|
1
|
Qin Z, Li Y, Shao X, Li K, Bai Y, Wang B, Ma F, Shi W, Song L, Zhuang A, He F, Ding C, Yang W. HNF4A functions as a hepatocellular carcinoma oncogene or tumor suppressor depending upon the AMPK pathway activity status. Cancer Lett 2025; 623:217732. [PMID: 40254090 DOI: 10.1016/j.canlet.2025.217732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 04/10/2025] [Accepted: 04/17/2025] [Indexed: 04/22/2025]
Abstract
Cancer cells frequently undergo energy metabolic stress induced by the increased dynamics of nutrient supply. Hepatocyte nuclear factor 4A (HNF4A) is a master transcription factor (TF) in hepatocytes that regulates metabolism and differentiation. However, the mechanism underlying how HNF4A functions in cancer progression remains unclear due to conflicting results observed in numerous studies. To address the roles of HNF4A in hepatocellular carcinoma (HCC), we investigated the regulatory functions of HNF4A in HCC cells under different glucose supply conditions. We found that HNF4A exhibited tumor-suppressive effects on the proliferation and migration of HCC cells in glucose-sufficient conditions and tumor-promotive effects on HCC cells in glucose-insufficient conditions. Further investigation revealed that this diverse function of HNF4A was dependent upon the AMPK pathway activity. Similarly, the prognosis predicted by HNF4A was also correlated with whether the AMPKa expression levels were low or high in clinical HCC patients. Multiomics approaches consisting of proteomics and ChIP-seq revealed that key HNF4A target genes, including NEDD4 and RPS6KA2, are involved in the diverse function of HNF4A in HCC in response to the AMPK activity status. Specifically, HNF4A could bind to the promoter region of NEDD4 and RPS6KA2, and upregulating their expression. Our study has demonstrated the relationship between and synergism of AMPK and HNF4A in the progression of HCC under diverse nutrient conditions.
Collapse
Affiliation(s)
- Zhaoyu Qin
- Department of Pediatric Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Yan Li
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Xiexiang Shao
- Department of Pediatric Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Kai Li
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Yihe Bai
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Bing Wang
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Fahan Ma
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Wenhao Shi
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China; School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Lei Song
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China
| | - Aojia Zhuang
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Fuchu He
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China; School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Chen Ding
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China
| | - Wenjun Yang
- Department of Pediatric Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
| |
Collapse
|
|
2
|
Zeng Y, Tao Y, Du G, Huang T, Chen S, Fan L, Zhang N. Advances in the mechanisms of HIF-1α-enhanced tumor glycolysis and its relation to dedifferentiation. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2025; 197:1-10. [PMID: 40373959 DOI: 10.1016/j.pbiomolbio.2025.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 05/07/2025] [Accepted: 05/12/2025] [Indexed: 05/17/2025]
Abstract
Metabolic reprogramming, a hallmark of malignancy, enables tumor cells to adapt to the harsh and dynamic tumor microenvironment (TME) by altering metabolic pathways. Hypoxia, prevalent in solid tumors, activates hypoxia inducible factor 1α (HIF-1α). HIF-1α drives metabolic reprogramming, enhancing glycolysis primarily through the Warburg effect to reduce oxygen dependence and facilitate tumor cell growth/proliferation. The above process is associated with accelerated tumor cell dedifferentiation and enhanced stemness, generating cancer stem cells (CSCs) which possesses the potential for self-renewal and differentiation that can differentiate into a wide range of subtypes of tumor cells and fuel tumor heterogeneity, metastasis, and recurrence, complicating therapy. This review examines the HIF-1α-glycolysis-dedifferentiation crosstalk mechanisms, expecting that indirect inhibition of HIF-1α by targeting metabolic enzymes, metabolites, or their signaling pathways will offer an effective therapeutic strategy to improve the cancer treatment outcomes.
Collapse
Affiliation(s)
- Yu Zeng
- Department of Urology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yonggang Tao
- Department of Urology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Guotu Du
- Department of Urology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Tianyu Huang
- Department of Urology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Shicheng Chen
- Department of Urology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Longmei Fan
- Department of Urology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Neng Zhang
- Department of Urology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
| |
Collapse
|
|
3
|
Kananivand M, Nouri F, Yousefi MH, Pajouhi A, Ghorbani H, Afkhami H, Razavi ZS. Mesenchymal stem cells and their exosomes: a novel approach to skin regeneration via signaling pathways activation. J Mol Histol 2025; 56:132. [PMID: 40208456 DOI: 10.1007/s10735-025-10394-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 03/06/2025] [Indexed: 04/11/2025]
Abstract
Accelerating wound healing is a crucial objective in surgical and regenerative medicine. The wound healing process involves three key stages: inflammation, cell proliferation, and tissue repair. Mesenchymal stem cells (MSCs) have demonstrated significant therapeutic potential in promoting tissue regeneration, particularly by enhancing epidermal cell migration and proliferation. However, the precise molecular mechanisms underlying MSC-mediated wound healing remain unclear. This review highlights the pivotal role of MSCs and their exosomes in wound repair, with a specific focus on critical signaling pathways, including PI3K/Akt, WNT/β-catenin, Notch, and MAPK. These pathways regulate essential cellular processes such as proliferation, differentiation, and angiogenesis. Moreover, in vitro and in vivo studies reveal that MSCs accelerate wound closure, enhance collagen deposition, and modulate immune responses, contributing to improved tissue regeneration. Understanding these mechanisms provides valuable insights into MSC-based therapeutic strategies for enhancing wound healing.
Collapse
Affiliation(s)
- Maryam Kananivand
- Medical Department, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Nouri
- Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University (SRBIAU), Tehran, Iran
| | - Mohammad Hasan Yousefi
- Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Student Research Committee, Qom University of Medical Sciences, Qom, Iran
| | - Ali Pajouhi
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Hakimeah Ghorbani
- Department of Sciences, Faculty of Biological Sciences, Tabriz University of Sciences, Tabriz, Iran
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran.
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran.
- Student Research Committee, Qom University of Medical Sciences, Qom, Iran.
| | - Zahra Sadat Razavi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
4
|
Nishida A, Andoh A. The Role of Inflammation in Cancer: Mechanisms of Tumor Initiation, Progression, and Metastasis. Cells 2025; 14:488. [PMID: 40214442 PMCID: PMC11987742 DOI: 10.3390/cells14070488] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 03/14/2025] [Accepted: 03/20/2025] [Indexed: 04/14/2025] Open
Abstract
Inflammation is an essential component of the immune response that protects the host against pathogens and facilitates tissue repair. Chronic inflammation is a critical factor in cancer development and progression. It affects every stage of tumor development, from initiation and promotion to invasion and metastasis. Tumors often create an inflammatory microenvironment that induces angiogenesis, immune suppression, and malignant growth. Immune cells within the tumor microenvironment interact actively with cancer cells, which drives progression through complex molecular mechanisms. Chronic inflammation is triggered by factors such as infections, obesity, and environmental toxins and is strongly linked to increased cancer risk. However, acute inflammatory responses can sometimes boost antitumor immunity; thus, inflammation presents both challenges and opportunities for therapeutic intervention. This review examines how inflammation contributes to tumor biology, emphasizing its dual role as a critical factor in tumorigenesis and as a potential therapeutic target.
Collapse
Affiliation(s)
- Atsushi Nishida
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Shiga, Japan;
| | | |
Collapse
|
|
5
|
Dhamdhere SG, Bansal A, Singh P, Kakani P, Agrawal S, Samaiya A, Shukla S. Hypoxia-induced ATF3 escalates breast cancer invasion by increasing collagen deposition via P4HA1. Cell Death Dis 2025; 16:142. [PMID: 40016181 PMCID: PMC11868403 DOI: 10.1038/s41419-025-07461-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 02/10/2025] [Accepted: 02/18/2025] [Indexed: 03/01/2025]
Abstract
Activating transcription factors (ATFs), members of the adaptive-response gene family, participate in cellular processes to aid adaptations in response to extra and/or intracellular changes. In this study, we observed that one of the ATFs, Activating transcription factor 3 (ATF3), is upregulated under hypoxia via alterations in the epigenetic landscape of its promoter, followed by transcriptional upregulation. Under hypoxic conditions, Hypoxia-inducible factor 1-alpha (HIF1ɑ) alleviates methylation at the ATF3 promoter by recruiting TET1 and induces ATF3 transcription. In addition, our RNA-seq analysis showed that ATF3 globally affects transcription under hypoxia and controls the processes of EMT and cancer invasion by stimulating the transcription of Prolyl 4-Hydroxylase Subunit Alpha 1 (P4HA1), an enzyme which enhances invasion-conducive extracellular matrix (ECM) under hypoxic conditions. Prolyl hydroxylases play a critical role in the hydroxylation and deposition of collagen in the extracellular matrix (ECM) during the evolution of cancer, which is necessary for metastasis. Importantly, P4HA1 undergoes alternative splicing under hypoxia, where the inclusion of exon 9a is increased. Interestingly, involvement of ATF3 in P4HA1 splicing was also evident, as binding of ATF3 at intron 9a led to demethylation of this DNA region via recruitment of TET1. Furthermore, we also show that the demethylated DNA region of intron 9a then becomes accessible to CCCTC-binding factor (CTCF). Thus, a cascade of demethylation via ATF3 recruited TET1, followed by increased RNA Pol II pause at intron 9a via CTCF, leads to inclusion of exon 9a. The P4HA1 9a isoform leads to enhanced invasion under hypoxic conditions by increasing deposition of collagen in the ECM. These results reveal a novel hypoxia-induced HIF1ɑ-ATF3-P4HA1 axis which can potentially be exploited as a therapeutic target to impede EMT and ultimately breast cancer invasion. Hypoxia induced ATF3 regulates P4HA1 expression and alternative splicing to promote breast cancer invasion.
Collapse
Affiliation(s)
- Shruti Ganesh Dhamdhere
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh, 462066, India
| | - Anamika Bansal
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh, 462066, India
| | - Pranjal Singh
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh, 462066, India
| | - Parik Kakani
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh, 462066, India
| | - Shruti Agrawal
- Department of Pathology, Bansal Hospital, Bhopal, Madhya Pradesh, 462016, India
| | - Atul Samaiya
- Department of Surgical Oncology, Bansal Hospital, Bhopal, Madhya Pradesh, 462016, India
| | - Sanjeev Shukla
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh, 462066, India.
| |
Collapse
|
|
6
|
Zhang G, Yan S, Liu Y, Du Z, Min Q, Qin S. PROTACs coupled with oligonucleotides to tackle the undruggable. Bioanalysis 2025; 17:261-276. [PMID: 39895280 PMCID: PMC11864318 DOI: 10.1080/17576180.2025.2459528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Accepted: 01/24/2025] [Indexed: 02/04/2025] Open
Abstract
Undruggable targets account for roughly 85% of human disease-related targets and represent a category of therapeutic targets that are difficult to tackle with traditional methods, but their considerable clinical importance. These targets are generally defined by planar functional interfaces and the absence of efficient ligand-binding pockets, making them unattainable for conventional pharmaceutical strategies. The advent of oligonucleotide-based proteolysis-targeting chimeras (PROTACs) has instilled renewed optimism in addressing these challenges. These PROTACs facilitate the targeted degradation of undruggable entities, including transcription factors (TFs) and RNA-binding proteins (RBPs), via proteasome-dependent mechanisms, thereby presenting novel therapeutic approaches for diseases linked to these targets. This review offers an in-depth examination of recent progress in the integration of PROTAC technology with oligonucleotides to target traditionally undruggable proteins, emphasizing the design principles and mechanisms of action of these innovative PROTACs.
