasion. Future Oncol 2015; 11:675-89. [DOI: 10.2217/fon.14.254] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
ABSTRACT Despite huge economic and intellectual investments, developing effective cancer treatments continues to be an overarching challenge. Engineered oncolytic viruses (OVs) present self-amplifying immunotherapy platforms capable of preferential cytotoxicity to cancer cells and simultaneous activation of host anti-tumor immunity. In preclinical studies, OVs are showing potent therapeutic effects when used in combination with other immune therapy strategies. In the clinic, the immunotherapeutic effects of OVs are showing promising results. Here we review current strategies for engineering OVs, and present a perspective of future directions within a discussion of the current outcomes of combinatorial approaches with other cancer immunotherapy platforms.
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Affiliation(s)
- Samuel T Workenhe
- Department of Pathology & Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada
| | - Meghan L Verschoor
- Department of Pathology & Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada
| | - Karen L Mossman
- Department of Pathology & Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada
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31
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Neuzillet C, Tijeras-Raballand A, Cohen R, Cros J, Faivre S, Raymond E, de Gramont A. Targeting the TGFβ pathway for cancer therapy. Pharmacol Ther 2014; 147:22-31. [PMID: 25444759 DOI: 10.1016/j.pharmthera.2014.11.001] [Citation(s) in RCA: 491] [Impact Index Per Article: 44.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 09/25/2014] [Indexed: 02/07/2023]
Abstract
The TGFβ signaling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, motility and invasion, extracellular matrix production, angiogenesis, and immune response. TGFβ signaling deregulation is frequent in tumors and has crucial roles in tumor initiation, development and metastasis. TGFβ signaling inhibition is an emerging strategy for cancer therapy. The role of the TGFβ pathway as a tumor-promoter or suppressor at the cancer cell level is still a matter of debate, due to its differential effects at the early and late stages of carcinogenesis. In contrast, at the microenvironment level, the TGFβ pathway contributes to generate a favorable microenvironment for tumor growth and metastasis throughout all the steps of carcinogenesis. Then, targeting the TGFβ pathway in cancer may be considered primarily as a microenvironment-targeted strategy. In this review, we focus on the TGFβ pathway as a target for cancer therapy. In the first part, we provide a comprehensive overview of the roles played by this pathway and its deregulation in cancer, at the cancer cell and microenvironment levels. We go on to describe the preclinical and clinical results of pharmacological strategies to target the TGFβ pathway, with a highlight on the effects on tumor microenvironment. We then explore the perspectives to optimize TGFβ inhibition therapy in different tumor settings.
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Affiliation(s)
- Cindy Neuzillet
- INSERM U728 & U773 and Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France
| | | | - Romain Cohen
- AAREC Filia Research, Translational Department, 1 place Paul Verlaine, 92100 Boulogne-Billancourt, France
| | - Jérôme Cros
- Department of Pathology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France
| | - Sandrine Faivre
- INSERM U728 & U773 and Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France
| | - Eric Raymond
- New Drug Evaluation Laboratory, Centre of Experimental Therapeutics and Medical Oncology, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland
| | - Armand de Gramont
- New Drug Evaluation Laboratory, Centre of Experimental Therapeutics and Medical Oncology, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland.
