Heterogeneity of Cancer-associated Fibroblasts: Opportunities for Precision Medicine

Overview

Journal Cancer Sci

Specialty Oncology

Date 2020 Jun 24

PMID 32573845

Citations 102

Authors

Ryu Kanzaki

Kristian Pietras

Affiliations

Soon will be listed here.

Abstract

Despite marked development in cancer therapies during recent decades, the prognosis for advanced cancer remains poor. The conventional tumor-cell-centric view of cancer can only explain part of cancer progression, and thus a thorough understanding of the tumor microenvironment (TME) is crucial. Among cells within the TME, cancer-associated fibroblasts (CAFs) are attracting attention as a target for cancer therapy. However, CAFs present a heterogeneous population of cells and more detailed classification of CAFs and investigation of functions of each subset is needed to develop novel CAF-targeted therapies. In this context, application of newly developed approaches to single-cell analysis has already made an impact on our understanding of the heterogeneity of CAFs. Here, we review the recent literature on CAF heterogeneity and function, and discuss the possibility of novel therapies targeting CAF subsets.

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References

Herrera M, Islam A, Herrera A, Martin P, Garcia V, Silva J . Functional heterogeneity of cancer-associated fibroblasts from human colon tumors shows specific prognostic gene expression signature. Clin Cancer Res. 2013; 19(21):5914-26. DOI: 10.1158/1078-0432.CCR-13-0694. 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

Neuzillet C, Tijeras-Raballand A, Ragulan C, Cros J, Patil Y, Martinet M . Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma. J Pathol. 2018; 248(1):51-65. PMC: 6492001. DOI: 10.1002/path.5224. View

Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida A, Ponz-Sarvise M . Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017; 214(3):579-596. PMC: 5339682. DOI: 10.1084/jem.20162024. View

Hinz B, Phan S, Thannickal V, Galli A, Bochaton-Piallat M, Gabbiani G . The myofibroblast: one function, multiple origins. Am J Pathol. 2007; 170(6):1807-16. PMC: 1899462. DOI: 10.2353/ajpath.2007.070112. View

Friedman G, Levi-Galibov O, David E, Bornstein C, Giladi A, Dadiani M . Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of S100A4 and PDPN CAFs to clinical outcome. Nat Cancer. 2022; 1(7):692-708. PMC: 7617059. DOI: 10.1038/s43018-020-0082-y. View

Bernard V, Semaan A, Huang J, San Lucas F, Mulu F, Stephens B . Single-Cell Transcriptomics of Pancreatic Cancer Precursors Demonstrates Epithelial and Microenvironmental Heterogeneity as an Early Event in Neoplastic Progression. Clin Cancer Res. 2018; 25(7):2194-2205. PMC: 6445737. DOI: 10.1158/1078-0432.CCR-18-1955. View

Lin E, Jones J, Li P, Zhu L, Whitney K, Muller W . Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol. 2003; 163(5):2113-26. PMC: 1892434. DOI: 10.1016/S0002-9440(10)63568-7. View

Jiang G, Xu W, Du J, Zhang K, Zhang Q, Wang X . The application of the fibroblast activation protein α-targeted immunotherapy strategy. Oncotarget. 2016; 7(22):33472-82. PMC: 5078111. DOI: 10.18632/oncotarget.8098. View

10.

Ishii G, Sangai T, Oda T, Aoyagi Y, Hasebe T, Kanomata N . Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem Biophys Res Commun. 2003; 309(1):232-40. DOI: 10.1016/s0006-291x(03)01544-4. View

11.

Lambrechts D, Wauters E, Boeckx B, Aibar S, Nittner D, Burton O . Phenotype molding of stromal cells in the lung tumor microenvironment. Nat Med. 2018; 24(8):1277-1289. DOI: 10.1038/s41591-018-0096-5. View

12.

Pelon F, Bourachot B, Kieffer Y, Magagna I, Mermet-Meillon F, Bonnet I . Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms. Nat Commun. 2020; 11(1):404. PMC: 6972713. DOI: 10.1038/s41467-019-14134-w. View

13.

Hosein A, Huang H, Wang Z, Parmar K, Du W, Huang J . Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution. JCI Insight. 2019; 5. PMC: 6777805. DOI: 10.1172/jci.insight.129212. View

14.

Bartoschek M, Oskolkov N, Bocci M, Lovrot J, Larsson C, Sommarin M . Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nat Commun. 2018; 9(1):5150. PMC: 6279758. DOI: 10.1038/s41467-018-07582-3. View

15.

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

16.

Hao J, Zeltz C, Pintilie M, Li Q, Sakashita S, Wang T . Characterization of Distinct Populations of Carcinoma-Associated Fibroblasts from Non-Small Cell Lung Carcinoma Reveals a Role for ST8SIA2 in Cancer Cell Invasion. Neoplasia. 2019; 21(5):482-493. PMC: 6458340. DOI: 10.1016/j.neo.2019.03.009. View

17.

Ren Y, Zhou X, Liu X, Jia H, Zhao X, Wang Q . Reprogramming carcinoma associated fibroblasts by AC1MMYR2 impedes tumor metastasis and improves chemotherapy efficacy. Cancer Lett. 2016; 374(1):96-106. DOI: 10.1016/j.canlet.2016.02.003. View

18.

Kojima Y, Acar A, Eaton E, Mellody K, Scheel C, Ben-Porath I . Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci U S A. 2010; 107(46):20009-14. PMC: 2993333. DOI: 10.1073/pnas.1013805107. View

19.

Guy C, Webster M, Schaller M, Parsons T, Cardiff R, Muller W . Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci U S A. 1992; 89(22):10578-82. PMC: 50384. DOI: 10.1073/pnas.89.22.10578. View

20.

Navab R, Strumpf D, Bandarchi B, Zhu C, Pintilie M, Ramnarine V . Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer. Proc Natl Acad Sci U S A. 2011; 108(17):7160-5. PMC: 3084093. DOI: 10.1073/pnas.1014506108. View