Collapse
Affiliation(s)
- Guangshuai Zhang
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, P.R.China
| | - Si Yan
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, P.R.China
| | - Yan Liu
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, P.R.China
| | - Ziwei Du
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, P.R.China
| | - Qin Min
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, P.R.China
| | - Shuanglin Qin
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, P.R.China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Research Center for Precision Medication of Chinese Medicine, FuRong Laboratory, Hunan University of Chinese Medicine, Changsha, P.R. China
| |
Collapse
|
|
7
|
Ko HH, Chou HYE, Hou HH, Kuo WT, Liu WW, Yen-Ping Kuo M, Cheng SJ. Oleanolic acid inhibits aldo-keto reductase family 1 member B10-induced cancer stemness and avoids cisplatin-based chemotherapy resistance via the Snail signaling pathway in oral squamous cell carcinoma cell lines. J Dent Sci 2025; 20:100-108. [PMID: 39873100 PMCID: PMC11762581 DOI: 10.1016/j.jds.2024.09.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 09/22/2024] [Indexed: 01/30/2025] Open
Abstract
Background/purpose Oral squamous cell carcinoma (OSCC) is a common malignancy often associated with poor prognosis due to chemoresistance. In this study, we investigated whether arecoline, a major alkaloid in betel nuts, can stimulate aldo-keto reductase family 1 member B10 (AKR1B10) levels in OSCC, promoting cancer stemness and leading to resistance to cisplatin (CDDP)-based chemotherapy. Materials and methods Gain- and Loss- of AKR1B10 functions were analyzed using WB and q-PCR of OSCC cells. Stemness, epithelial mesenchymal transition (EMT) markers, and CDDP drug resistance in overexpressed AKR1B10 were also identified. Results Upregulated AKR1B10 in OSCC significantly increased cell motility and aggregation. The results also showed that the canonical TGF-β1-Smad3 pathway was involved in arecoline-induced AKR1B10 expression, further increasing cancer stemness with CDDP resistance via the Snail-dependent EMT pathway. Moreover, oleanolic acid (OA) and ROS/RNS (reactive oxygen/nitrogen species) inhibitors effectively reversed AKR1B10-induced CDDP-resistance. Conclusion Arecoline-induced ROS/RNS to hyper-activate AKR1B10 in tumor sphere cells via the TGF-β1-Smad3 pathway. Furthermore, AKR1B10 enhanced CDDP resistance in OSCC cells via EMT-inducing markers. Finally, Finally, OA may efficiently target CDDP resistance, reverse stemness in OSCC cells, and have the potential as a novel anticancer drug.
Collapse
Affiliation(s)
- Hui-Hsin Ko
- Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan
| | - Han-Yi E. Chou
- School of Dentistry, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan
- Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan
| | - Hsin-Han Hou
- School of Dentistry, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan
- Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan
| | - Wei-Ting Kuo
- School of Dentistry, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan
- Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan
| | - Wei-Wen Liu
- School of Dentistry, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan
- Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan
| | - Mark Yen-Ping Kuo
- Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan
- School of Dentistry, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan
| | - Shih-Jung Cheng
- Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan
- School of Dentistry, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan
- Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan
| |
Collapse
|
|
8
|
Nisar H, Brauny M, Labonté FM, Schmitz C, Konda B, Hellweg CE. DNA Damage and Inflammatory Response of p53 Null H358 Non-Small Cell Lung Cancer Cells to X-Ray Exposure Under Chronic Hypoxia. Int J Mol Sci 2024; 25:12590. [PMID: 39684302 DOI: 10.3390/ijms252312590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/13/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024] Open
Abstract
Hypoxia-induced radioresistance limits therapeutic success in cancer. In addition, p53 mutations are widespread in tumors including non-small cell lung carcinomas (NSCLCs), and they might modify the radiation response of hypoxic tumor cells. We therefore analyzed the DNA damage and inflammatory response in chronically hypoxic (1% O2, 48 h) p53 null H358 NSCLC cells after X-ray exposure. We used the colony-forming ability assay to determine cell survival, γH2AX immunofluorescence microscopy to quantify DNA double-strand breaks (DSBs), flow cytometry of DAPI-stained cells to measure cell cycle distribution, ELISAs to quantify IL-6 and IL-8 secretion in cell culture supernatants, and RNA sequencing to determine gene expression. Chronic hypoxia increased the colony-forming ability and radioresistance of H358 cells. It did not affect the formation or resolution of X-ray-induced DSBs. It reduced the fraction of cells undergoing G2 arrest after X-ray exposure and delayed the onset of G2 arrest. Hypoxia led to an earlier enhancement in cytokines secretion rate after X-irradiation compared to normoxic controls. Gene expression changes were most pronounced after the combined exposure to hypoxia and X-rays and pertained to senescence and different cell death pathways. In conclusion, hypoxia-induced radioresistance is present despite the absence of functional p53. This resistance is related to differences in clonogenicity, cell cycle regulation, cytokine secretion, and gene expression under chronic hypoxia, but not to differences in DNA DSB repair kinetics.
Collapse
Affiliation(s)
- Hasan Nisar
- Department of Radiation Biology, Institute of Aerospace Medicine, German Aerospace Center (DLR), 51147 Cologne, Germany
- Department of Medical Sciences, Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad 44000, Pakistan
| | - Melanie Brauny
- Department of Radiation Biology, Institute of Aerospace Medicine, German Aerospace Center (DLR), 51147 Cologne, Germany
- Interfaculty Institute of Microbiology and Infection Medicine, Faculty of Science & Faculty of Medicine, University of Tübingen, 72074 Tübingen, Germany
| | - Frederik M Labonté
- Department of Radiation Biology, Institute of Aerospace Medicine, German Aerospace Center (DLR), 51147 Cologne, Germany
- Department of Biology, Faculty of Mathematics and Natural Sciences, University of Cologne, 50923 Cologne, Germany
| | - Claudia Schmitz
- Department of Radiation Biology, Institute of Aerospace Medicine, German Aerospace Center (DLR), 51147 Cologne, Germany
| | - Bikash Konda
- Department of Radiation Biology, Institute of Aerospace Medicine, German Aerospace Center (DLR), 51147 Cologne, Germany
| | - Christine E Hellweg
- Department of Radiation Biology, Institute of Aerospace Medicine, German Aerospace Center (DLR), 51147 Cologne, Germany
| |
Collapse
|
|
9
|
Rong Y, Ning Y, Zhu J, Feng P, Zhu W, Zhao X, Xiong Z, Ruan C, Jin J, Wang H, Cai T, Zhang S, Yang Y. Oncolytic adenovirus encoding decorin and CD40 ligand inhibits tumor growth and liver metastasis via immune activation in murine colorectal tumor model. MOLECULAR BIOMEDICINE 2024; 5:39. [PMID: 39306655 PMCID: PMC11416448 DOI: 10.1186/s43556-024-00202-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 08/20/2024] [Indexed: 09/25/2024] Open
Abstract
Colorectal cancer (CRC) is the second common cause of cancer mortality worldwide, and it still lacks effective approaches for relapsed and metastatic CRC. Recently, oncolytic virus has been emerged as a promising immune therapeutic strategy. In this study, we develop a novel oncolytic adenovirus, rAd.mDCN.mCD40L, which drive oncolytic activity by telomerase reverse transcriptase promoter (TERTp). rAd.mDCN.mCD40L expressed both mouse genes of decorin (mDCN) and CD40 ligand (mCD40L), and produced effective cytotoxicity in both human and mouse CRC cells. Moreover, oncolytic adenovirus mediated mDCN over-expression inhibited Met expression in vitro. In CT26 subcutaneous tumor model, intratumorally delivery of oncolytic adenoviruses could inhibit tumor growth and liver metastasis, while mDCN and/or mCD40L armed oncolytic adenoviruses produced much more impressive responses. No obvious toxicity was detected in lung, liver and spleen. Moreover, mDCN and/or mCD40L armed oncolytic adenoviruses altered the immune state to activate anti-tumor responses, including increasing CD8+ T effector cells and CD4+ memory T cells, reducing MDSCs and Tregs in peripheral blood. Furthermore, mDCN and/or mCD40L armed oncolytic adenoviruses mediated mDCN and/or mCD40L expression in tumors, and up-regulated Th1 cytokines and reduced Th2 cytokines in tumors, which will be benefit for remodeling tumor microenvironment. Importantly, rAd.mDCN.mCD40L and rAd.mCD40L prevented tumor liver metastasis much more effectively than rAd.Null and rAd.mDCN. Therefore, rAd.mDCN.mCD40L and rAd.mCD40L are promising approaches for CRC therapy.
Collapse
Affiliation(s)
- Yejing Rong
- Department of Experimental Medical Science, Ningbo No.2 Hospital, Ningbo, 315010, China
| | - Yingjun Ning
- Department of Experimental Medical Science, Ningbo No.2 Hospital, Ningbo, 315010, China
| | - Jianping Zhu
- Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | - Pei Feng
- Ningbo Qianyang Talent Service Co., Ltd, Ningbo, 315020, China
| | - Weixin Zhu
- Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, 315032, China
| | - Xin Zhao
- Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, 315032, China
| | - Zi Xiong
- Department of Experimental Medical Science, Ningbo No.2 Hospital, Ningbo, 315010, China
| | - Chunyan Ruan
- Department of Experimental Medical Science, Ningbo No.2 Hospital, Ningbo, 315010, China
| | - Jiachang Jin
- Jiangbei Center For Disease Control and Prevention Ningbo, Ningbo, 315020, China
| | - Hua Wang
- Department of Experimental Haematology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, China
| | - Ting Cai
- Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, 315032, China.
| | - Shun Zhang
- Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, 315032, China.
| | - Yuefeng Yang
- Department of Experimental Medical Science, Ningbo No.2 Hospital, Ningbo, 315010, China.
| |
Collapse
|
|
10
|
Kumar A, Saha L. Colorectal cancer cell dormancy: An insight into pathways. World J Gastroenterol 2024; 30:3810-3817. [PMID: 39351431 PMCID: PMC11438629 DOI: 10.3748/wjg.v30.i33.3810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 07/23/2024] [Accepted: 07/26/2024] [Indexed: 09/02/2024] Open
Abstract
Cancer cell dormancy (CCD) in colorectal cancer (CRC) poses a significant challenge to effective treatment. In CRC, CCD contributes to tumour recurrence, drug resistance, and amplifying the disease's burden. The molecular mechanisms governing CCD and strategies for eliminating dormant cancer cells remain largely unexplored. Therefore, understanding the molecular mechanisms governing dormancy is crucial for improving patient outcomes and developing targeted therapies. This editorial highlights the complex interplay of signalling pathways and factors involved in colorectal CCD, emphasizing the roles of Hippo/YAP, pluripotent transcription factors such as NANOG, HIF-1α signalling, and Notch signalling pathways. Additionally, ERK/p38α/β/MAPK pathways, AKT signalling pathway, and Extracellular Matrix Metalloproteinase Inducer, along with some potential less explored pathways such as STAT/p53 switch and canonical and non-canonical Wnt and SMAD signalling, are also involved in promoting colorectal CCD. Highlighting their clinical significance, these findings may offer the potential for identifying key dormancy regulator pathways, improving treatment strategies, surmounting drug resistance, and advancing personalized medicine approaches. Moreover, insights into dormancy mechanisms could lead to the development of predictive biomarkers for identifying patients at risk of recurrence and the tailoring of targeted therapies based on individual dormancy profiles. It is essential to conduct further research into these pathways and their modulation to fully comprehend CRC dormancy mechanisms and enhance patient outcomes.
Collapse
Affiliation(s)
- Anil Kumar
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Lekha Saha
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| |
Collapse
|
|
11
|
Lou W, Xiao S, Lin K. Identification of a hypoxia-suppressed lncRNA RAMP2-AS1 in breast cancer. Noncoding RNA Res 2024; 9:782-795. [PMID: 38590436 PMCID: PMC10999373 DOI: 10.1016/j.ncrna.2024.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 01/08/2024] [Accepted: 02/06/2024] [Indexed: 04/10/2024] Open
Abstract
Hypoxia is a critical feature of solid tumors and exerts crucial roles in cancers, including breast cancer. However, the detailed relationship between lncRNA-miRNA-mRNA triple network and hypoxia in breast cancer is still indistinct. In this study, a series of in silico analyses and online databases or tools were employed to establish a hypoxia-related lncRNA-miRNA-mRNA network in breast cancer based on competing endogenous RNA mechanism at single-cell resolution. RAMP2-AS1 was, eventually, identified as the most potential lncRNA, which was significantly negatively associated with hypoxia in breast cancer. Compared with normal controls, RAMP2-AS1 was markedly downregulated in breast cancer. Moreover, survival analysis revealed favorable prognostic values of RAMP2-AS1 in total or in specific clinicopathological breast cancer patients. Next, miR-660-5p, miR-2277-5p and miR-1301-3p, upregulated and possessed poor prognostic values in breast cancer, were identified as three potential downstream miRNAs of RAMP2-AS1. Then, the most potential downstream hypoxia-related genes (ATM and MYH11) of RAMP2-AS1/miRNA axis in breast cancer were screened out. Intriguingly, in vitro experiments confirmed that RAMP2-AS1 was a hypoxia-suppressed lncRNA and miR-660-5p/ATM was a potential downstream axis of RAMP2-AS1 in breast cancer. Collectively, our current data elucidated a key hypoxia-suppressed lncRNA RAMP2-AS1 and its possible miRNA-mRNA regulatory mechanism in breast cancer.