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32
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Quantitative method for in vitro matrigel invasiveness measurement through image analysis software. Mol Biol Rep 2014; 41:6335-41. [DOI: 10.1007/s11033-014-3556-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 06/20/2014] [Indexed: 10/25/2022]
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33
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Salvo E, Garasa S, Dotor J, Morales X, Peláez R, Altevogt P, Rouzaut A. Combined targeting of TGF-β1 and integrin β3 impairs lymph node metastasis in a mouse model of non-small-cell lung cancer. Mol Cancer 2014; 13:112. [PMID: 24884715 PMCID: PMC4049383 DOI: 10.1186/1476-4598-13-112] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 05/09/2014] [Indexed: 12/31/2022] Open
Abstract
Background Transforming Growth Factor beta (TGF-β) acts as a tumor suppressor early in carcinogenesis but turns into tumor promoter in later disease stages. In fact, TGF-β is a known inducer of integrin expression by tumor cells which contributes to cancer metastatic spread and TGF-β inhibition has been shown to attenuate metastasis in mouse models. However, carcinoma cells often become refractory to TGF-β-mediated growth inhibition. Therefore identifying patients that may benefit from anti-TGF-β therapy requires careful selection. Methods We performed in vitro analysis of the effects of exposure to TGF-β in NSCLC cell chemotaxis and adhesion to lymphatic endothelial cells. We also studied in an orthotopic model of NSCLC the incidence of metastases to the lymph nodes after inhibition of TGF-β signaling, β3 integrin expression or both. Results We offer evidences of increased β3-integrin dependent NSCLC adhesion to lymphatic endothelium after TGF-β exposure. In vivo experiments show that targeting of TGF-β and β3 integrin significantly reduces the incidence of lymph node metastasis. Even more, blockade of β3 integrin expression in tumors that did not respond to TGF-β inhibition severely impaired the ability of the tumor to metastasize towards the lymph nodes. Conclusion These findings suggest that lung cancer tumors refractory to TGF-β monotherapy can be effectively treated using dual therapy that combines the inhibition of tumor cell adhesion to lymphatic vessels with stromal TGF-β inhibition.
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34
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Tumor initiating cells and chemoresistance: which is the best strategy to target colon cancer stem cells? BIOMED RESEARCH INTERNATIONAL 2014; 2014:859871. [PMID: 24527460 PMCID: PMC3914574 DOI: 10.1155/2014/859871] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Accepted: 10/24/2013] [Indexed: 12/12/2022]
Abstract
There is an emerging body of evidence that chemoresistance and minimal residual disease result from selective resistance of a cell subpopulation from the original tumor that is molecularly and phenotypically distinct. These cells are called “cancer stem cells” (CSCs). In this review, we analyze the potential targeting strategies for eradicating CSCs specifically in order to develop more effective therapeutic strategies for metastatic colon cancer. These include induction of terminal epithelial differentiation of CSCs or targeting some genes expressed only in CSCs and involved in self-renewal and chemoresistance. Ideal targets could be cell regulators that simultaneously control the stemness and the resistance of CSCs. Another important aspect of cancer biology, which can also be harnessed to create novel broad-spectrum anticancer agents, is the Warburg effect, also known as aerobic glycolysis. Actually, little is yet known with regard to the metabolism of CSCs population, leaving an exciting unstudied avenue in the dawn of the emerging field of metabolomics.
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Nacif M, Shaker O. Targeting Transforming Growth Factor-<i>β</i> (TGF-<i>β</i>) in Cancer and Non-Neoplastic Diseases. ACTA ACUST UNITED AC 2014. [DOI: 10.4236/jct.2014.57082] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Abstract
Effective antitumor immunity requires the generation and persistence of functional tumor-specific T-cell responses. Among the critical factors that often control these responses is how the antigen is delivered and presented to T cells. The use of peptide-based vaccination has been found to be a promising means to induce antitumor T-cell responses but with limited effects even if the peptide is co-delivered with a potent adjuvant. This limited response could be due to cancer-induced dysfunction in dendritic cells (DC), which play a central role in shaping the quantity and quality of antitumor immunity. Therefore, DC-based peptide delivery of tumor antigen is becoming a potential approach in cancer immunotherapy. In this approach, autologous DC are generated from their precursors in bone marrow or peripheral blood mononuclear cells, loaded with tumor antigen(s) and then infused back to the tumor-bearing host in about 7 days. This DC-based vaccination can act as an antigen delivery vehicle as well as a potent adjuvant, resulting in measurable antitumor immunity in several cancer settings in preclinical and clinical studies. This chapter focuses on DC-based vaccination and how this approach can be more efficacious in cancer immunotherapy.Effective antitumor immunity requires the generation and persistence of functional tumor-specific T-cell responses. Among the critical factors that often control these responses is how the antigen is delivered and presented to T cells. The use of peptide-based vaccination has been found to be a promising means to induce antitumor T-cell responses but with limited effects even if the peptide is co-delivered with a potent adjuvant. This limited response could be due to cancer-induced dysfunction in dendritic cells (DC), which play a central role in shaping the quantity and quality of antitumor immunity. Therefore, DC-based peptide delivery of tumor antigen is becoming a potential approach in cancer immunotherapy. In this approach, autologous DC are generated from their precursors in bone marrow or peripheral blood mononuclear cells, loaded with tumor antigen(s) and then infused back to the tumor-bearing host in about 7 days. This DC-based vaccination can act as an antigen delivery vehicle as well as a potent adjuvant, resulting in measurable antitumor immunity in several cancer settings in preclinical and clinical studies. This chapter focuses on DC-based vaccination and how this approach can be more efficacious in cancer immunotherapy.
