|
1
|
Bakrim S, El Hachlafi N, Khalid A, Abdalla AN, El Omari N, Aboulaghras S, Sakran AM, Goh KW, Ming LC, Razi P, Bouyahya A. Recent advances and molecular mechanisms of TGF-β signaling in colorectal cancer, with focus on bioactive compounds targeting. Biomed Pharmacother 2024; 177:116886. [PMID: 38945700 DOI: 10.1016/j.biopha.2024.116886] [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: 03/03/2024] [Revised: 05/30/2024] [Accepted: 06/03/2024] [Indexed: 07/02/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most significant forms of human cancer. It is characterized by its heterogeneity because several molecular factors are involved in contiguity and can link it to others without having a linear correlation. Among the factors influencing tumor transformation in CRC, transforming growth factor-beta (TGF-β) plays a key promoter role. This factor is associated with human colorectal tumors with a very high prognosis: it increases the survival, invasion, and metastasis of CRC cells, thus functioning as an oncogene. The inhibition of this factor can constitute a major therapeutic route for CRC treatment. Various chemical drugs including synthetic molecules and biotherapies have been developed as TGF-β inhibitors. Moreover, the scientific community has recently shown a major interest in screening natural drugs inhibiting TGF-β in CRC. In this context, we carried out this review article using computerized databases, such as PubMed, Google Scholar, Springer Link, Science Direct, Cochrane Library, Embase, Web of Science, and Scopus, to highlight the molecular mechanism of TGF-β in CRC induction and progression and current advances in the pharmacodynamic effects of natural bioactive substances targeting TGF-β in CRC.
Collapse
Affiliation(s)
- Saad Bakrim
- Geo-Bio-Environment Engineering and Innovation Laboratory, Molecular Engineering, Biotechnology and Innovation Team, Polydisciplinary Faculty of Taroudant, Ibn Zohr University, Agadir 80000, Morocco
| | - Naoufal El Hachlafi
- Microbial Biotechnology and Bioactive Molecules Laboratory, Sciences and Technologies Faculty, Sidi Mohmed Ben Abdellah University, P.O.Box-2002, Imouzzer Road, Fez, Morocco
| | - Asaad Khalid
- Health Research Center, Jazan University, P.O. Box: 114, Jazan 45142, Saudi Arabia.
| | - Ashraf N Abdalla
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Nasreddine El Omari
- High Institute of Nursing Professions and Health Techniques of Tetouan, Tetouan, Morocco
| | - Sara Aboulaghras
- Laboratory of Human Pathologies Biology, Faculty of Sciences, Mohammed V University in Rabat, Rabat 10106, Morocco
| | - Ashraf M Sakran
- Department of Anatomy, Faculty of Medicine, Umm Alqura University, Makkah 21955, Saudi Arabia
| | - Khang Wen Goh
- Faculty of Data Science and Information Technology, INTI International University, Nilai, Malaysia
| | - Long Chiau Ming
- School of Medical and Life Sciences, Sunway University, Sunway City, Malaysia.
| | - Pakhrur Razi
- Center of Disaster Monitoring and Earth Observation, Universitas Negeri Padang, Padang, Indonesia.