Collapse
Affiliation(s)
- Weiyang Lou
- Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China
| | - Shuyuan Xiao
- Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Kuailu Lin
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325015, China
| |
Collapse
|
|
12
|
Li S, Sheng J, Zhang D, Qin H. Targeting tumor-associated macrophages to reverse antitumor drug resistance. Aging (Albany NY) 2024; 16:10165-10196. [PMID: 38787372 PMCID: PMC11210230 DOI: 10.18632/aging.205858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 04/22/2024] [Indexed: 05/25/2024]
Abstract
Currently, antitumor drugs show limited clinical outcomes, mainly due to adaptive resistance. Clinical evidence has highlighted the importance of the tumor microenvironment (TME) and tumor-associated macrophages (TAMs) in tumor response to conventional antitumor drugs. Preclinical studies show that TAMs following antitumor agent can be reprogrammed to an immunosuppressive phenotype and proangiogenic activities through different mechanisms, mediating drug resistance and poor prognosis. Potential extrinsic inhibitors targeting TAMs repolarize to an M1-like phenotype or downregulate proangiogenic function, enhancing therapeutic efficacy of anti-tumor therapy. Moreover, pharmacological modulation of macrophages that restore the immune stimulatory characteristics is useful to reshaping the tumor microenvironment, thus further limiting tumor growth. This review aims to introduce macrophage response in tumor therapy and provide a potential therapeutic combination strategy of TAM-targeting immunomodulation with conventional antitumor drugs.
Collapse
Affiliation(s)
- Sheng Li
- The Second Hospital of Jilin University, Changchun, China
| | - Jiyao Sheng
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, China
| | - Dan Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, China
| | - Hanjiao Qin
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
13
|
Zhi S, Chen C, Huang H, Zhang Z, Zeng F, Zhang S. Hypoxia-inducible factor in breast cancer: role and target for breast cancer treatment. Front Immunol 2024; 15:1370800. [PMID: 38799423 PMCID: PMC11116789 DOI: 10.3389/fimmu.2024.1370800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 04/26/2024] [Indexed: 05/29/2024] Open
Abstract
Globally, breast cancer stands as the most prevalent form of cancer among women. The tumor microenvironment of breast cancer often exhibits hypoxia. Hypoxia-inducible factor 1-alpha, a transcription factor, is found to be overexpressed and activated in breast cancer, playing a pivotal role in the anoxic microenvironment by mediating a series of reactions. Hypoxia-inducible factor 1-alpha is involved in regulating downstream pathways and target genes, which are crucial in hypoxic conditions, including glycolysis, angiogenesis, and metastasis. These processes significantly contribute to breast cancer progression by managing cancer-related activities linked to tumor invasion, metastasis, immune evasion, and drug resistance, resulting in poor prognosis for patients. Consequently, there is a significant interest in Hypoxia-inducible factor 1-alpha as a potential target for cancer therapy. Presently, research on drugs targeting Hypoxia-inducible factor 1-alpha is predominantly in the preclinical phase, highlighting the need for an in-depth understanding of HIF-1α and its regulatory pathway. It is anticipated that the future will see the introduction of effective HIF-1α inhibitors into clinical trials, offering new hope for breast cancer patients. Therefore, this review focuses on the structure and function of HIF-1α, its role in advancing breast cancer, and strategies to combat HIF-1α-dependent drug resistance, underlining its therapeutic potential.
Collapse
Affiliation(s)
| | | | | | | | - Fancai Zeng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China
| | - Shujun Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China
| |
Collapse
|
|
14
|
Hefny SM, El-Moselhy TF, El-Din N, Giovannuzzi S, Bin Traiki T, Vaali-Mohammed MA, El-Dessouki AM, Yamaguchi K, Sugiura M, Shaldam MA, Supuran CT, Abdulla MH, Eldehna WM, Tawfik HO. Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles. J Med Chem 2024; 67:7406-7430. [PMID: 38642371 DOI: 10.1021/acs.jmedchem.4c00239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/22/2024]
Abstract
A dual-targeting approach is predicted to yield better cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles (5a-h, 6, and 7a-e) were designed and constructed as potential carbonic anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions of the target compounds were assessed against CA isoforms IX and VEGFR-2. The assay results showed that coumarin-based thiazoles 5a, 5d, and 5e can effectively inhibit both targets. 5a, 5d, and 5e cytotoxic effects were tested on pancreatic, breast, and prostate cancer cells (PANC1, MCF7, and PC3). Further mechanistic investigation disclosed the ability of 5e to interrupt the PANC1 cell progression in the S stage by triggering the apoptotic cascade, as seen by increased levels of caspases 3, 9, and BAX, alongside the Bcl-2 decline. Moreover, the in vivo efficacy of compound 5e as an antitumor agent was evaluated. Also, molecular docking and dynamics displayed distinctive interactions between 5e and CA IX and VEGFR-2 binding pockets.
Collapse
Affiliation(s)
- Salma M Hefny
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
| | - Tarek F El-Moselhy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
| | - Nabaweya El-Din
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
| | - Simone Giovannuzzi
- Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze Italy
| | - Thamer Bin Traiki
- Department of Surgery, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | | | - Ahmed M El-Dessouki
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, sixth of October City, Giza 12566, Egypt
| | - Koki Yamaguchi
- Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan
| | - Masaharu Sugiura
- Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan
| | - Moataz A Shaldam
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Claudiu T Supuran
- Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze Italy
| | - Maha-Hamadien Abdulla
- Department of Surgery, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Wagdy M Eldehna
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Haytham O Tawfik
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
| |
Collapse
|
|
15
|
Luu N, Zhang S, Lam RHW, Chen W. Mechanical Constraints in Tumor Guide Emergent Spatial Patterns of Glioblastoma Cancer Stem Cells. MECHANOBIOLOGY IN MEDICINE 2024; 2:100027. [PMID: 38770108 PMCID: PMC11105673 DOI: 10.1016/j.mbm.2023.100027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
The mechanical constraints in the overcrowding glioblastoma (GBM) microenvironment have been implicated in the regulation of tumor heterogeneity and disease progression. Especially, such mechanical cues can alter cellular DNA transcription and give rise to a subpopulation of tumor cells called cancer stem cells (CSCs). These CSCs with stem-like properties are critical drivers of tumorigenesis, metastasis, and treatment resistance. Yet, the biophysical and molecular machinery underlying the emergence of CSCs in tumor remained unexplored. This work employed a two-dimensional micropatterned multicellular model to examine the impact of mechanical constraints arisen from geometric confinement on the emergence and spatial patterning of CSCs in GBM tumor. Our study identified distinct spatial distributions of GBM CSCs in different geometric patterns, where CSCs mostly emerged in the peripheral regions. The spatial pattern of CSCs was found to correspond to the gradients of mechanical stresses resulted from the interplay between the cell-ECM and cell-cell interactions within the confined environment. Further mechanistic study highlighted a Piezo1-RhoA-focal adhesion signaling axis in regulating GBM cell mechanosensing and the subsequent CSC phenotypic transformation. These findings provide new insights into the biophysical origin of the unique spatial pattern of CSCs in GBM tumor and offer potential avenues for targeted therapeutic interventions.
Collapse
Affiliation(s)
- Ngoc Luu
- Department of Biomedical Engineering, New York University, Brooklyn, NY, USA
| | - Shuhao Zhang
- Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, NY, USA
| | - Raymond H. W. Lam
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong SAR, China
- Centre for Biosystems, Neuroscience, and Nanotechnology, City University of Hong Kong, Hong Kong SAR, China
- City University of Hong Kong Shenzhen Research Institute, Shenzhen, China
| | - Weiqiang Chen
- Department of Biomedical Engineering, New York University, Brooklyn, NY, USA
- Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, NY, USA
- Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, USA
| |
Collapse
|
|
16
|
Premachandran S, Dhinakaran AK, Das S, Venkatakrishnan K, Tan B, Sharma M. Detection of lung cancer metastasis from blood using L-MISC nanosensor: Targeting circulating metastatic cues for improved diagnosis. Biosens Bioelectron 2024; 243:115782. [PMID: 37890388 DOI: 10.1016/j.bios.2023.115782] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/13/2023] [Accepted: 10/21/2023] [Indexed: 10/29/2023]
Abstract
Metastatic lung cancers are considered one of the most clinically significant malignancies, comprising about 40% of deaths caused by cancers. Detection of lung cancer metastasis prior to symptomatic relapse is critical for timely diagnosis and clinical management. The onset of cancer metastasis is indicated by the manifestation of tumor-shed signatures from the primary tumor in peripheral circulation. A subset of this population, characterized as the metastasis-initiating stem cells, are capable of invasion, tumor initiation, and propagation of metastasis at distant sites. In this study, we have developed a SERS-functionalised L-MISC (Lung-Metastasis Initiating Stem Cells) nanosensor to accurately capture the trace levels of metastatic signatures directly from patient blood. We investigated the signatures of cancer stem cell enriched heterogenous population of primary and metastatic lung cancer cells to establish a metastatic profile unique to lung cancer. Multivariate statistical analyses revealed statistically significant differences in the molecular profiles of healthy, primary, and metastatic cell populations. The single-cell sensitivity of L-MISC nanosensor enabled a label-free detection of MISCs with high sensitivity and specificity. By employing a robust machine learning model, our diagnostic methodology can accurately detect metastatic lung cancer from not more than 5 μl of blood. A pilot validation of our study was carried out using clinical samples for the prediction of metastatic lung cancers resulting in 100% diagnostic sensitivity. The L-MISC nanosensor is a potential tool for highly rapid, non-invasive, and accurate diagnosis of lung cancer metastasis.
Collapse
Affiliation(s)
- Srilakshmi Premachandran
- Institute for Biomedical Engineering, Science and Technology (I BEST), Partnership Between Toronto Metropolitan University and St. Michael's Hospital, Toronto, Ontario, M5B 1W8, Canada; Ultrashort Laser Nanomanufacturing Research Facility, Department of Mechanical and Industrial Engineering, Toronto Metropolitan University, 350 Victoria Street, Toronto, ON, M5B 2K3, Canada; Nano-Bio Interface Facility, Department of Mechanical and Industrial Engineering, Toronto Metropolitan University, 350 Victoria Street, Toronto, ON, M5B 2K3, Canada
| | - Ashok Kumar Dhinakaran
- Institute for Biomedical Engineering, Science and Technology (I BEST), Partnership Between Toronto Metropolitan University and St. Michael's Hospital, Toronto, Ontario, M5B 1W8, Canada; Ultrashort Laser Nanomanufacturing Research Facility, Department of Mechanical and Industrial Engineering, Toronto Metropolitan University, 350 Victoria Street, Toronto, ON, M5B 2K3, Canada; Nano-Bio Interface Facility, Department of Mechanical and Industrial Engineering, Toronto Metropolitan University, 350 Victoria Street, Toronto, ON, M5B 2K3, Canada
| | - Sunit Das
- Department of Surgery, Division of Neurosurgery, University of Toronto, Toronto, Canada
| | - Krishnan Venkatakrishnan
- Keenan Research Center for Biomedical Science, Unity Health Toronto, Toronto, Ontario, M5B 1W8, Canada; Ultrashort Laser Nanomanufacturing Research Facility, Department of Mechanical and Industrial Engineering, Toronto Metropolitan University, 350 Victoria Street, Toronto, ON, M5B 2K3, Canada; Nano-Bio Interface Facility, Department of Mechanical and Industrial Engineering, Toronto Metropolitan University, 350 Victoria Street, Toronto, ON, M5B 2K3, Canada.
| | - Bo Tan
- Keenan Research Center for Biomedical Science, Unity Health Toronto, Toronto, Ontario, M5B 1W8, Canada; Nano Characterization Laboratory, Department of Aerospace Engineering, Toronto Metropolitan University, 350 Victoria Street, Toronto, Ontario, M5B 2K3, Canada; Nano-Bio Interface Facility, Department of Mechanical and Industrial Engineering, Toronto Metropolitan University, 350 Victoria Street, Toronto, ON, M5B 2K3, Canada
| | - Mansi Sharma
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala, India
| |
Collapse
|
|
17
|
Yadav S, Zhou S, He B, Du Y, Garmire LX. Deep learning and transfer learning identify breast cancer survival subtypes from single-cell imaging data. COMMUNICATIONS MEDICINE 2023; 3:187. [PMID: 38114659 PMCID: PMC10730890 DOI: 10.1038/s43856-023-00414-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 11/23/2023] [Indexed: 12/21/2023] Open
Abstract
BACKGROUND Single-cell multiplex imaging data have provided new insights into disease subtypes and prognoses recently. However, quantitative models that explicitly capture single-cell resolution cell-cell interaction features to predict patient survival at a population scale are currently missing. METHODS We quantified hundreds of single-cell resolution cell-cell interaction features through neighborhood calculation, in addition to cellular phenotypes. We applied these features to a neural-network-based Cox-nnet survival model to identify survival-associated features. We used non-negative matrix factorization (NMF) to identify patient survival subtypes. We identified atypical subpopulations of triple-negative breast cancer (TNBC) patients with moderate prognosis and Luminal A patients with poor prognosis and validated these subpopulations by label transferring using the UNION-COM method. RESULTS The neural-network-based Cox-nnet survival model using all cellular phenotype and cell-cell interaction features is highly predictive of patient survival in the test data (Concordance Index > 0.8). We identify seven survival subtypes using the top survival features, presenting distinct profiles of epithelial, immune, and fibroblast cells and their interactions. We reveal atypical subpopulations of TNBC patients with moderate prognosis (marked by GATA3 over-expression) and Luminal A patients with poor prognosis (marked by KRT6 and ACTA2 over-expression and CDH1 under-expression). These atypical subpopulations are validated in TCGA-BRCA and METABRIC datasets. CONCLUSIONS This work provides an approach to bridge single-cell level information toward population-level survival prediction.