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Affiliation(s)
- Mohamed L Salem
- Immunology and Biotechnology Unit, Zoology Department, Faculty of Science, Tanta University, Tanta, Egypt
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Lozano T, Casares N, Lasarte JJ. Searching for the Achilles Heel of FOXP3. Front Oncol 2013; 3:294. [PMID: 24350059 PMCID: PMC3847665 DOI: 10.3389/fonc.2013.00294] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Accepted: 11/18/2013] [Indexed: 01/01/2023] Open
Abstract
FOXP3 is a multifaceted transcription factor with a major role in the control of immune homeostasis mediated by T regulatory cells (Treg). The immunoregulatory function of FOXP3 may hinder the induction of immune responses against cancer and infectious agents, and thus, development of inhibitors of its functions might give new therapeutic opportunities for these diseases. But also, FOXP3 is an important tumor suppressor factor in some types of cancers, and therefore, understanding the structure and function of FOXP3 is crucial to gaining insights into the development of FOXP3-targeted therapeutic strategies. FOXP3 homodimerize and likely form supramolecular complexes which might include hundreds of proteins which constitute the FOXP3 interactome. Many of the functions of FOXP3 are clearly regulated by the interactions with these cofactors contributing importantly on the establishment of Treg-cell signature. We summarize here the structural/functional information on this FOXP3 complex, to identify potential opportunities for the development of new strategies to modulate FOXP3 activity.
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Affiliation(s)
- Teresa Lozano
- Gene Therapy and Hepatology Area, Center for Applied Medical Research (CIMA), University of Navarra , Pamplona , Spain
| | - Noelia Casares
- Gene Therapy and Hepatology Area, Center for Applied Medical Research (CIMA), University of Navarra , Pamplona , Spain
| | - Juan José Lasarte
- Gene Therapy and Hepatology Area, Center for Applied Medical Research (CIMA), University of Navarra , Pamplona , Spain
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Devaud C, John LB, Westwood JA, Darcy PK, Kershaw MH. Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy. Oncoimmunology 2013; 2:e25961. [PMID: 24083084 PMCID: PMC3782527 DOI: 10.4161/onci.25961] [Citation(s) in RCA: 157] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Accepted: 07/29/2013] [Indexed: 12/21/2022] Open
Abstract
There is much promise in the use of immunotherapy for the treatment of cancer. Approaches such as those using antibodies or adoptive cell transfer can mediate complete tumor regression in a proportion of patients. However, the tumor microenvironment can inhibit immune responses leading to ineffective or suboptimal responses of tumors to immunotherapy in the majority of cases. As our knowledge of the tumor microenvironment increases, many strategies are emerging for changing the immunosuppressive nature of the tumor toward a microenvironment able to support immunity. These strategies aim to enhance the ability of immunotherapies to initiate effective immune responses able to destroy tumors. In this article, we review approaches that use immunomodulators specifically to modify the tumor microenvironment, and their use in combination with other immune-based strategies for cancer therapy.
