The Multi-faceted Roles of Cancer-associated Fibroblasts in Pancreatic Cancer

Overview

Journal Cell Signal

Date 2025 Jan 5

PMID 39756502

Authors

John Y Kwon

Renzo E Vera

Martin E Fernandez-Zapico

Affiliations

Soon will be listed here.

Abstract

The tumor microenvironment (TME) has been linked with the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer. A central component of the TME are cancer-associated fibroblasts (CAFs), which can either suppress or promote tumor growth in a context-dependent manner. In this review, we will discuss the multi-faceted roles of CAFs in tumor-stroma interactions influencing cancer initiation, progression and therapeutic response.

References

Melisi D, Garcia-Carbonero R, Macarulla T, Pezet D, Deplanque G, Fuchs M . TGFβ receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer. Cancer Chemother Pharmacol. 2019; 83(5):975-991. DOI: 10.1007/s00280-019-03807-4. View

Olivares O, Mayers J, Gouirand V, Torrence M, Gicquel T, Borge L . Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nat Commun. 2017; 8:16031. PMC: 5504351. DOI: 10.1038/ncomms16031. View

Sandoval P, Jimenez-Heffernan J, Rynne-Vidal A, Perez-Lozano M, Gilsanz A, Ruiz-Carpio V . Carcinoma-associated fibroblasts derive from mesothelial cells via mesothelial-to-mesenchymal transition in peritoneal metastasis. J Pathol. 2013; 231(4):517-31. DOI: 10.1002/path.4281. View

Webb B, Chimenti M, Jacobson M, Barber D . Dysregulated pH: a perfect storm for cancer progression. Nat Rev Cancer. 2011; 11(9):671-7. DOI: 10.1038/nrc3110. View

De Jesus-Acosta A, Sugar E, ODwyer P, Ramanathan R, Von Hoff D, Rasheed Z . Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma. Br J Cancer. 2019; 122(4):498-505. PMC: 7029016. DOI: 10.1038/s41416-019-0683-3. View

Zeisberg E, Potenta S, Xie L, Zeisberg M, Kalluri R . Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 2007; 67(21):10123-8. DOI: 10.1158/0008-5472.CAN-07-3127. View

Qian D, Lu Z, Xu Q, Wu P, Tian L, Zhao L . Galectin-1-driven upregulation of SDF-1 in pancreatic stellate cells promotes pancreatic cancer metastasis. Cancer Lett. 2017; 397:43-51. DOI: 10.1016/j.canlet.2017.03.024. View

Vincent T, Neve E, Johnson J, Kukalev A, Rojo F, Albanell J . A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition. Nat Cell Biol. 2009; 11(8):943-50. PMC: 3769970. DOI: 10.1038/ncb1905. View

Lee J, Stone M, Porrett P, Thomas S, Komar C, Li J . Hepatocytes direct the formation of a pro-metastatic niche in the liver. Nature. 2019; 567(7747):249-252. PMC: 6430113. DOI: 10.1038/s41586-019-1004-y. View

10.

Lone S, Nisar S, Masoodi T, Singh M, Rizwan A, Hashem S . Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments. Mol Cancer. 2022; 21(1):79. PMC: 8932066. DOI: 10.1186/s12943-022-01543-7. View

11.

Tjomsland V, Spangeus A, Valila J, Sandstrom P, Borch K, Druid H . Interleukin 1α sustains the expression of inflammatory factors in human pancreatic cancer microenvironment by targeting cancer-associated fibroblasts. Neoplasia. 2011; 13(8):664-75. PMC: 3156657. DOI: 10.1593/neo.11332. View

12.

Sousa C, Biancur D, Wang X, Halbrook C, Sherman M, Zhang L . Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature. 2016; 536(7617):479-83. PMC: 5228623. DOI: 10.1038/nature19084. View

13.

Ozdemir B, Pentcheva-Hoang T, Carstens J, Zheng X, Wu C, Simpson T . Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014; 25(6):719-34. PMC: 4180632. DOI: 10.1016/j.ccr.2014.04.005. View

14.

Ostapoff K, Cenik B, Wang M, Ye R, Xu X, Nugent D . Neutralizing murine TGFβR2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis. Cancer Res. 2014; 74(18):4996-5007. PMC: 4167492. DOI: 10.1158/0008-5472.CAN-13-1807. View

15.

Motzer R, Escudier B, Mcdermott D, Frontera O, Melichar B, Powles T . Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020; 8(2). PMC: 7359377. DOI: 10.1136/jitc-2020-000891. View

16.

Knudsen E, Balaji U, Freinkman E, McCue P, Witkiewicz A . Unique metabolic features of pancreatic cancer stroma: relevance to the tumor compartment, prognosis, and invasive potential. Oncotarget. 2016; 7(48):78396-78411. PMC: 5346648. DOI: 10.18632/oncotarget.11893. View

17.

Weng C, Hawse J, Subramaniam M, Chang V, Yu W, Hung W . KLF10 loss in the pancreas provokes activation of SDF-1 and induces distant metastases of pancreatic ductal adenocarcinoma in the Kras p53 model. Oncogene. 2017; 36(39):5532-5543. DOI: 10.1038/onc.2017.155. View

18.

Nair N, Sanchez Calle A, Zahra M, Prieto-Vila M, Oo A, Hurley L . A cancer stem cell model as the point of origin of cancer-associated fibroblasts in tumor microenvironment. Sci Rep. 2017; 7(1):6838. PMC: 5533745. DOI: 10.1038/s41598-017-07144-5. View

19.

Wang M, Fer N, Galeas J, Collisson E, Kim S, Sharib J . Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer. Nat Commun. 2019; 10(1):3055. PMC: 6624260. DOI: 10.1038/s41467-019-11044-9. View

20.

Biffi G, Oni T, Spielman B, Hao Y, Elyada E, Park Y . IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. Cancer Discov. 2018; 9(2):282-301. PMC: 6368881. DOI: 10.1158/2159-8290.CD-18-0710. View