Collapse
Affiliation(s)
- Shashank Yadav
- Department of Computational Medicine and Bioinformatics, University of Michigan, Michigan, MI, 48105, USA
| | - Shu Zhou
- Department of Computational Medicine and Bioinformatics, University of Michigan, Michigan, MI, 48105, USA
| | - Bing He
- Department of Computational Medicine and Bioinformatics, University of Michigan, Michigan, MI, 48105, USA
| | - Yuheng Du
- Department of Computational Medicine and Bioinformatics, University of Michigan, Michigan, MI, 48105, USA
| | - Lana X Garmire
- Department of Computational Medicine and Bioinformatics, University of Michigan, Michigan, MI, 48105, USA.
| |
Collapse
|
|
18
|
Molika P, Leetanaporn K, Rungkamoltip P, Roytrakul S, Hanprasertpong J, Navakanitworakul R. Proteomic analysis of small extracellular vesicles unique to cervical cancer. Transl Cancer Res 2023; 12:3113-3128. [PMID: 38130315 PMCID: PMC10731333 DOI: 10.21037/tcr-23-517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 09/22/2023] [Indexed: 12/23/2023]
Abstract
Background Cervical cancer (CC) is the fourth most common cancer in females worldwide. Existing biomarkers for CC, such as squamous cell carcinoma antigens, show low specificity. Hence, a novel biomarker for the diagnosis of CC is required. Through proteomic analysis, this study aimed to distinguish between the small extracellular vesicle (sEV) protein profiles of healthy controls (HC) and CC sera and to identify potential sEV proteins that can serve as biomarkers for CC diagnosis. Methods The number and size distribution of sEVs in HC and CC sera were measured using nanoparticle tracking analysis. Differential ultracentrifugation combined with size-exclusion chromatography was used to isolate and purify sEVs. Liquid chromatography-tandem mass spectrometry was used to identify and compare the protein profiles between patients with CC and HC. Differentially expressed extracellular vesicle (EV) proteins were validated using The Cancer Genome Atlas database. Results The EV particle concentration in patients with CC was marginally higher than that in HC. Proteomic and functional protein analyses revealed a difference in the EV protein profiles between HC and CC and identified proteins that can serve as biomarkers for CC. Conclusions This study provides insights into the potential of sEVs as less invasive biomarkers for CC diagnosis. Validation with a well-designed cohort should be performed to determine the clinical diagnostic value of specific protein markers for CC.
Collapse
Affiliation(s)
- Piyatida Molika
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Kittinun Leetanaporn
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Phetploy Rungkamoltip
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Sittiruk Roytrakul
- National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Jitti Hanprasertpong
- Department of Research and Medical Innovation, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand
| | - Raphatphorn Navakanitworakul
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| |
Collapse
|
|
19
|
Chakraborty S, Banerjee S. Understanding crosstalk of organ tropism, tumor microenvironment and noncoding RNAs in breast cancer metastasis. Mol Biol Rep 2023; 50:9601-9623. [PMID: 37792172 DOI: 10.1007/s11033-023-08852-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 09/26/2023] [Indexed: 10/05/2023]
Abstract
Cancer metastasis is one of the major clinical challenges worldwide due to limited existing effective treatments. Metastasis roots from the host organ of origin and gradually migrates to different regional and distant organs. In different breast cancer subtypes, different organs like bones, liver, lungs and brain are targeted by the metastatic tumor cells. Cancer renders mortality to their respective metastasizing sites like bones, brain, liver, and lungs. Metastatic breast cancers are best treated and managed if detected at an early stage. Metastasis is regulated by various molecular activators and suppressors. The conventional theory of 'seed and soil' states that metastatic tumor cells move to tumor microenvironment that has favorable conditions like blood flow for them to grow just like seeds grows when planted in fertile land. Additionally, different coding as well as non-coding RNAs play a very significant role in the process of metastasis by modulating their expression levels leading to a crosstalk of various tumorigenic cascades. Treatments for metastasis is also very critical in controlling this lethal process. Detecting breast cancer metastasis at an early stage is crucial for managing and predicting metastatic progression. In this review, we have compiled several factors that can be targeted to manage the onset and gradual stages of breast cancer metastasis.
Collapse
Affiliation(s)
- Sohini Chakraborty
- Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India
| | - Satarupa Banerjee
- Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India.
| |
Collapse
|
|
20
|
Arechaga-Ocampo E. Epigenetics as a determinant of radiation response in cancer. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 383:145-190. [PMID: 38359968 DOI: 10.1016/bs.ircmb.2023.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
Radiation therapy is a cornerstone of modern cancer treatment. Treatment is based on depositing focal radiation to the tumor to inhibit cell growth, proliferation and metastasis, and to promote the death of cancer cells. In addition, radiation also affects non-tumor cells in the tumor microenvironmental (TME). Radiation resistance of the tumor cells is the most common cause of treatment failure, allowing survival of cancer cell and subsequent tumor growing. Molecular radioresistance comprises genetic and epigenetic characteristics inherent in cancer cells, or characteristics acquired after exposure to radiation. Furthermore, cancer stem cells (CSCs) and non-tumor cells into the TME as stromal and immune cells have a role in promoting and maintaining radioresistant tumor phenotypes. Different regulatory molecules and pathways distinctive of radiation resistance include DNA repair, survival signaling and cell death pathways. Epigenetic mechanisms are one of the most relevant events that occur after radiotherapy to regulate the expression and function of key genes and proteins in the differential radiation-response. This article reviews recent data on the main molecular mechanisms and signaling pathways related to the biological response to radiotherapy in cancer; highlighting the epigenetic control exerted by DNA methylation, histone marks, chromatin remodeling and m6A RNA methylation on gene expression and activation of signaling pathways related to radiation therapy response.
Collapse
Affiliation(s)
- Elena Arechaga-Ocampo
- Departamento de Ciencias Naturales, Unidad Cuajimalpa, Universidad Autonoma Metropolitana, Mexico City, Mexico.
| |
Collapse
|
|
21
|
Yadav S, Zhou S, He B, Du Y, Garmire LX. Deep-learning and transfer learning identify new breast cancer survival subtypes from single-cell imaging data. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.09.14.23295578. [PMID: 37745392 PMCID: PMC10516066 DOI: 10.1101/2023.09.14.23295578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Quantitative models that explicitly capture single-cell resolution cell-cell interaction features to predict patient survival at population scale are currently missing. Here, we computationally extracted hundreds of features describing single-cell based cell-cell interactions and cellular phenotypes from a large, published cohort of cyto-images of breast cancer patients. We applied these features to a neural-network based Cox-nnet survival model and obtained high accuracy in predicting patient survival in test data (Concordance Index > 0.8). We identified seven survival subtypes using the top survival features, which present distinct profiles of epithelial, immune, fibroblast cells, and their interactions. We identified atypical subpopulations of TNBC patients with moderate prognosis (marked by GATA3 over-expression) and Luminal A patients with poor prognosis (marked by KRT6 and ACTA2 over-expression and CDH1 under-expression). These atypical subpopulations are validated in TCGA-BRCA and METABRIC datasets. This work provides important guidelines on bridging single-cell level information towards population-level survival prediction. STATEMENT OF TRANSLATIONAL RELEVANCE Our findings from a breast cancer population cohort demonstrate the clinical utility of using the single-cell level imaging mass cytometry (IMC) data as a new type of patient prognosis prediction marker. Not only did the prognosis prediction achieve high accuracy with a Concordance index score greater than 0.8, it also enabled the discovery of seven survival subtypes that are more distinguishable than the molecular subtypes. These new subtypes present distinct profiles of epithelial, immune, fibroblast cells, and their interactions. Most importantly, this study identified and validated atypical subpopulations of TNBC patients with moderate prognosis (GATA3 over-expression) and Luminal A patients with poor prognosis (KRT6 and ACTA2 over-expression and CDH1 under-expression), using multiple large breast cancer cohorts.
Collapse
|
|
22
|
Sun H, Meng K, Wang Y, Wang Y, Yuan X, Li X. LncRNAs regulate the cyclic growth and development of hair follicles in Dorper sheep. Front Vet Sci 2023; 10:1186294. [PMID: 37583467 PMCID: PMC10423938 DOI: 10.3389/fvets.2023.1186294] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 07/11/2023] [Indexed: 08/17/2023] Open
Abstract
Introduction Hair follicles in Dorper sheep are characterized by seasonal cyclic growth and development, consequently resulting in hair shedding during spring. The cyclic growth and development of hair follicles are regulated by several influencing factors such as photoperiods, hormones, age of the animal, genes, long non-coding RNAs (lncRNAs), and signaling pathways. Methods In the present study, skin samples of five shedding sheep (S), used as experimental animals, and three non-shedding sheep (N), used as controls, were collected at three time points (September 27, 2019; January 3, 2020; and March 17, 2020) for RNA sequencing (RNA-seq) technology. Nine different groups (S1-vs-S2, S1-vs-S3, S2-vs-S3, N1- vs-N2, N1-vs-N3, N2-vs-N3, S1-vs-N1, S2-vs-N2, and S3-vs-N3) were compared using FDR < 0.05 and log 21 FC >as thresholds to assess the differences in the expression of lncRNAs. Results and discussion In total, 395 differentially expressed (DE) lncRNAs were screened. Cluster heatmap analysis identified two types of expression patterns, namely, high expression during the anagen phase (A pattern) and high expression during the telogen phase (T pattern). Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that the target genes were largely enriched in the Estrogen signaling pathway, PI3K-Akt signaling pathway, Fc gamma R-mediated phagocytosis, and cell adhesion molecules (CAMs), which are associated with hair follicle cyclic growth and development-related pathways. In addition, 17 pairs of lncRNAs-target genes related to hair follicle cyclic growth and development were screened, and a regulatory network was constructed. Altogether, candidate lncRNAs and their regulated target genes were screened that contributed to sheep hair follicle cyclic growth and development. We believe these findings will provide useful insights into the underlying regulatory mechanisms.
Collapse
Affiliation(s)
| | | | | | | | | | - Xinhai Li
- College of Animal Science and Technology, Ningxia University, Yinchuan, China
| |
Collapse
|
|
23
|
Srivastava N, Usmani SS, Subbarayan R, Saini R, Pandey PK. Hypoxia: syndicating triple negative breast cancer against various therapeutic regimens. Front Oncol 2023; 13:1199105. [PMID: 37492478 PMCID: PMC10363988 DOI: 10.3389/fonc.2023.1199105] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 06/05/2023] [Indexed: 07/27/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer (BC) for its high aggressiveness, heterogeneity, and hypoxic nature. Based on biological and clinical observations the TNBC related mortality is very high worldwide. Emerging studies have clearly demonstrated that hypoxia regulates the critical metabolic, developmental, and survival pathways in TNBC, which include glycolysis and angiogenesis. Alterations to these pathways accelerate the cancer stem cells (CSCs) enrichment and immune escape, which further lead to tumor invasion, migration, and metastasis. Beside this, hypoxia also manipulates the epigenetic plasticity and DNA damage response (DDR) to syndicate TNBC survival and its progression. Hypoxia fundamentally creates the low oxygen condition responsible for the alteration in Hypoxia-Inducible Factor-1alpha (HIF-1α) signaling within the tumor microenvironment, allowing tumors to survive and making them resistant to various therapies. Therefore, there is an urgent need for society to establish target-based therapies that overcome the resistance and limitations of the current treatment plan for TNBC. In this review article, we have thoroughly discussed the plausible significance of HIF-1α as a target in various therapeutic regimens such as chemotherapy, radiotherapy, immunotherapy, anti-angiogenic therapy, adjuvant therapy photodynamic therapy, adoptive cell therapy, combination therapies, antibody drug conjugates and cancer vaccines. Further, we also reviewed here the intrinsic mechanism and existing issues in targeting HIF-1α while improvising the current therapeutic strategies. This review highlights and discusses the future perspectives and the major alternatives to overcome TNBC resistance by targeting hypoxia-induced signaling.