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Affiliation(s)
- Christel Devaud
- Cancer Immunology Research Program; Sir Peter MacCallum Department of Oncology; University of Melbourne; Parkville, VIC Australia
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39
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Stevenson JP, Kindler HL, Papasavvas E, Sun J, Jacobs-Small M, Hull J, Schwed D, Ranganathan A, Newick K, Heitjan DF, Langer CJ, McPherson JM, Montaner LJ, Albelda SM. Immunological effects of the TGFβ-blocking antibody GC1008 in malignant pleural mesothelioma patients. Oncoimmunology 2013; 2:e26218. [PMID: 24179709 PMCID: PMC3812201 DOI: 10.4161/onci.26218] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 08/05/2013] [Accepted: 08/06/2013] [Indexed: 12/14/2022] Open
Abstract
We evaluated a neutralizing anti-TGFβ antibody (GC1008) in cancer patients with malignant pleura mesothelioma (MPM). The goal of this study was to assess immunoregulatory effects in relation to clinical safety and clinical response. Patients with progressive MPM and 1-2 prior systemic therapies received GC1008 at 3mg/kg IV over 90 min every 21 d as part of an open-label, two-center Phase II trial. Following TGFβ blockade therapy, clinical safety and patient survival were monitored along with the effects of anti-TGFβ antibodies on serum biomarkers and peripheral blood mononuclear cells (PBMC). Although designed as a larger trial, only 13 patients were enrolled when the manufacturer discontinued further development of the antibody for oncology indications. All participants tolerated therapy. Although partial or complete radiographic responses were not observed, three patients showed stable disease at 3 mo. GC1008 had no effect in the expression of NK, CD4+, or CD8+ T cell activating and inhibitory markers, other than a decrease in the expression of 2B4 and DNAM-1 on NK cells. However, serum from 5 patients showed new or enhanced levels of antibodies against MPM tumor lysates as measured by immunoblotting. Patients who produced anti-tumor antibodies had increased median overall survival (OS) (15 vs 7.5 mo, p < 0.03) compared with those who did not. To our knowledge, these data represent the first immune analysis of TGFβ- blockade in human cancer patients.
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Affiliation(s)
- James P Stevenson
- Penn Mesothelioma and Pleural Program; Perelman School of Medicine of the University of Pennsylvania; Philadelphia, PA USA
| | - Hedy L Kindler
- Section of Hematology/Oncology; University of Chicago School of Medicine; Chicago, IL USA
| | | | - Jing Sun
- Penn Mesothelioma and Pleural Program; Perelman School of Medicine of the University of Pennsylvania; Philadelphia, PA USA
| | - Mona Jacobs-Small
- Penn Mesothelioma and Pleural Program; Perelman School of Medicine of the University of Pennsylvania; Philadelphia, PA USA
| | - Jennifer Hull
- Section of Hematology/Oncology; University of Chicago School of Medicine; Chicago, IL USA
| | - Daniel Schwed
- Penn Mesothelioma and Pleural Program; Perelman School of Medicine of the University of Pennsylvania; Philadelphia, PA USA
| | - Anjana Ranganathan
- Penn Mesothelioma and Pleural Program; Perelman School of Medicine of the University of Pennsylvania; Philadelphia, PA USA
| | - Kheng Newick
- Penn Mesothelioma and Pleural Program; Perelman School of Medicine of the University of Pennsylvania; Philadelphia, PA USA
| | - Daniel F Heitjan
- Penn Mesothelioma and Pleural Program; Perelman School of Medicine of the University of Pennsylvania; Philadelphia, PA USA
| | - Corey J Langer
- Penn Mesothelioma and Pleural Program; Perelman School of Medicine of the University of Pennsylvania; Philadelphia, PA USA
| | | | | | - Steven M Albelda
- Penn Mesothelioma and Pleural Program; Perelman School of Medicine of the University of Pennsylvania; Philadelphia, PA USA
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40
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Fridlender ZG, Jassar A, Mishalian I, Wang LC, Kapoor V, Cheng G, Sun J, Singhal S, Levy L, Albelda SM. Using macrophage activation to augment immunotherapy of established tumours. Br J Cancer 2013; 108:1288-97. [PMID: 23481183 PMCID: PMC3619255 DOI: 10.1038/bjc.2013.93] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Background: Successful immunotherapy will require alteration of the tumour microenvironment and/or decreased immune suppression. Tumour-associated macrophages (TAMs) are one major factor affecting tumour microenvironment. We hypothesised that altering TAM phenotype would augment the efficacy of immunotherapy. Methods: We and