The Role of Cancer⁃Associated Fibroblasts (Cafs) In Tumor Development
DOI:
https://doi.org/10.54097/zmw1bv40Keywords:
CAFs; Warburg Effect; TGF-β/Smad; Medicine.Abstract
Today, cancer is still the key threaten to life, and CAFs are one of the mostly studied risk factor. This article reviews the mechanism of respiration of CAFS cells in cancer like Reverse Warburg Effect of CAFs, as well as the mechanism of TGF-β/Smad, the related diseases and corresponding drugs by targeting CAFs production. In tumor microenvironment(TME), CAFs are closely associated with the development, transfer and aggression of tumor cells. ‘Reverse Warburg Effect is one of the ways for CAFs to achieve metabolic cross-talk with tumor cells. Through oxidative glycolysis, CAFs can produce plenty of energy-rich substrate, like pyruvate, fat acid and lactate, those substrates are transported to mitochondria in tumor cells in order to produce many ATP by OXPHOS. Besides, CAFs transfer lactate in hypoxia by MCT4 and then MCT1 on tumor cells surface, which can support themselves. In addition, the TGF-β/Smad, the main pathway promoting the development of CAFs and tumor cells, is also dissected. By conducting a thorough analysis on the mechanism of TGF-β based malignant cells and CAFs production, the relevant drugs are introduced. Those findings can not only enhance our understanding of the complexity of tumor metabolism, but it also provides a theoretical basis for the development of new therapeutic strategies and potential targets.
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[1] Xu M, Zhang T, Xia R, Wei Y, Wei X. Targeting the tumor stroma for cancer therapy. Mol Cancer. 2022 Nov 2;21(1):208. doi: 10.1186/s12943-022-01670-1. PMID: 36324128; PMCID: PMC9628074.
[2] Turley SJ, Cremasco V, Astarita JL. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat Rev Immunol. 2015 Nov;15(11):669-82. doi: 10.1038/nri3902. Epub 2015 Oct 16. PMID: 26471778.
[3] 2018, 22 (3): 235-242. CHEN Xi, YANG Li-fang, LI Dan. The Activation Mechanism of CAFs and Its Role in the Development of Tumor. Life Science Research, 2018, 22 (3): 235-242
[4] Zheng Rongshou, Chen Ru, Han Bingfeng, Wang Shaoming, Li Li, Sun Kexin, Zeng Hongmei, Wei Wenqiang, He Jie.Cancer incidence and mortality in China, 2022.ChinJOncol .2024,46(3): 221-231.DOI:10.3760/cma.j.cn112152-20240119-00035
[5] Kim B G, Malek E, Choi S H, et al. Novel therapies emerging in oncology to target the TGF-β pathway [J]. Journal of Hematology & Oncology, 2021, 14(1).
[6] Haque S, Morris J C. Transforming growth factor-β: A therapeutic target for cancer[J]. Human Vaccines & Immunotherapeutics, 2017.
[7] Mullard, A. Cancer drug approvals and setbacks in 2021. Nat Cancer 2, 1246–1247 (2021).
[8] Yan Y. Role of cancer-associated fibroblasts in invasion and metastasis of gastric cancer[J]. World Journal of Gastroenterology, 2015, 21(33): 9717.DOI:10.3748/wjg. v21.i33.9717.
[9] Meng XM,Nikolic-Paterson DJ,Lan HY. TGF-β: the master regulator of fibrosis [J]. Nat Rev Nephrol,2016,12(6): 325-338
[10] Chen L, Yang T, Lu DW, et al. Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment[J]. Biomed Pharmacother,2018,101:670-681.
[11] Meng XM,Tang Patrick MK,Li J,et al. TGF-β/Smad signaling in renal fibrosis [J]. Front Physiol,2015,6(82):1-8
[12] Alfarouk KO,Shayoub ME, Muddathir AK, Elhassan GO and Bashir AH:Evolution of tumor metabolism might reflect carcinogenesis as a reverse evolution process (Dismantling of Multicellularity).Cancers (Basel)3:3002-3017, 2011.
[13] Xu XD, Shao SX,Jiang HP,Cao YW, Wang YH,Yang XC,Wang YL,Wang XS and Niu HT: Warburg effect or reverse Warbrug effect? A review of cancer metabolism. Oncol ResTreat38:117-122,2015.
[14] Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T,Naeem R, Carey VJ, Richardson AL and Weinberg RA: Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL 12 secretion. Cell 121: 335-348, 2005.
[15] Arcucci A, Ruocco MR, Granato G, Sacco AM and Montagnani S: Cancer: An oxidative crosstalk between solid tumor cells and cancer associated fibroblasts. Biomed Res Int 2016: 4502846, 2016.
[16] Pertega-Gomes N, Vizcaino JR, Attig J, Jurmeister S, Lopes C and Baltazar F: A lactate shuttle system between tumor and stromal cells is associated with poor prognosis in prostate cancer. BMC Cancer 14:352, 2014.
[17] Pereira Nunes A, Afonso J, Granja S and Baltazar F: Lactate and lactate transporters as key players in the maintenance of the warburg effect. Adv Exp Med Biol 1219: 51 74, 2020.
[18] Draoui N and Feron O: Lactate shuttles at a glance: From physiological paradigms to anti-cancer treatments. Dis Model Mech 4: 727 732, 2011.
[19] Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC and Harris AL: Pyruvate dehydrogenase and pyruvate dehydrogenase kinase expression in non-small cell lung cancer and tumor associated stroma. Neoplasia 7: 1 6, 2005.
[20] Lee M and Yoon JH: Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication. World J Biol Chem 6: 148 161, 2015.
[21] Chen D and Che G: Value of caveolin 1 in cancer progression and prognosis: Emphasis on cancer associated fibroblasts, human cancer cells and mechanism of caveolin 1 expression (Review). Oncol Lett 8: 1409 1421, 2014.
[22] Chen F, Barman S, Yu Y, Haigh S, Wang Y, Black SM, Rafikov R, Dou H, Bagi Z, Han W, et al: Caveolin 1 is a negative regulator of NADPH oxidase derived reactive oxygen species. Free Radic Biol Med 73: 201 213, 2014.
[23] Semenza GL: HIF 1: Upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20: 51 56, 2010.
[24] Fu Y, Liu S, Yin S, Niu W, Xiong W, Tan M, Li G and Zhou M: The reverse Warburg effect is likely to be an Achilles' heel of cancer that can be exploited for cancer therapy. Oncotarget 8: 57813 57825, 2017.
[25] The antisense oligonucleotide trabedersen (AP 12009) for the targeted inhibition of TGF-β2
[26] Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Second-Line Treatment of Patients With NSCLC
[27] Vactosertib, a novel TGF-β1 type I receptor kinase inhibitor, improves T-cell fitness: a single-arm, phase 1b trial in relapsed/refractory multiple myeloma
[28] Melisi D, Garcia-Carbonero R, Macarulla T, et al. Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer. Br J Cancer 2018; 119:1208–14. 10.1038/s41416-018-0246-z [PMC free article] [PubMed] [CrossRef] [Google Scholar]
[29] INTERNATIONAL JOURNAL OF ONCOLOGY 60: 67, 2022
[30] Xin X, Cheng X, Zeng F, Xu Q, Hou L. The Role of TGF-β/SMAD Signaling in Hepatocellular Carcinoma: from Mechanism to Therapy and Prognosis. Int J Biol Sci. 2024 Feb 4;20(4):1436-1451. doi: 10.7150/ijbs.89568. PMID: 38385079; PMCID: PMC10878151.
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