Collapse
Affiliation(s)
- Nityanand Srivastava
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Salman Sadullah Usmani
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Rajasekaran Subbarayan
- Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, United States
- Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Educations, Chennai, India
| | - Rashmi Saini
- Department of Zoology, Gargi College, University of Delhi, New Delhi, India
| | - Pranav Kumar Pandey
- Dr. R.P. Centre for Opthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| |
Collapse
|
|
24
|
Hegde MM, Sandbhor P, J. A, Gota V, Goda JS. Insight into lipid-based nanoplatform-mediated drug and gene delivery in neuro-oncology and their clinical prospects. Front Oncol 2023; 13:1168454. [PMID: 37483515 PMCID: PMC10357293 DOI: 10.3389/fonc.2023.1168454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 06/16/2023] [Indexed: 07/25/2023] Open
Abstract
Tumors of the Central nervous System (CNS) are a spectrum of neoplasms that range from benign lesions to highly malignant and aggressive lesions. Despite aggressive multimodal treatment approaches, the morbidity and mortality are high with dismal survival outcomes in these malignant tumors. Moreover, the non-specificity of conventional treatments substantiates the rationale for precise therapeutic strategies that selectively target infiltrating tumor cells within the brain, and minimize systemic and collateral damage. With the recent advancement of nanoplatforms for biomaterials applications, lipid-based nanoparticulate systems present an attractive and breakthrough impact on CNS tumor management. Lipid nanoparticles centered immunotherapeutic agents treating malignant CNS tumors could convene the clear need for precise treatment strategies. Immunotherapeutic agents can selectively induce specific immune responses by active or innate immune responses at the local site within the brain. In this review, we discuss the therapeutic applications of lipid-based nanoplatforms for CNS tumors with an emphasis on revolutionary approaches in brain targeting, imaging, and drug and gene delivery with immunotherapy. Lipid-based nanoparticle platforms represent one of the most promising colloidal carriers for chemotherapeutic, and immunotherapeutic drugs. Their current application in oncology especially in brain tumors has brought about a paradigm shift in cancer treatment by improving the antitumor activity of several agents that could be used to selectively target brain tumors. Subsequently, the lab-to-clinic transformation and challenges towards translational feasibility of lipid-based nanoplatforms for drug and gene/immunotherapy delivery in the context of CNS tumor management is addressed.
Collapse
Affiliation(s)
- Manasa Manjunath Hegde
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Puja Sandbhor
- Department of Biosciences and Bioengineering, Indian Institute of Technology, Mumbai, India
| | - Aishwarya J.
- Advance Centre for Treatment Research and Education in Cancer, Tata Memorial Centre and Homi Bhabha National Institute, Mumbai, India
| | - Vikram Gota
- Advance Centre for Treatment Research and Education in Cancer, Tata Memorial Centre and Homi Bhabha National Institute, Mumbai, India
| | - Jayant S. Goda
- Advance Centre for Treatment Research and Education in Cancer, Tata Memorial Centre and Homi Bhabha National Institute, Mumbai, India
| |
Collapse
|
|
25
|
Kharouf N, Flanagan TW, Hassan SY, Shalaby H, Khabaz M, Hassan SL, Megahed M, Haikel Y, Santourlidis S, Hassan M. Tumor Microenvironment as a Therapeutic Target in Melanoma Treatment. Cancers (Basel) 2023; 15:3147. [PMID: 37370757 DOI: 10.3390/cancers15123147] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/02/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
The role of the tumor microenvironment in tumor growth and therapy has recently attracted more attention in research and drug development. The ability of the microenvironment to trigger tumor maintenance, progression, and resistance is the main cause for treatment failure and tumor relapse. Accumulated evidence indicates that the maintenance and progression of tumor cells is determined by components of the microenvironment, which include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), extracellular matrix (ECM), and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, ECM, and soluble molecules. Melanoma cells are continuously in interaction with the components of the microenvironment. In the present review, we focus on the role of the tumor microenvironment components in the modulation of tumor progression and treatment resistance as well as the impact of the tumor microenvironment as a therapeutic target in melanoma.
Collapse
Affiliation(s)
- Naji Kharouf
- Biomaterials and Bioengineering, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Unité Mixte de Recherche 1121, 67000 Strasbourg, France
- Department of Endodontics and Conservative Dentistry, Faculty of Dental Medicine, University of Strasbourg, 67000 Strasbourg, France
| | - Thomas W Flanagan
- Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, LA 70112, USA
| | - Sofie-Yasmin Hassan
- Department of Chemistry, Faculty of Science, Heinrich-Heine University Duesseldorf, 40225 Dusseldorf, Germany
| | - Hosam Shalaby
- Department of Urology, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Marla Khabaz
- Department of Production, Beta Factory for Veterinary Pharmaceutical Industries, Damascus 0100, Syria
| | - Sarah-Lilly Hassan
- Department of Chemistry, Faculty of Science, Heinrich-Heine University Duesseldorf, 40225 Dusseldorf, Germany
| | - Mosaad Megahed
- Clinic of Dermatology, University Hospital of Aachen, 52074 Aachen, Germany
| | - Youssef Haikel
- Biomaterials and Bioengineering, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Unité Mixte de Recherche 1121, 67000 Strasbourg, France
- Department of Endodontics and Conservative Dentistry, Faculty of Dental Medicine, University of Strasbourg, 67000 Strasbourg, France
- Pôle de Médecine et Chirurgie Bucco-Dentaire, Hôpital Civil, Hôpitaux Universitaire de Strasbourg, 67000 Strasbourg, France
| | - Simeon Santourlidis
- Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany
| | - Mohamed Hassan
- Biomaterials and Bioengineering, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Unité Mixte de Recherche 1121, 67000 Strasbourg, France
- Department of Endodontics and Conservative Dentistry, Faculty of Dental Medicine, University of Strasbourg, 67000 Strasbourg, France
- Research Laboratory of Surgery-Oncology, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| |
Collapse
|
|
26
|
Cao M, Liu Z, You D, Pan Y, Zhang Q. TMT-based quantitative proteomic analysis of spheroid cells of endometrial cancer possessing cancer stem cell properties. Stem Cell Res Ther 2023; 14:119. [PMID: 37143105 PMCID: PMC10161517 DOI: 10.1186/s13287-023-03348-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 04/19/2023] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND Cancer stem cells (CSCs) play an important role in endometrial cancer progression and it is potential to isolate CSCs from spheroid cells. Further understanding of spheroid cells at protein level would help find novel CSC markers. METHODS Spheroid cells from endometrial cancer cell lines, Ishikawa and HEC1A, exhibited increased colony forming, subsphere forming, chemo-drug resistance, migration, invasion ability and tumorigenicity, verifying their cancer stem-like cell properties. The up-regulated CD90, CD117, CD133 and W5C5 expression also indicated stemness of spheroid cells. TMT-based quantitative proteomic analysis was performed to explore the potential alterations between parent cells and cancer stem-like spheroid cells. HK2-siRNA was transfected to Ishikawa and HEC1A cells to explore the roles and molecular mechanism of HK2 in endometrial cancer. RESULTS We identified and quantified a total of 5735 proteins and 167 overlapped differentially expressed proteins of two cell types, 43 proteins were up-regulated and 124 were down-regulated in spheroid cells comparing with parent cells. KEGG pathway revealed a significant role of HIF-1 pathway in spheroid cells. qRT-PCR and western blot results of GPRC5A, PFKFB3 and HK2 of HIF-1 pathway confirmed their elevated expressions in spheroid cells which were consistent with proteomic results. HK2 promoted cancer stemness in endometrial cancer. CONCLUSION These findings indicate that spheroid cells from endometrial cancer cell lines possess cancer stem-like cell properties and enrich CSCs. HIF-1 pathway is activated in endometrial cancer stem-like spheroid cells.
Collapse
Affiliation(s)
- Mingzhu Cao
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, No.63, Duobao Road, Guangzhou, China
- Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhi Liu
- Department of Ultrasound, Nanfang Hospital, Southern Medical University, No.1838, Baiyun Road North, Guangzhou, China
| | - Danming You
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yingying Pan
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Qingyan Zhang
- Reproductive Medicine Center, The First Affiliated Hospital, Sun Yat-Sen University, No. 1, Zhongshan 2nd Road, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Reproductive Medicine, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
| |
Collapse
|
|
27
|
Mulchandani V, Banerjee A, Vadlamannati AV, Kumar S, Das Sarma J. Connexin 43 trafficking and regulation of gap junctional intercellular communication alters ovarian cancer cell migration and tumorigenesis. Biomed Pharmacother 2023; 159:114296. [PMID: 36701988 DOI: 10.1016/j.biopha.2023.114296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 01/16/2023] [Accepted: 01/20/2023] [Indexed: 01/27/2023] Open
Abstract
Ovarian cancer persists to be the most lethal gynecological malignancy, demanding rigorous treatments involving radio-chemotherapy that trigger toxicity and consequently mortality among patients. An improved understanding of the disease progression may pioneer curative therapies. Mouse epithelial ovarian cancer cell lines, ID8 and ID8-VEGF (overexpressing VEGF) were intraperitoneally injected in C57BL/6 female mice to develop a Syngeneic Ovarian cancer mouse model. It was observed that ID8-VEGF cells were able to induce aggressive tumor growth in mice compared to ID8 cells. Furthermore, results of the current in vitro study comparing ID8 and ID8-VEGF demonstrated that highly tumorigenic ID8-VEGF had reduced gap junctional intercellular communication (GJIC) due to intracellular Connexin 43 (Cx43) expression. Additionally, ID8 cells with reduced tumorigenic capability expressed significant GJIC. Furthermore, loss of GJIC in ID8-VEGF cells induced shorter tunneling nanotube formations, while ID8 cells develops longer tunneling nanotube to maintain cellular crosstalk. The administration of a pharmacological drug 4-phenylbutyrate (4PBA) ensured the restoration of GJIC in both the ovarian cancer cell lines. Additionally, 4PBA treatment significantly inhibited the migration of ovarian cancer cell lines and tumor formation in ovarian cancer mice models. In summary, the 4PBA-mediated restoration of GJIC suppressed migration (in vitro) and tumorigenesis (in vivo) of ovarian cancer cells. The present study suggests that Cx43 assembled GJIC and its supportive signaling pathways are a prospective target for restricting ovarian cancer progression.
Collapse
Affiliation(s)
- Vaishali Mulchandani
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
| | - Anurag Banerjee
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
| | - Arunima Vijaya Vadlamannati
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
| | - Saurav Kumar
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
| | - Jayasri Das Sarma
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India; Department of Ophthalmology, University of Pennsylvania, Philadelphia, USA.
| |
Collapse
|
|
28
|
Identity matters: cancer stem cells and tumour plasticity in head and neck squamous cell carcinoma. Expert Rev Mol Med 2023; 25:e8. [PMID: 36740973 DOI: 10.1017/erm.2023.4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Head and neck squamous cell carcinoma (HNSCC) represents frequent yet aggressive tumours that encompass complex ecosystems of stromal and neoplastic components including a dynamic population of cancer stem cells (CSCs). Recently, research in the field of CSCs has gained increased momentum owing in part to their role in tumourigenicity, metastasis, therapy resistance and relapse. We provide herein a comprehensive assessment of the latest progress in comprehending CSC plasticity, including newly discovered influencing factors and their possible application in HNSCC. We further discuss the dynamic interplay of CSCs within tumour microenvironment considering our evolving appreciation of the contribution of oral microbiota and the pressing need for relevant models depicting their features. In sum, CSCs and tumour plasticity represent an exciting and expanding battleground with great implications for cancer therapy that are only beginning to be appreciated in head and neck oncology.
Collapse
|
|
29
|
Liu Y, Xu W, Li M, Yang Y, Sun D, Chen L, Li H, Chen L. The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer. Acta Pharm Sin B 2023; 13:1438-1466. [PMID: 37139412 PMCID: PMC10149907 DOI: 10.1016/j.apsb.2022.12.019] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/07/2022] [Accepted: 11/18/2022] [Indexed: 02/04/2023] Open
Abstract
Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG). Mutants of IDH1 or IDH2 can produce d-2-hydroxyglutarate (D-2HG) with α-KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2, implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.