others have reported that 5,6-Dimethylxanthenone-4-acetic-acid (DMXAA, Vadimezan) has the ability to change TAM phenotypes, inducing a tumour microenvironment conducive to antitumour immune responses. We therefore combined DMXAA with active immunotherapies, and evaluated anti-tumour efficacy, immune cell phenotypes (flow cytometry), and tumour microenvironment (RT–PCR). Results: In several different murine models of immunotherapy for lung cancer, DMXAA-induced macrophage activation significantly augmented the therapeutic effects of immunotherapy. By increasing influx of neutrophils and anti-tumour (M1) macrophages to the tumour, DMXAA altered myeloid cell phenotypes, thus changing the intratumoural M2/non-M2 TAM immunoinhibitory ratio. It also altered the tumour microenvironment to be more pro-inflammatory. Modulating macrophages during immunotherapy resulted in increased numbers, activity, and antigen-specificity of intratumoural CD8+ T cells. Macrophage depletion reduced the effect of combining immunotherapy with macrophage activation, supporting the importance of TAMs in the combined effect. Conclusion: Modulating intratumoural macrophages dramatically augmented the effect of immunotherapy. Our observations suggest that addition of agents that activate TAMs to immunotherapy should be considered in future trials.
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Affiliation(s)
- Z G Fridlender
- Institute of Pulmonary Medicine, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel.
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41
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Abstract
Tolerance has been defined as graft-specific survival in the absence of continued immunosuppression. The mechanisms of central and peripheral tolerance are discussed in this review, as well as the barriers and limitations in achieving graft-specific tolerance. The need remains for definitive laboratory assays to determine the presence of a tolerant state. Genetic biomarker analysis pre-transplant may allow for better donor: recipient matching, lessening the need for immunosuppression, while post-transplant analysis of biomarkers, certain cytokines, and regulatory leukocytes may permit minimally invasive assessment of graft function and potentially, of graft-specific tolerance.
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Affiliation(s)
- Colin Brinkman
- Departments of Surgery and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
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Epithelial to mesenchymal transition and cancer stem cell phenotypes leading to liver metastasis are abrogated by the novel TGFβ1-targeting peptides P17 and P144. Exp Cell Res 2012; 319:12-22. [PMID: 23153552 DOI: 10.1016/j.yexcr.2012.11.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2012] [Revised: 10/02/2012] [Accepted: 11/05/2012] [Indexed: 12/15/2022]
Abstract
Colorectal cancer (CRC) frequently metastasizes to the liver, a phenomenon that involves the participation of transforming-growth-factor-β(1) (TGFβ(1)). Blockade of the protumorigenic effects elicited by TGFβ(1) in advanced CRC could attenuate liver metastasis. We aimed in the present study to assess the antimetastatic effect of TGFβ(1)-blocking peptides P17 and P144, and to study mechanisms responsible for this activity in a mouse model. Colon adenocarcinoma cells expressing luciferase were pretreated with TGFβ(1) (Mc38-luc(TGFβ1) cells), injected into the spleen of mice and monitored for tumor development. TGFβ(1) increased primary tumor growth and liver metastasis, whereas systemic treatment of mice with either P17 or P144 significantly reduced tumor burden (p<0.01). In metastatic nodules, mitotic/apoptotic ratio, mesenchymal traits and angiogenesis (evaluated by CD-31, as well as circulating endothelial and progenitor cells) induced by TGFβ(1) were consistently reduced following injection of peptides. In vitro experiments revealed a direct effect of TGFβ(1) in Mc38 cells, which resulted in activation of Smad2, Smad3 and Smad1/5/8, and increased invasion and transendothelial migration, whereas blockade of TGFβ(1)-signaling reverted these features. Because TGFβ(1)-mediated epithelial-mesenchymal transition (EMT) has been suggested to induce a cancer stem cell (CSC) phenotype, we analyzed the ability of this cytokine to induce tumorsphere formation and the expression of CSC markers. In TGFβ(1)-treated cells, tumorspheres were enriched in CD44 and SOX2, which were diminished in the presence of P17. Our data provide a preclinical rationale to evaluate P17 and P144 as potential therapeutic options for the treatment of metastatic CRC.