| | - Abdelhakim Bouyahya
- Laboratory of Human Pathologies Biology, Faculty of Sciences, Mohammed V University in Rabat, Rabat 10106, Morocco
| |
Collapse
|
|
2
|
Cui G, Li Z, Florholmen J, Goll R. Dynamic stromal cellular reaction throughout human colorectal adenoma-carcinoma sequence: A role of TH17/IL-17A. Biomed Pharmacother 2021; 140:111761. [PMID: 34044278 DOI: 10.1016/j.biopha.2021.111761] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/07/2021] [Accepted: 05/20/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Accumulating data suggest that the tumour stroma rapidly undergoes dynamic mechanical and cellular changes by which creates a supportive milieu to promote disease progression and metastasis. Cytokines are reported to play a key role in the modulation of tumour stromal response. METHODS The activation of TH17/interleukin (IL)-17A network in association with tumour stromal proliferative and cellular response in samples from 50 patients with colorectal adenoma, 45 with colorectal cancer (CRCs) were elucidated with quantitative real-time PCR (q-PCR), immunohistochemistry and double immunofluorescence. RESULTS q-PCR results showed that retinoic acid-receptor-related orphan receptor-C, a critical transcriptional factor for TH17 cell differentiation, was significantly increased at the adenoma stage and slightly decreased at the CRC stage, but was still higher than that at normal controls. The level of TH17 signature cytokine IL-17A was shown in an increasing gradient throughout the adenoma-carcinoma sequence. Immunohistochemistry revealed an activated proliferative rate evaluated by Ki67 and population expansion of myofibroblasts in the adenoma/CRC stroma. Notably, densities of IL-17A-expressing cells were associated with populations of Ki67-positive cells and myofibroblasts in the adenoma/CRC stroma. Finally, CD146-positive stromal cells are an important participator for stroma remodelling, double immunofluorescence image demonstrated that IL-17 receptor C, one of the key elements for IL-17 receptor complex, was highly expressed in CD146-positive adenoma/CRC stromal cells. CONCLUSIONS An activated TH17/IL-17A network in the tumour microenvironment is significantly associated with dynamic stromal cellular response throughout the adenoma-carcinoma sequence, which might provide a supportive environment for the initiation and progression of CRC.
Collapse
Affiliation(s)
- Guanglin Cui
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Faculty of Heath Science, Nord University at Levanger, Norway.
| | - Zhenfeng Li
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jon Florholmen
- Research Group Gastroenterology Nutrition, Arctic University Norway, Tromsø, Norway
| | - Rasmus Goll
- Research Group Gastroenterology Nutrition, Arctic University Norway, Tromsø, Norway
| |
Collapse
|
|
3
|
Dadey RE, Workman CJ, Vignali DAA. Regulatory T Cells in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1273:105-134. [PMID: 33119878 DOI: 10.1007/978-3-030-49270-0_6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Regulatory T cells (Tregs) are an immunosuppressive subpopulation of CD4+ T cells that are endowed with potent suppressive activity and function to limit immune activation and maintain homeostasis. These cells are identified by the hallmark transcription factor FOXP3 and the high-affinity interleukin-2 (IL-2) receptor chain CD25. Tregs can be recruited to and persist within the tumor microenvironment (TME), acting as a potent barrier to effective antitumor immunity. This chapter will discuss [i] the history and hallmarks of Tregs; [ii] the recruitment, development, and persistence of Tregs within the TME; [iii] Treg function within TME; asnd [iv] the therapeutic targeting of Tregs in the clinic. This chapter will conclude with a discussion of likely trends and future directions.
Collapse
Affiliation(s)
- Rebekah E Dadey
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.,Tumor Microenvironment Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, USA.,Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.,Graduate Program of Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Creg J Workman
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.,Tumor Microenvironment Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, USA.,Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Dario A A Vignali
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. .,Tumor Microenvironment Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, USA. .,Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
| |
Collapse
|
|
4
|
Chen XL, Chen ZQ, Zhu SL, Liu TW, Wen Y, Su YS, Xi XJ, Hu Y, Lian L, Liu FB. Prognostic value of transforming growth factor-beta in patients with colorectal cancer who undergo surgery: a meta-analysis. BMC Cancer 2017; 17:240. [PMID: 28376764 PMCID: PMC5379512 DOI: 10.1186/s12885-017-3215-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 03/22/2017] [Indexed: 02/07/2023] Open
Abstract
Background Transforming growth factor-beta (TGF-β) is associated with a higher incidence of distant metastasis and decreased survival. Whether TGF-β can be used as a prognostic indicator of colorectal cancer (CRC) remains controversial. Methods The Medline, EMBASE and Cochrane databases were searched from their inception to March 2016. The studies that focused on TGF-β as a prognostic factor in patients with CRC were included in this analysis. Overall survival (OS) and disease-free survival (DFS) were analysed separately. A meta-analysis was performed, and hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Results Twelve studies were included in the analysis, of which 8 were used for OS and 7 for DFS. In all, 1622 patients with CRC undergoing surgery were included. Combined HRs suggested that high expression of TGF-β had a favourable impact on OS (HR = 1.68, 95% CI: 1.10–2.59) and DFS (HR = 1.11, 95% CI: 1.03–1.19) in CRC patients. For OS, the combined HRs of Asian studies and Western studies were 1.50 (95% CI: 0.61–3.68) and 1.80 (95% CI: 1.33–2.45), respectively. For DFS, the combined HRs of Asian studies and Western studies were 1.42 (95% CI: 0.61–3.31) and 1.11 (95% CI: 1.03–1.20), respectively. Conclusions This meta-analysis demonstrates that TGF-β can be used as a prognostic biomarker for CRC patients undergoing surgery, especially for CRC patients from Western countries. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3215-7) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Xin-Lin Chen
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhuo-Qun Chen
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shui-Lian Zhu
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Tian-Wen Liu
- Guangdong Province Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi Wen
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi-Sheng Su
- Guangdong Province Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xu-Jie Xi
- Guangdong Province Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yue Hu
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lei Lian
- Department of Colorectal Surgery, Sun Yat-sen University, Guangzhou, China.