Collapse
|
|
30
|
Nallasamy P, Nimmakayala RK, Parte S, Are AC, Batra SK, Ponnusamy MP. Tumor microenvironment enriches the stemness features: the architectural event of therapy resistance and metastasis. Mol Cancer 2022; 21:225. [PMID: 36550571 PMCID: PMC9773588 DOI: 10.1186/s12943-022-01682-x] [Citation(s) in RCA: 112] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 11/16/2022] [Indexed: 12/24/2022] Open
Abstract
Cancer divergence has many facets other than being considered a genetic term. It is a tremendous challenge to understand the metastasis and therapy response in cancer biology; however, it postulates the opportunity to explore the possible mechanism in the surrounding tumor environment. Most deadly solid malignancies are distinctly characterized by their tumor microenvironment (TME). TME consists of stromal components such as immune, inflammatory, endothelial, adipocytes, and fibroblast cells. Cancer stem cells (CSCs) or cancer stem-like cells are a small sub-set of the population within cancer cells believed to be a responsible player in the self-renewal, metastasis, and therapy response of cancer cells. The correlation between TME and CSCs remains an enigma in understanding the events of metastasis and therapy resistance in cancer biology. Recent evidence suggests that TME dictates the CSCs maintenance to arbitrate cancer progression and metastasis. The immune, inflammatory, endothelial, adipocyte, and fibroblast cells in the TME release growth factors, cytokines, chemokines, microRNAs, and exosomes that provide cues for the gain and maintenance of CSC features. These intricate cross-talks are fueled to evolve into aggressive, invasive, migratory phenotypes for cancer development. In this review, we have abridged the recent developments in the role of the TME factors in CSC maintenance and how these events influence the transition of tumor progression to further translate into metastasis and therapy resistance in cancer.
Collapse
Affiliation(s)
- Palanisamy Nallasamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Rama Krishna Nimmakayala
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Seema Parte
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Abhirup C Are
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
| |
Collapse
|
|
31
|
Weinstein AG, Godet I, Gilkes DM. The rise of viperin: the emerging role of viperin in cancer progression. J Clin Invest 2022; 132:165907. [PMID: 36519538 PMCID: PMC9753986 DOI: 10.1172/jci165907] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Viperin, an IFN-regulated gene product, is known to inhibit fatty acid β-oxidation in the mitochondria, which enhances glycolysis and lipogenesis during viral infections. Yet, its role in altering the phenotype of cancer cells has not been established. In this issue of the JCI, Choi, Kim, and co-authors report on a role of viperin in regulating metabolic alterations in cancer cells. The authors showed a correlation between clinical outcomes and viperin expression levels in multiple cancer tissues and proposed that viperin expression was upregulated in the tumor microenvironment via the JAK/STAT and PI3K/AKT/mTOR/HIF-1α pathways. Functionally, viperin increased lipogenesis and glycolysis in cancer cells by inhibiting fatty acid β-oxidation. Viperin expression also enhanced cancer stem cell properties, ultimately promoting tumor initiation in murine models. This study proposes a protumorigenic role for viperin and identifies HIF-1α as a transcription factor that increases viperin expression under serum starvation and hypoxia.
Collapse
Affiliation(s)
- Alyssa G. Weinstein
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center and,Biochemistry and Molecular Biology Program, The Johns Hopkins University School of Public Health, Baltimore, Maryland, USA
| | - Inês Godet
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center and,Department of Chemical and Biomolecular Engineering and,Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland, USA
| | - Daniele M. Gilkes
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center and,Department of Chemical and Biomolecular Engineering and,Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland, USA.,Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
|
32
|
Zhang Y, Beketaev I, Ma Y, Wang J. Sumoylation-deficient phosphoglycerate mutase 2 impairs myogenic differentiation. Front Cell Dev Biol 2022; 10:1052363. [PMID: 36589741 PMCID: PMC9795042 DOI: 10.3389/fcell.2022.1052363] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022] Open
Abstract
Phosphoglycerate mutase 2 (PGAM2) is a critical glycolytic enzyme that is highly expressed in skeletal muscle. In humans, naturally occurring mutations in Phosphoglycerate mutase 2 have been etiologically linked to glycogen storage disease X (GSDX). Phosphoglycerate mutase 2 activity is regulated by several posttranslational modifications such as ubiquitination and acetylation. Here, we report that Phosphoglycerate mutase 2 activity is regulated by sumoylation-a covalent conjugation involved in a wide spectrum of cellular events. We found that Phosphoglycerate mutase 2 contains two primary SUMO acceptor sites, lysine (K)49 and K176, and that the mutation of either K to arginine (R) abolished Phosphoglycerate mutase 2 sumoylation. Given that K176 is more highly evolutionarily conserved across paralogs and orthologs than K49 is, we used the CRISPR-mediated homologous recombination technique in myogenic C2C12 cells to generate homozygous K176R knock-in cells (PGAM2K176R/K176R). Compared with wild-type (WT) C2C12 cells, PGAM2K176R/K176R C2C12 cells exhibited impaired myogenic differentiation, as indicated by decreased differentiation and fusion indexes. Furthermore, the results of glycolytic and mitochondrial stress assays with the XF96 Extracellular Flux analyzer revealed a reduced proton efflux rate (PER), glycolytic PER (glycoPER), extracellular acidification rate (ECAR), and oxygen consumption rate (OCR) in PGAM2K176R/K176R C2C12 cells, both at baseline and in response to stress. Impaired mitochondrial function was also observed in PGAM2K176R/K176R P19 cells, a carcinoma cell line. These findings indicate that the PGAM2-K176R mutation impaired glycolysis and mitochondrial function. Gene ontology term analysis of RNA sequencing data further revealed that several downregulated genes in PGAM2K176R/K176R C2C12 cells were associated with muscle differentiation/development/contraction programs. Finally, PGAM2 with either of two naturally occurring missense mutations linked to GSDX, E89A (conversion of glutamic acid 89 to alanine) or R90W (conversion of arginine 90 to tryptophan), exhibited reduced Phosphoglycerate mutase 2 sumoylation. Thus, sumoylation is an important mechanism that mediates Phosphoglycerate mutase 2 activity and is potentially implicated in Phosphoglycerate mutase 2 mutation-linked disease in humans.
Collapse
Affiliation(s)
- Yi Zhang
- Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Reproductive Medical Center, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, China,Stem Cell Engineering, Texas Heart Institute, Houston, TX, United States
| | - Ilimbek Beketaev
- Stem Cell Engineering, Texas Heart Institute, Houston, TX, United States
| | - Yanlin Ma
- Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Reproductive Medical Center, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, China,Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, China,*Correspondence: Yanlin Ma, ; Jun Wang,
| | - Jun Wang
- Stem Cell Engineering, Texas Heart Institute, Houston, TX, United States,*Correspondence: Yanlin Ma, ; Jun Wang,
| |
Collapse
|
|
33
|
Ervin EH, French R, Chang CH, Pauklin S. Inside the stemness engine: Mechanistic links between deregulated transcription factors and stemness in cancer. Semin Cancer Biol 2022; 87:48-83. [PMID: 36347438 DOI: 10.1016/j.semcancer.2022.11.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/22/2022] [Accepted: 11/03/2022] [Indexed: 11/07/2022]
Abstract
Cell identity is largely determined by its transcriptional profile. In tumour, deregulation of transcription factor expression and/or activity enables cancer cell to acquire a stem-like state characterised by capacity to self-renew, differentiate and form tumours in vivo. These stem-like cancer cells are highly metastatic and therapy resistant, thus warranting a more complete understanding of the molecular mechanisms downstream of the transcription factors that mediate the establishment of stemness state. Here, we review recent research findings that provide a mechanistic link between the commonly deregulated transcription factors and stemness in cancer. In particular, we describe the role of master transcription factors (SOX, OCT4, NANOG, KLF, BRACHYURY, SALL, HOX, FOX and RUNX), signalling-regulated transcription factors (SMAD, β-catenin, YAP, TAZ, AP-1, NOTCH, STAT, GLI, ETS and NF-κB) and unclassified transcription factors (c-MYC, HIF, EMT transcription factors and P53) across diverse tumour types, thereby yielding a comprehensive overview identifying shared downstream targets, highlighting unique mechanisms and discussing complexities.
Collapse
Affiliation(s)
- Egle-Helene Ervin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
| | - Rhiannon French
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
| | - Chao-Hui Chang
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
| |
Collapse
|
|
34
|
Abstract
Despite advancement in therapeutic options, Non-Small Cell lung cancer (NSCLC) remains a lethal disease mostly due to late diagnosis at metastatic phase and drug resistance. Bone is one of the more frequent sites for NSCLC metastatization. A defined subset of cancer stem cells (CSCs) that possess motile properties, mesenchymal features and tumor initiation potential are defined as metastasis initiating cells (MICs). A better understanding of the mechanisms supporting MIC dissemination and interaction with bone microenvironment is fundamental to design novel rational therapeutic option for long lasting efficient treatment of NSCLC. In this review we will summarize findings about bone metastatic process initiated by NSCLC MICs. We will review how MICs can reach bone and interact with its microenvironment that supports their extravasation, seeding, dormancy/proliferation. The role of different cell types inside the bone metastatic niche, such as endothelial cells, bone cells, hematopoietic stem cells and immune cells will be discussed in regards of their impact in dictating the success of metastasis establishment by MICs. Finally, novel therapeutic options to target NSCLC MIC-induced bone metastases, increasing the survival of patients, will be presented.
Collapse
|
|
35
|
Luo S, Jiang Y, Anfu Zheng, Zhao Y, Wu X, Li M, Du F, Chen Y, Deng S, Chen M, Li W, Li X, Gu L, Sun Y, Xiao Z, Shen J. Targeting hypoxia-inducible factors for breast cancer therapy: A narrative review. Front Pharmacol 2022; 13:1064661. [PMID: 36532768 PMCID: PMC9751339 DOI: 10.3389/fphar.2022.1064661] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 11/18/2022] [Indexed: 09/15/2023] Open
Abstract
Hypoxia-inducible factors (HIFs), central regulators for cells to adapt to low cellular oxygen levels, are often overexpressed and activated in breast cancer. HIFs modulate the primary transcriptional response of downstream pathways and target genes in response to hypoxia, including glycolysis, angiogenesis and metastasis. They can promote the development of breast cancer and are associated with poor prognosis of breast cancer patients by regulating cancer processes closely related to tumor invasion, metastasis and drug resistance. Thus, specific targeting of HIFs may improve the efficiency of cancer therapy. In this review, we summarize the advances in HIF-related molecular mechanisms and clinical and preclinical studies of drugs targeting HIFs in breast cancer. Given the rapid progression in this field and nanotechnology, drug delivery systems (DDSs) for HIF targeting are increasingly being developed. Therefore, we highlight the HIF related DDS, including liposomes, polymers, metal-based or carbon-based nanoparticles.
Collapse
Affiliation(s)
- Shuang Luo
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
- Department of Pharmacy, The Second People’s Hospital of Jiangyou, Mianyang, China
| | - Yu Jiang
- Department of Pharmacy, The People’s Hospital of Wusheng, Guang’an, China
| | - Anfu Zheng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Meijuan Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Wanping Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Xiaobing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Li Gu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Yuhong Sun
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Zhangang Xiao
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| |
Collapse
|
|
36
|
Li H, Gu J, Tian Y, Li S, Zhang H, Dai Z, Wang Z, Zhang N, Peng R. A prognostic signature consisting of metabolism-related genes and SLC17A4 serves as a potential biomarker of immunotherapeutic prediction in prostate cancer. Front Immunol 2022; 13:982628. [PMID: 36325340 PMCID: PMC9620963 DOI: 10.3389/fimmu.2022.982628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/05/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Prostate cancer (PCa), a prevalent malignant cancer in males worldwide, screening for patients might benefit more from immuno-/chemo-therapy remained inadequate and challenging due to the heterogeneity of PCa patients. Thus, the study aimed to explore the metabolic (Meta) characteristics and develop a metabolism-based signature to predict the prognosis and immuno-/chemo-therapy response for PCa patients. METHODS Differentially expressed genes were screened among 2577 metabolism-associated genes. Univariate Cox analysis and random forest algorithms was used for features screening. Multivariate Cox regression analysis was conducted to construct a prognostic Meta-model based on all combinations of metabolism-related features. Then the correlation between MetaScore and tumor was deeply explored from prognostic, genomic variant, functional and immunological perspectives, and chemo-/immuno-therapy response. Multiple algorithms were applied to estimate the immunotherapeutic responses of two MeteScore groups. Further in vitro functional experiments were performed using PCa cells to validate the association between the expression of hub gene SLC17A4 which is one of the model component genes and tumor progression. GDSC database was employed to determine the sensitivity of chemotherapy drugs. RESULTS Two metabolism-related clusters presented different features in overall survival (OS). A metabolic model was developed weighted by the estimated regression coefficients in the multivariate Cox regression analysis (0.5154*GAS2 + 0.395*SLC17A4 - 0.1211*NTM + 0.2939*GC). This Meta-scoring system highlights the relationship between the metabolic profiles and genomic alterations, gene pathways, functional annotation, and tumor microenvironment including stromal, immune cells, and immune checkpoint in PCa. Low MetaScore is correlated with increased mutation burden and microsatellite instability, indicating a superior response to immunotherapy. Several medications that might improve patients` prognosis in the MetaScore group were identified. Additionally, our cellular experiments suggested knock-down of SLC17A4 contributes to inhibiting invasion, colony formation, and proliferation in PCa cells in vitro. CONCLUSIONS Our study supports the metabolism-based four-gene signature as a novel and robust model for predicting prognosis, and chemo-/immuno-therapy response in PCa patients. The potential mechanisms for metabolism-associated genes in PCa oncogenesis and progression were further determined.