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43
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Abstract
Many drugs that target transforming growth factor-β (TGFβ) signalling have been developed, some of which have reached Phase III clinical trials for a number of disease applications. Preclinical and clinical studies indicate the utility of these agents in fibrosis and oncology, particularly in augmentation of existing cancer therapies, such as radiation and chemotherapy, as well as in tumour vaccines. There are also reports of specialized applications, such as the reduction of vascular symptoms of Marfan syndrome. Here, we consider why the TGFβ signalling pathway is a drug target, the potential clinical applications of TGFβ inhibition, the issues arising with anti-TGFβ therapy and how these might be tackled using personalized approaches to dosing, monitoring of biomarkers as well as brief and/or localized drug-dosing regimens.
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Affiliation(s)
- Rosemary J Akhurst
- Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94158, USA.
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44
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Wilson S, Levy D. A mathematical model of the enhancement of tumor vaccine efficacy by immunotherapy. Bull Math Biol 2012; 74:1485-500. [PMID: 22438084 DOI: 10.1007/s11538-012-9722-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2011] [Accepted: 03/01/2012] [Indexed: 11/28/2022]
Abstract
TGF-β is an immunoregulatory protein that contributes to inadequate antitumor immune responses in cancer patients. Recent experimental data suggests that TGF-β inhibition alone, provides few clinical benefits, yet it can significantly amplify the anti-tumor immune response when combined with a tumor vaccine. We develop a mathematical model in order to gain insight into the cooperative interaction between anti-TGF-β and vaccine treatments. The mathematical model follows the dynamics of the tumor size, TGF-β concentration, activated cytotoxic effector cells, and regulatory T cells. Using numerical simulations and stability analysis, we study the following scenarios: a control case of no treatment, anti-TGF-β treatment, vaccine treatment, and combined anti-TGF-β vaccine treatments. We show that our model is capable of capturing the observed experimental results, and hence can be potentially used in designing future experiments involving this approach to immunotherapy.
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Affiliation(s)
- Shelby Wilson
- Department of Mathematics and Center for Scientific Computation and Mathematical Modeling (CSCAMM), University of Maryland, College Park, MD 20742, USA.
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45
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Franco OE, Hayward SW. Targeting the tumor stroma as a novel therapeutic approach for prostate cancer. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2012; 65:267-313. [PMID: 22959029 DOI: 10.1016/b978-0-12-397927-8.00009-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Interactions between epithelium and the surrounding stroma are required to maintain organ function. These interactions provide proliferative and migratory restraints that define anatomical and positional information, mediated by growth factors and extracellular matrix components. When cancer develops, transformed cells lose these constraints while stroma adapts and coevolves to support the "function" of the tumor. The prostate is a good example of an organ that relies on its surrounding stroma during normal development and cancer progression. Carcinoma-associated fibroblasts (CAFs) constitute a substantial volume of the tumor stroma and play a pivotal role in tumor maintenance, dissemination, and even drug resistance. The origins of CAF and the exact mechanisms by which they promote tumor progression are still debated. CAF acquire an activated phenotype quite similar to the one seen during wound repair in sites of injury. Here, we describe the CAF ontogeny, the similarities with activated fibroblasts during physiological wound repair, and potential pathways that can be targeted to prevent their appearance in tumors and their protumorigenic functions in cancer progression. A strategy to identify aspects of stromal cell biology for therapeutic targeting is becoming increasingly plausible, driven by the increased understanding of the complex interplays between the cells and tissues of which tumors are comprised. Several preclinical and clinical studies show that targeting the stroma may be a promising and attractive therapeutic option for the treatment of cancer and has the potential to play an increasingly prominent role in future treatment strategies.