| | - Feng-Bin Liu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.
| |
Collapse
|
|
5
|
Nagaraju GP, Bramhachari PV, Raghu G, El-Rayes BF. Hypoxia inducible factor-1α: Its role in colorectal carcinogenesis and metastasis. Cancer Lett 2015; 366:11-8. [PMID: 26116902 DOI: 10.1016/j.canlet.2015.06.005] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 05/29/2015] [Accepted: 06/09/2015] [Indexed: 01/05/2023]
Abstract
Tumor growth creates a hypoxic microenvironment, which promotes angiogenesis and aggressive tumor growth and invasion. HIF1α is a central molecule involved in mediating these effects of hypoxia. In colorectal cancer (CRC), hypoxia stabilizes the transcription factor HIF1α, leading to the expression of genes that are involved in tumor vascularization, metastasis/migration, cell survival and chemo-resistance. Therefore, HIF1α is a rational target for the development of new therapeutics for CRC. This article reviews the central role of HIF1α in CRC angiogenesis, metastasis, and progression as well as the strategies to target HIF1α stabilization.
Collapse
Affiliation(s)
- Ganji Purnachandra Nagaraju
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
| | | | - Godi Raghu
- Department of Biotechnology, Krishna University, Machilipatnam, AP-521001, India
| | - Bassel F El-Rayes
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
| |
Collapse
|
|
6
|
Hypoxia triggers a Nur77-β-catenin feed-forward loop to promote the invasive growth of colon cancer cells. Br J Cancer 2014; 110:935-45. [PMID: 24423919 PMCID: PMC3929893 DOI: 10.1038/bjc.2013.816] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Revised: 11/20/2013] [Accepted: 12/10/2013] [Indexed: 01/10/2023] Open
Abstract
Background: β-Catenin is a potent oncogenic protein in colorectal cancer (CRC), but the targets and regulation of this important signalling molecule are not completely understood. Hypoxia is a prominent feature of solid tumours that contributes to cancer progression. Methods: Here, we analysed the regulation between Nur77 and β-catenin under hypoxic conditions. Cell proliferation, migration, and invasion assays were performed to assess functional consequences. Results: We showed that hypoxia stimulated co-upregulation of β-catenin and Nur77 in a number of human CRC cell lines. Interestingly, expression of β-catenin and Nur77 by hypoxia formed a mutual feedback regulation circuits that conferred aggressive growth of CRC. Overexpression of β-catenin increased Nur77 transcription through hypoxia-inducible factor-1α rather than T-cell factor. Nur77-mediated activation of β-catenin by hypoxia was independent of both DNA binding and transactivation. Further, we showed that hypoxic activation of β-catenin was independent of the classical adenomatous polyposis coli and p53 pathways, but stimulated by phosphatidylinositol 3-kinase/Akt in a Nur77-dependent manner. Under hypoxic conditions, enhanced β-catenin and Nur77 expression synergistically stimulated CRC cell migration, invasion, and epithelial–mesenchymal transition. Conclusion: These findings provide a novel molecular mechanism for hypoxic CRCs that may contribute to tumour progression, and its targeting may represent an effective therapeutic avenue.