Collapse
Affiliation(s)
- He Li
- The Animal Laboratory Center, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Jie Gu
- Department of Geriatric Urology, Xiangya International Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Yuqiu Tian
- Department of Infectious Disease, Zhuzhou Central Hospital, Zhuzhou, Hunan, China
| | - Shuyu Li
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hao Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ziyu Dai
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zeyu Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Nan Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- One‑Third Lab, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Hei Longjiang, China
| | - Renjun Peng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| |
Collapse
|
|
37
|
Redox-Regulation in Cancer Stem Cells. Biomedicines 2022; 10:biomedicines10102413. [PMID: 36289675 PMCID: PMC9598867 DOI: 10.3390/biomedicines10102413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 09/19/2022] [Accepted: 09/21/2022] [Indexed: 11/18/2022] Open
Abstract
Cancer stem cells (CSCs) represent a small subset of slowly dividing cells with tumor-initiating ability. They can self-renew and differentiate into all the distinct cell populations within a tumor. CSCs are naturally resistant to chemotherapy or radiotherapy. CSCs, thus, can repopulate a tumor after therapy and are responsible for recurrence of disease. Stemness manifests itself through, among other things, the expression of stem cell markers, the ability to induce sphere formation and tumor growth in vivo, and resistance to chemotherapeutics and irradiation. Stemness is maintained by keeping levels of reactive oxygen species (ROS) low, which is achieved by enhanced activity of antioxidant pathways. Here, cellular sources of ROS, antioxidant pathways employed by CSCs, and underlying mechanisms to overcome resistance are discussed.
Collapse
|
|
38
|
The Role of Hypoxia-Inducible Factor Isoforms in Breast Cancer and Perspectives on Their Inhibition in Therapy. Cancers (Basel) 2022; 14:cancers14184518. [PMID: 36139678 PMCID: PMC9496909 DOI: 10.3390/cancers14184518] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/04/2022] [Accepted: 09/14/2022] [Indexed: 11/25/2022] Open
Abstract
Simple Summary In many types of cancers, the activity of the hypoxia-inducible factors enhances hallmarks such as suppression of the immune response, altered metabolism, angiogenesis, invasion, metastasis, and more. As a result of observing these features, HIFs became attractive targets in designing anticancer therapy. The lack of effective breast treatment based on HIFs inhibitors and the elusive role of those factors in this type of cancer raises the concern wheter targeting hypoxia-inducible factors is the right path. Results of the study on breast cancer cell lines suggest the need to consider aspects like HIF-1α versus HIF-2α isoforms inhibition, double versus singular isoform inhibition, different hormone receptors status, metastases, and perhaps different not yet investigated issues. In other words, targeting hypoxia-inducible factors in breast cancers should be preceded by a better understanding of their role in this type of cancer. The aim of this paper is to review the role, functions, and perspectives on hypoxia-inducible factors inhibition in breast cancer. Abstract Hypoxia is a common feature associated with many types of cancer. The activity of the hypoxia-inducible factors (HIFs), the critical element of response and adaptation to hypoxia, enhances cancer hallmarks such as suppression of the immune response, altered metabolism, angiogenesis, invasion, metastasis, and more. The HIF-1α and HIF-2α isoforms show similar regulation characteristics, although they are active in different types of hypoxia and can show different or even opposite effects. Breast cancers present several unique ways of non-canonical hypoxia-inducible factors activity induction, not limited to the hypoxia itself. This review summarizes different effects of HIFs activation in breast cancer, where areas such as metabolism, evasion of the immune response, cell survival and death, angiogenesis, invasion, metastasis, cancer stem cells, and hormone receptors status have been covered. The differences between HIF-1α and HIF-2α activity and their impacts are given special attention. The paper also discusses perspectives on using hypoxia-inducible factors as targets in anticancer therapy, given current knowledge acquired in molecular studies.
Collapse
|
|
39
|
Piorecka K, Kurjata J, Stanczyk WA. Acriflavine, an Acridine Derivative for Biomedical Application: Current State of the Art. J Med Chem 2022; 65:11415-11432. [PMID: 36018000 PMCID: PMC9469206 DOI: 10.1021/acs.jmedchem.2c00573] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
![]()
Acriflavine (ACF) has been known for years as an antibacterial
drug. The identification of key oncogenic mechanisms has brought,
in recent years, a significant increase in studies on ACF as a multipurpose
drug that would improve the prognosis for cancer patients. ACF interferes
with the expression of the hypoxia inducible factor, thus acting on
metastatic niches of tumors and significantly enhancing the effects
of other anticancer therapies. It has been recognized as the most
potent HIF-1 inhibitor out of the 336 drugs approved by the FDA. This
work presents up-to-date knowledge about the mechanisms of action
of ACF and its related prodrug systems in the context of anticancer
and SARS-CoV-2 inhibitory properties. It explains the multitask nature
of this drug and suggests mechanisms of ACF’s action on the
coronavirus. Other recent reports on ACF-based systems as potential
antibacterial and antiviral drugs are also described.
Collapse
Affiliation(s)
- Kinga Piorecka
- Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences,Sienkiewicza 112, 90-363 Lodz, Poland
| | - Jan Kurjata
- Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences,Sienkiewicza 112, 90-363 Lodz, Poland
| | - Wlodzimierz A Stanczyk
- Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences,Sienkiewicza 112, 90-363 Lodz, Poland
| |
Collapse
|
|
40
|
The Function of N-Myc Downstream-Regulated Gene 2 (NDRG2) as a Negative Regulator in Tumor Cell Metastasis. Int J Mol Sci 2022; 23:ijms23169365. [PMID: 36012631 PMCID: PMC9408851 DOI: 10.3390/ijms23169365] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/18/2022] [Accepted: 08/18/2022] [Indexed: 11/23/2022] Open
Abstract
N-myc downstream-regulated gene 2 (NDRG2) is a tumor-suppressor gene that suppresses tumorigenesis and metastasis of tumors and increases sensitivity to anti-cancer drugs. In this review, we summarize information on the clinicopathological characteristics of tumor patients according to NDRG2 expression in various tumor tissues and provide information on the metastasis inhibition-related cell signaling modulation by NDRG2. Loss of NDRG2 expression is a prognostic factor that correlates with TNM grade and tumor metastasis and has an inverse relationship with patient survival in various tumor patients. NDRG2 inhibits cell signaling, such as AKT-, NF-κB-, STAT3-, and TGF-β-mediated signaling, to induce tumor metastasis, and induces activation of GSK-3β which has anti-tumor effects. Although NDRG2 operates as an adaptor protein to mediate the interaction between kinases and phosphatases, which is essential in regulating cell signaling related to tumor metastasis, the molecular mechanism of NDRG2 as an adapter protein does not seem to be fully elucidated. This review aims to assist the research design regarding NDRG2 function as an adaptor protein and suggests NDRG2 as a molecular target to inhibit tumor metastasis and improve the prognosis in tumor patients.
Collapse
|
|
41
|
Wang X, Brea L, Lu X, Gritsina G, Park SH, Xie W, Zhao JC, Yu J. FOXA1 inhibits hypoxia programs through transcriptional repression of HIF1A. Oncogene 2022; 41:4259-4270. [PMID: 35931888 PMCID: PMC9464719 DOI: 10.1038/s41388-022-02423-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 07/18/2022] [Accepted: 07/21/2022] [Indexed: 12/11/2022]
Abstract
Intratumoral hypoxia is associated with castration-resistant prostate cancer (CRPC), a lethal disease. FOXA1 is an epithelial transcription factor that is down-regulated in CRPC. We have previously reported that FOXA1 loss induces epithelial-mesenchymal transition (EMT) and cell motility through elevated TGFβ signaling. However, whether FOXA1 directly regulates hypoxia pathways of CRPC tumors has not been previously studied. Here we report that FOXA1 down-regulation induces hypoxia transcriptional programs, and FOXA1 level is negatively correlated with hypoxia markers in clinical prostate cancer (PCa) samples. Mechanistically, FOXA1 directly binds to an intragenic enhancer of HIF1A to inhibit its expression, and HIF1A, in turn, is critical in mediating FOXA1 loss-induced hypoxia gene expression. Further, we identify CCL2, a chemokine ligand that modulates tumor microenvironment and promotes cancer progression, as a crucial target of the FOXA1-HIF1A axis. We found that FOXA1 loss leads to immunosuppressive macrophage infiltration and increased cell invasion, dependent on HIF1A expression. Critically, therapeutic targeting of HIF1A-CCL2 using pharmacological inhibitors abolishes FOXA1 loss-induced macrophage infiltration and PCa cell invasion. In summary, our study reveals an essential role of FOXA1 in controlling the hypoxic tumor microenvironment and establishes the HIF1A-CCL2 axis as one mechanism of FOXA1 loss-induced CRPC progression.
Collapse
Affiliation(s)
- Xiaohai Wang
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA,Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lourdes Brea
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Xiaodong Lu
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Galina Gritsina
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Su H. Park
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Wanqing Xie
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jonathan C. Zhao
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jindan Yu
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. .,Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. .,Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| |
Collapse
|
|
42
|
Kim H, Kim D, Kim W, Kim E, Jang WI, Kim MS. The Efficacy of Radiation is Enhanced by Metformin and Hyperthermia Alone or Combined Against FSaII Fibrosarcoma in C3H Mice. Radiat Res 2022; 198:190-199. [DOI: 10.1667/rade-21-00231.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 05/16/2022] [Indexed: 11/03/2022]
Affiliation(s)
- Hyunkyung Kim
- Clinical Translational Research Team, Korea Institute of Radiological & Medical Sciences, Seoul, Korea
| | - Dohyeon Kim
- Clinical Translational Research Team, Korea Institute of Radiological & Medical Sciences, Seoul, Korea
| | - Wonwoo Kim
- Clinical Translational Research Team, Korea Institute of Radiological & Medical Sciences, Seoul, Korea
| | - EunJi Kim
- Department of Radiation Oncology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea
| | - Won Il Jang
- Department of Radiation Oncology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea
| | - Mi-Sook Kim
- Department of Radiation Oncology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea
| |
Collapse
|
|
43
|
AMPK's double-faced role in advanced stages of prostate cancer. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2022; 24:2064-2073. [PMID: 35781781 DOI: 10.1007/s12094-022-02874-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 06/08/2022] [Indexed: 10/17/2022]
Abstract
Prostate cancer (PCa) is the second leading cause of cancer deaths in men. Unfortunately, a very limited number of drugs are available for the relapsed and advanced stages of PCa, adding only a few months to survival; therefore, it is vital to develop new drugs. 5´ AMP-activated protein kinase (AMPK) is a master regulator of cell metabolism. It plays a significant role in the metabolism of PCa; hence, it can serve well as a treatment option for the advanced stages of PCa. However, whether this pathway contributes to cancer cell survival or death remains unknown. The present study reviews the possible pathways by which AMPK plays role in the advanced stages of PCa, drug resistance, and metastasis: (1) AMPK has a contradictory role in promoting glycolysis and the Warburg effect which are correlated with cancer stem cells (CSCs) survival and advanced PCa. It exerts its effect by interacting with hypoxia-induced factor 1 (HIF1) α, pyruvate kinase 2 (PKM2), glucose transporter (GLUT) 1 and pyruvate dehydrogenase complex (PDHC), which are key regulators of glycolysis; however, whether it promotes or discourage glycolysis is not conclusive. It can also exert an anti-CSC effect by negative regulation of NANOG and epithelial-mesenchymal transition (EMT) transcription factors, which are the major drivers of CSC maintenance; (2) the regulatory effect of AMPK on autophagy is also noticeable. Androgen receptors' expression increases AMPK activation through Calcium/calmodulin-dependent protein kinase 2 (CaMKK2) and induces autophagy. In addition, AMPK itself increases autophagy by downregulating the mammalian target of rapamycin complex (mTORC). However, whether increased autophagy inhibits or promotes cell death and drug resistance is contradictory. This study reveals that there are numerous pathways other than cell metabolism by which AMPK exerts its effects in the advanced stages of PCa, making it a priceless treatment target. Finally, we mention some drugs developed to treat the advanced stages of PCa by acting on AMPK.