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Affiliation(s)
- Omar E Franco
- Department of Urologic Surgery, Vanderbilt University, Nashville, TN, USA
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46
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Understanding the role of cytokines in Glioblastoma Multiforme pathogenesis. Cancer Lett 2011; 316:139-50. [PMID: 22075379 DOI: 10.1016/j.canlet.2011.11.001] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Revised: 10/31/2011] [Accepted: 11/01/2011] [Indexed: 12/16/2022]
Abstract
Cytokines play a significant role in cancer diagnosis, prognosis and therapy. The immune system's failure to recognize the malignant tumor cells and mount an effective response may be the result of tumor-associated cytokine deregulation. Glioblastoma Multiforme (GBM) has a characteristic cytokine expression pattern, and abnormalities in cytokine expression have been implicated in gliomagenesis. Within the heterogeneous GBM microenvironment, the tumor cells, normal brain cells, immune cells, and stem cells interact with each other through the complex cytokine network. This review summarizes the current understanding of the functions of key cytokines on GBM, and highlights potential therapeutic applications targeting these cytokines.
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47
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Zu X, Zhang Q, Cao R, Liu J, Zhong J, Wen G, Cao D. Transforming growth factor-β signaling in tumor initiation, progression and therapy in breast cancer: an update. Cell Tissue Res 2011; 347:73-84. [PMID: 21845401 DOI: 10.1007/s00441-011-1225-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Accepted: 07/22/2011] [Indexed: 01/06/2023]
Abstract
Transforming growth factor-β (TGF-β) is a ubiquitous cytokine playing an essential role in cell proliferation, differentiation, apoptosis, adhesion and invasion, as well as in cellular microenvironment. In malignant diseases, TGF-β signaling features a growth inhibitory effect at an early stage but aggressive oncogenic activity at the advanced malignant state. Here, we update the current understanding of TGF-β signaling in cancer development and progression with a focus on breast cancer. We also review the current approaches of TGF-β signaling-targeted therapeutics for human malignancies.
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Affiliation(s)
- Xuyu Zu
- Clinical Research Institution, First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, People's Republic of China
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48
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Echeverria I, Pereboev A, Silva L, Zabaleta A, Riezu-Boj JI, Bes M, Cubero M, Borras-Cuesta F, Lasarte JJ, Esteban JI, Prieto J, Sarobe P. Enhanced T cell responses against hepatitis C virus by ex vivo targeting of adenoviral particles to dendritic cells. Hepatology 2011; 54:28-37. [PMID: 21452282 DOI: 10.1002/hep.24325] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Accepted: 03/19/2011] [Indexed: 12/31/2022]
Abstract
UNLABELLED Injection of dendritic cells (DCs) presenting viral proteins constitutes a promising approach to stimulate T cell immunity against hepatitis C virus (HCV). Here we describe a strategy to enhance antigen loading and immunostimulatory functions of DCs useful in the preparation of therapeutic vaccines. Incubation of murine DCs with CFm40L, an adapter molecule containing the coxsackie-adenovirus receptor fused to the ecto-domain of murine CD40L-induced DC maturation, produced high amounts of interleukin-12 and up-regulation of molecules associated with T helper 1 responses. Accordingly, targeting of an adenovirus encoding HCV NS3 protein (AdNS3) to DCs with CFm40L strongly enhanced NS3 presentation in vitro, activating interferon-γ-producing T cells. Moreover, immunization of mice with these DCs promoted strong CD4 and CD8 T cell responses against HCV NS3. CFh40L, a similar adapter molecule containing human CD40L, enhanced transduction and maturation of human monocyte-derived DCs. Comparison of DCs transduced with AdNS3 and CFh40L from patients with chronic HCV infection and healthy donors revealed similar maturation levels. More importantly, DCs from the patients induced NS3-specific responses when transduced with AdNS3 and CFh40L but not with AdNS3 alone. CONCLUSION DCs transduced with AdNS3 and the adapter molecule CFm/h40L exhibit enhanced immunostimulatory functions, induce robust anti-HCV NS3 immunity in animals, and can induce antiviral immune responses in subjects with chronic HCV infection. This strategy may serve as therapeutic vaccination for patients with chronic hepatitis C.