Collapse
|
|
7
|
Zhang Q, Bai X, Chen W, Ma T, Hu Q, Liang C, Xie S, Chen C, Hu L, Xu S, Liang T. Wnt/β-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1α signaling. Carcinogenesis 2013; 34:962-973. [PMID: 23358852 DOI: 10.1093/carcin/bgt027] [Citation(s) in RCA: 190] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a critical process for tumor invasion and metastasis. Hypoxia may induce EMT, and upregulated β-catenin expression has been found in various tumors. In this study, we investigate the role of β-catenin in hypoxia-induced EMT in hepatocellular carcinoma (HCC). Induction of EMT in HCC cell lines by hypoxia was confirmed by altered morphology, expression change of EMT-associated markers and enhanced invasion capacity. We showed that hypoxia-induced EMT could be enhanced by addition of recombinant Wnt3a while it was repressed by β-catenin small interfering RNA. An interaction between β-catenin and hypoxia-induced factor-1α (hif-1α) was found, and an underlying competition for β-catenin between hif-1α and T-cell factor-4 was implied. Notably, increased hif-1α activity was accompanied with more significant EMT features. We also showed that the pro-EMT effect of β-catenin in hypoxia was deprived in the absence of hif-1α. Moreover, β-catenin was found to be responsible for the maintenance of viability and proliferation for tumor cells undergoing hypoxia. We further showed a correlation between hif-1α and β-catenin expression, and corresponding expression of EMT-associated markers in human HCC tissues. Our results suggest that Wnt/β-catenin signaling enhances hypoxia-induced EMT in HCC by increasing the EMT-associated activity of hif-1α and preventing tumor cell death.
Collapse
Affiliation(s)
- Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
8
|
Kockar F, Yildrim H, Sagkan RI, Hagemann C, Soysal Y, Anacker J, Hamza AA, Vordermark D, Flentje M, Said HM. Hypoxia and cytokines regulate carbonic anhydrase 9 expression in hepatocellular carcinoma cells in vitro. World J Clin Oncol 2012; 3:82-91. [PMID: 22724087 PMCID: PMC3380102 DOI: 10.5306/wjco.v3.i6.82] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Revised: 05/30/2012] [Accepted: 06/05/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the expression of carbonic anhydrase (CA) 9 in human hepatocellular carcinoma (HCC) cells.
METHODS: We studied CA9 protein, CA9 mRNA and hypoxia-inducible factor-1 alpha (HIF-1α) protein levels in Hep3B cells exposed in different parallel approaches. In one of these approaches, HCC cells were exposed to extreme in vitro hypoxia (24 h 0.1% O2) without or with interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) stimulation for the same hypoxic exposure time or exposed to normoxic oxygenation conditions without or with cytokine stimulation.
RESULTS: The tumour cell line analysed showed a strong hypoxic CA9 mRNA expression pattern in response to prolonged severe hypoxia with cell-line specific patterns and a marked induction of CA9 protein in response to severe hypoxia. These results were paralleled by the results for HIF-1α protein under identical oxygenation conditions with a similar expression tendency to that displayed during the CA9 protein expression experimental series. Continuous stimulation with the cytokines, IL-1, IL-6, TNF-α and TGF-β, under normoxic conditions significantly increased the carbonic anhydrase 9 expression level at both the protein and mRNA level, almost doubling the CA9 mRNA and CA9 and HIF-1α protein expression levels found under hypoxia. The findings from these experiments indicated that hypoxia is a positive regulator of CA9 expression in HCC, and the four signal transduction pathways, IL-1, IL-6, TNF-α and TGF-β, positively influence CA9 expression under both normoxic and hypoxic conditions.
CONCLUSION: These findings may potentially be considered in the design of anti- cancer therapeutic approaches involving hypoxia-induced or cytokine stimulatory effects on expression. In addition, they provide evidence of the stimulatory role of the examined cytokine families resulting in an increase in CA9 expression under different oxygenation conditions in human cancer, especially HCC, and on the role of the CA9 gene as a positive disease regulator in human cancer.
Collapse
Affiliation(s)
- Feray Kockar
- Feray Kockar, Hatice Yildrim, Department of Biology, Faculty of Art and Science, Balikesir University, 10145 Balikesir, Turkey
| | | | | | | | | | | | | | | | | | | |
Collapse
|