Collapse
|
|
44
|
Banik A, Sharma R, Chauhan A, Singh S. Cutting the umbilical cord: Cancer stem cell-targeted therapeutics. Life Sci 2022; 299:120502. [PMID: 35351466 DOI: 10.1016/j.lfs.2022.120502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 03/14/2022] [Accepted: 03/22/2022] [Indexed: 10/18/2022]
Abstract
Cancer Stem Cells (CSCs) are a notoriously quiescent subpopulation of cells within heterogeneous tumors exhibiting self-renewal, differentiation and drug-resistant capabilities leading to tumor relapse. Heterogeneous cell populations in tumor microenvironment develop an elaborate network of signalling and factors supporting the CSC population within a niche. Identification of specific biomarkers for CSCs facilitates their isolation. CSCs demonstrate abilities that bypass immune surveillance, exhibit resistance to therapy, and induce cancer recurrence while promoting altered metabolism of the bulk tumor, thereby encouraging metastasis. The fight against cancer is prone to relapse without discussing the issue of CSCs, making it imperative for encapsulation of current studies. In this review, we provide extensive knowledge of recent therapeutics developed that target CSCs via multiple signalling cascades, altered metabolism and the tumor microenvironment. Thorough understanding of the functioning of CSCs, their interaction with different cells in the tumor microenvironment as well as current gaps in knowledge are addressed. We present possible strategies to disrupt the cellular and molecular interplay within the tumor microenvironment and make it less conducive for CSCs, which may aid in their eradication with subsequently better treatment outcomes. In conclusion, we discuss a brief yet functional idea of emerging concepts in CSC biology to develop efficient therapeutics acting on cancer recurrence and metastasis.
Collapse
Affiliation(s)
- Ankit Banik
- Department of Biotechnology, Pondicherry University, Chinna Kalapet, Puducherry 605014, India
| | - Rishika Sharma
- Department of Biotechnology, Indian Institute of Technology, Roorkee, Roorkee 247667, India
| | - Akansha Chauhan
- Amity Institute of Physiology and Allied Sciences, Amity University, Noida, India
| | - Sandhya Singh
- Amity Institute of Physiology and Allied Sciences, Amity University, Noida, India.
| |
Collapse
|
|
45
|
Hydroxytyrosol Alleviated Hypoxia-Mediated PC12 Cell Damage through Activating PI3K/AKT/mTOR-HIF-1α Signaling. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8673728. [PMID: 35693707 PMCID: PMC9187455 DOI: 10.1155/2022/8673728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 03/22/2022] [Accepted: 05/13/2022] [Indexed: 12/18/2022]
Abstract
Background Hypoxia exerts pressure on cells and organisms, and this pressure can occur under both pathological and nonpathological conditions. There are many reports confirmed that hydroxytyrosol has good in vitro antioxidant activity, while the research about hydroxytyrosol on hypoxia-mediated cell damage is still unclear. Purpose The aim of this study was to investigate the effect and mechanism of hydroxytyrosol on hypoxia-mediated cell damage. Methods We studied the effects of hydroxytyrosol on the content of reactive oxygen species, the change of antioxidant enzymes activity of SOD, CAT, and GSH-Px and the content of oxidation products MDA and GSH, and the changes of cell membrane potential and effect on PI3K/AKT/mTOR-HIF-1α signaling pathway under hypoxia-mediated PC12 cell. Results PC12 cell treated with hydroxytyrosol abated the cell apoptosis and alleviated the oxidative stress through scavenging of reactive oxygen species, improving the enzyme activity and changing the content of oxidation products and alleviating mitochondria damage. Western blotting confirmed that the mechanism maybe related to the PI3K/AKT/mTOR-HIF-1α signaling pathway. The inhibition experiment confirmed that hydroxytyrosol takes part in the expression of protein PI3K and p-mTOR. Conclusion Hydroxytyrosol reduced the oxidative stress and resisted the inhibition of PI3K/AKT/mTOR-HIF-1α signaling pathway caused by hypoxia, improved cell apoptosis, and ameliorated the antihypoxia ability of PC12 cells under hypoxia.
Collapse
|
|
46
|
Zhang W, Sang S, Peng C, Li GQ, Ou L, Feng Z, Zou Y, Yuan Y, Yao M. Network Pharmacology and Transcriptomic Sequencing Analyses Reveal the Molecular Mechanism of Sanguisorba officinalis Against Colorectal Cancer. Front Oncol 2022; 12:807718. [PMID: 35646655 PMCID: PMC9133337 DOI: 10.3389/fonc.2022.807718] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 04/11/2022] [Indexed: 11/23/2022] Open
Abstract
Background Colorectal cancer (CRC) is the most common malignant cancer worldwide. Sanguisorba officinalis has been shown to have anti-inflammatory, anti-bacterial, antioxidant, and anti-tumor effects, while its molecular mechanism against CRC remains unclear. The aim of this study is to explore the underlying mechanism of S. officinalis against CRC cell lines using network pharmacology and transcriptomic sequencing methods. Method Firstly, the active ingredients and potential targets of S. officinalis against CRC were screened from databases. Secondly, the networks of ingredient–target, ingredient–target–CRC and protein–protein interaction were constructed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of network pharmacology and transcriptomic sequencing were performed. Finally, the effect of S. officinalis against CRC was verified by in vitro experiments. Results In total, 14 active ingredients and 273 potential targets against CRC were identified in S. officinalis by network pharmacology. PI3K–Akt, HIF-1, and MAPK signaling pathways related to cell proliferation were regulated by S. officinalis in enrichment analyses and transcriptomic sequencing. In vitro, S. officinalis inhibited the proliferation and migration of CRC cells and arrested the cell cycle at the G0–G1 phase. The western blot showed that S. officinalis downregulated the expression of p-PI3K, p-Akt, HIF-1A, VEGFA, cyclin D1, c-Myc, and p-MAPK proteins in CRC cells. Conclusion In conclusion, network pharmacology and transcriptomic sequencing analyses, in combination with in vitro studies, have been successfully applied to study the underlying mechanism of S. officinalis against CRC cells. Our results demonstrate that S. officinalis suppresses the proliferation, survival, and migration of CRC cells through regulating the PI3K–Akt, HIF-1, and MAPK signaling pathways.
Collapse
Affiliation(s)
- Weijia Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Shuyi Sang
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Chang Peng
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - George Q Li
- Institute of Natural Products and Metabolomics, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ling Ou
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Zhong Feng
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Yuanjing Zou
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Yuemei Yuan
- School of Ecology, Sun Yat-sen University, Guangzhou, China
| | - Meicun Yao
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, China
| |
Collapse
|
|
47
|
Koltai T, Reshkin SJ, Carvalho TMA, Di Molfetta D, Greco MR, Alfarouk KO, Cardone RA. Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review. Cancers (Basel) 2022; 14:2486. [PMID: 35626089 PMCID: PMC9139729 DOI: 10.3390/cancers14102486] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.
Collapse
Affiliation(s)
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Khalid Omer Alfarouk
- Zamzam Research Center, Zamzam University College, Khartoum 11123, Sudan;
- Alfarouk Biomedical Research LLC, Temple Terrace, FL 33617, USA
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| |
Collapse
|
|
48
|
Guo Y, Ren Y, Dong X, Kan X, Zheng C. An Overview of Hepatocellular Carcinoma After Insufficient Radiofrequency Ablation. J Hepatocell Carcinoma 2022; 9:343-355. [PMID: 35502292 PMCID: PMC9056053 DOI: 10.2147/jhc.s358539] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 04/04/2022] [Indexed: 12/13/2022] Open
Abstract
Radiofrequency ablation (RFA) is a commonly used treatment for hepatocellular carcinoma (HCC), however, various complex conditions in clinical practice may lead to insufficient radiofrequency ablation (IRFA), allowing residual HCC to survive. In clinical practice and laboratory models, IRFA plays an important role in rapid tumor progression. Therefore, targeting the residual HCC and avoiding IRFA were worthwhile methods. A deeper understanding of IRFA is required; IRFA contributes to the improvement of proliferative activity, migration rates, and invasive capacity, and this may be due to the involvement of multiple complex processes or proteins, including epithelial mesenchymal transitions (EMTs), cancer stem cells (CSCs), autophagy, heat shock proteins (HSPs), changes of non-tumor cells and extracellular matrix, altered immune microenvironment, hypoxia-inducible factors (HIFs), growth factors, epigenetic alterations, and metabolic reprogramming. We focus on the processes of the above mechanisms and possible therapeutic approach, with a review of the literature. Additionally, we recapitulated the construction methods of various experimental models of IRFA (in vivo and in vitro).
Collapse
Affiliation(s)
- Yusheng Guo
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Yanqiao Ren
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Xiangjun Dong
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Xuefeng Kan
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
- Correspondence: Chuansheng Zheng, Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China, Tel/Fax +86-27-85726290, Email
| |
Collapse
|
|
49
|
Zhao R, Trainor PA. Epithelial to mesenchymal transition during mammalian neural crest cell delamination. Semin Cell Dev Biol 2022; 138:54-67. [PMID: 35277330 DOI: 10.1016/j.semcdb.2022.02.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 02/08/2022] [Accepted: 02/21/2022] [Indexed: 11/18/2022]
Abstract
Epithelial to mesenchymal transition (EMT) is a well-defined cellular process that was discovered in chicken embryos and described as "epithelial to mesenchymal transformation" [1]. During EMT, epithelial cells lose their epithelial features and acquire mesenchymal character with migratory potential. EMT has subsequently been shown to be essential for both developmental and pathological processes including embryo morphogenesis, wound healing, tissue fibrosis and cancer [2]. During the past 5 years, interest and study of EMT especially in cancer biology have increased exponentially due to the implied role of EMT in multiple aspects of malignancy such as cell invasion, survival, stemness, metastasis, therapeutic resistance and tumor heterogeneity [3]. Since the process of EMT in embryogenesis and cancer progression shares similar phenotypic changes, core transcription factors and molecular mechanisms, it has been proposed that the initiation and development of carcinoma could be attributed to abnormal activation of EMT factors usually required for normal embryo development. Therefore, developmental EMT mechanisms, whose timing, location, and tissue origin are strictly regulated, could prove useful for uncovering new insights into the phenotypic changes and corresponding gene regulatory control of EMT under pathological conditions. In this review, we initially provide an overview of the phenotypic and molecular mechanisms involved in EMT and discuss the newly emerging concept of epithelial to mesenchymal plasticity (EMP). Then we focus on our current knowledge of a classic developmental EMT event, neural crest cell (NCC) delamination, highlighting key differences in our understanding of NCC EMT between mammalian and non-mammalian species. Lastly, we highlight available tools and future directions to advance our understanding of mammalian NCC EMT.
Collapse
Affiliation(s)
- Ruonan Zhao
- Stowers Institute for Medical Research, Kansas City, MO, USA; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Paul A Trainor
- Stowers Institute for Medical Research, Kansas City, MO, USA; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
| |
Collapse
|
|
50
|
Byun JY, Huang K, Lee JS, Huang W, Hu L, Zheng X, Tang X, Li F, Jo DG, Song X, Huang C. Targeting HIF-1α/NOTCH1 pathway eliminates CD44 + cancer stem-like cell phenotypes, malignancy, and resistance to therapy in head and neck squamous cell carcinoma. Oncogene 2022; 41:1352-1363. [PMID: 35013621 DOI: 10.1038/s41388-021-02166-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 12/03/2021] [Accepted: 12/22/2021] [Indexed: 01/16/2023]
Abstract
Poor prognosis of head and neck squamous cell carcinomas (HNSCCs) results from resistance to chemotherapy and radiotherapy. To uncover the drivers of HNSCC resistance, including stemness and hypoxia, in this study, we compared the gene expression between CD44+ and CD44- HNSCC cells and assessed the correlation of CD44 and hypoxia-inducible factor 1α (HIF-1α) expression with mouse features and outcomes of patients with HNSCC. We combined the knockdown or activation of HIF-1α with in vitro and in vivo assays to evaluate effects on stemness and resistance of HNSCC cells. Analysis of clinical data showed that activation of HIF-1α in CD44+ patients with HNSCC was correlated with worse prognosis. Functional assays showed that HIF-1α promoted stemness, resistance, and epithelial-mesenchymal transition in HNSCC CD44+ cells. HIF-1α activated NOTCH1 signaling in HNSCC stem-like cells characterized by CD44 expression. Moreover, inhibition of these signaling proteins using shRNA or Evofosfamide (Evo) development for cancer treatment, reversed chemoresistance in vitro and in vivo. Taken together, our results indicated that targeting HIF-1α attenuated NOTCH1-induced stemness, which regulates responses to chemotherapy or radiotherapy and malignancy in CD44+ HNSCCs. HIF-1α/NOTCH1 signaling may represent a target for HNSCC treatment.
Collapse
Affiliation(s)
- Joo-Yun Byun
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Kun Huang
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jong Suk Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Wenjie Huang
- Key Laboratory of Diagnostic Medicine designated by the Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Li Hu
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xuyu Zheng
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xin Tang
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Fengzeng Li
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dong-Gyu Jo
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Xinmao Song
- Department of Radiation Oncology, Eye, Ear, Nose and Throat Hospital of Fudan University, Shanghai, China.
| | - Chuang Huang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China.
| |
Collapse
|