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Affiliation(s)
- Itziar Echeverria
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
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49
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Aranda F, Llopiz D, Díaz-Valdés N, Riezu-Boj JI, Bezunartea J, Ruiz M, Martínez M, Durantez M, Mansilla C, Prieto J, Lasarte JJ, Borrás-Cuesta F, Sarobe P. Adjuvant combination and antigen targeting as a strategy to induce polyfunctional and high-avidity T-cell responses against poorly immunogenic tumors. Cancer Res 2011; 71:3214-24. [PMID: 21402711 DOI: 10.1158/0008-5472.can-10-3259] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Low antigen expression and an absence of coimmunostimulatory signals may be partly responsible for the low immunogenicity of many tumors. It may be possible to overcome this situation by defining a combination of adjuvants and antigens that can activate a high-avidity antitumor response. Using the poorly immunogenic B16-OVA melanoma cells as tumor model, we tested different combinations of adjuvants and antigens to treat established tumors. In the absence of exogenous antigens, repeated administration of the TLR7 ligand Imiquimod together with anti-CD40 agonistic antibodies activated only innate immunity, which was insufficient to reject intradermal tumors. Administering this adjuvant combination together with OVA as a tumor antigen induced T-cell responses that delayed tumor growth. However, administering a combination of anti-CD40 plus TLR3 and TLR7 ligands, together with antigen targeting to dendritic cells through TLR4, was sufficient to induce tumor rejection in 50% of mice. This response was associated with a greater activation of innate immunity and induction of high-avidity polyfunctional CD8(+) T-cell responses, which each contributed to tumor rejection. This therapy activated T-cell responses not only against OVA, which conferred protection against a rechallenge with B16-OVA cells, but also activated T-cell responses against other melanoma-associated antigens. Our findings support the concept that multiple adjuvant combination and antigen targeting may be a useful immunotherapeutic strategy against poorly immunogenic tumors.
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Affiliation(s)
- Fernando Aranda
- University of Navarra, Center for Applied Medical Research, Pamplona, Spain
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50
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Díaz-Valdés N, Basagoiti M, Dotor J, Aranda F, Monreal I, Riezu-Boj JI, Borrás-Cuesta F, Sarobe P, Feijoó E. Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression. Cancer Res 2010; 71:812-21. [PMID: 21159663 DOI: 10.1158/0008-5472.can-10-2698] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Melanoma progression is associated with the expression of different growth factors, cytokines, and chemokines. Because TGFβ1 is a pleiotropic cytokine involved not only in physiologic processes but also in cancer development, we analyzed in A375 human melanoma cells, the effect of TGFβ1 on monocyte chemoattractant protein-1 (MCP-1) and interleukin-10 (IL-10) expression, two known factors responsible for melanoma progression. TGFβ1 increased the expression of MCP-1 and IL-10 in A375 cells, an effect mediated by the cross-talk between Smad, PI3K (phosphoinositide 3-kinase)/AKT, and BRAF-MAPK (mitogen activated protein kinase) signaling pathways. Supernatants from TGFβ1-treated A375 cells enhanced MCP-1-dependent migration of monocytes, which, in turn, expressed high levels of TGF,β1, bFGF, and VEGF mRNA. Moreover, these supernatants also inhibited functional properties of dendritic cells through IL-10-dependent mechanisms. When using in vitro, the TGFβ1-blocking peptide P144, TGFβ1-dependent Smad3 phosphorylation, and expression of MCP-1 and IL-10 were inhibited. In vivo, treatment of A375 tumor-bearing athymic mice with P144 significantly reduced tumor growth, associated with a lower macrophage infiltrate and decreased intratumor MCP-1 and VEGF levels, as well as angiogenesis. Finally, in C57BL/6 mice with B16-OVA melanoma tumors, when administered with immunotherapy, P144 decreased tumor growth and intratumor IL-10 levels, linked to enhanced activation of dendritic cells and natural killer cells, as well as anti-OVA T-cell responses. These results show new effects of TGFβ1 on melanoma cells, which promote tumor progression and immunosuppression, strongly reinforcing the relevance of this cytokine as a molecular target in melanoma.
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Affiliation(s)
- Nancy Díaz-Valdés
- Universidad de Navarra, Centro de Investigación Médica Aplicada, Área de Hepatología y Terapia Génica, Pamplona, Spain
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