Heterogeneity of Primary and Metastatic CAFs: From Differential Treatment Outcomes to Treatment Opportunities (Review)

Overview

Journal Int J Oncol

Specialty Oncology

Date 2024 Apr 5

PMID 38577950

Authors

Zixing Kou

Cun Liu

Wenfeng Zhang

Changgang Sun

Lijuan Liu

Qiming Zhang

Affiliations

Soon will be listed here.

Abstract

Compared with primary tumor sites, metastatic sites appear more resistant to treatments and respond differently to the treatment regimen. It may be due to the heterogeneity in the microenvironment between metastatic sites and primary tumors. Cancer‑associated fibroblasts (CAFs) are widely present in the tumor stroma as key components of the tumor microenvironment. Primary tumor CAFs (pCAFs) and metastatic CAFs (mCAFs) are heterogeneous in terms of source, activation mode, markers and functional phenotypes. They can shape the tumor microenvironment according to organ, showing heterogeneity between primary tumors and metastases, which may affect the sensitivity of these sites to treatment. It was hypothesized that understanding the heterogeneity between pCAFs and mCAFs can provide a glimpse into the difference in treatment outcomes, providing new ideas for improving the rate of metastasis control in various cancers.

Citing Articles

Integrative Analysis and Validation of a Cancer-associated Fibroblasts Senescence-related Signature for Risk Stratification and Therapeutic Prediction in Esophageal Squamous Cell Carcinoma.

Zhang H, Hong K, Song Q, Zhu B, Wu G, Yu B J Cancer. 2024; 15(17):5742-5761.

PMID: 39308671 PMC: 11414623. DOI: 10.7150/jca.100430.

References

DArcangelo E, Wu N, Cadavid J, McGuigan A . The life cycle of cancer-associated fibroblasts within the tumour stroma and its importance in disease outcome. Br J Cancer. 2020; 122(7):931-942. PMC: 7109057. DOI: 10.1038/s41416-019-0705-1. View

Levental K, Yu H, Kass L, Lakins J, Egeblad M, Erler J . Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009; 139(5):891-906. PMC: 2788004. DOI: 10.1016/j.cell.2009.10.027. View

Chen Z, Zhou L, Liu L, Hou Y, Xiong M, Yang Y . Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma. Nat Commun. 2020; 11(1):5077. PMC: 7545162. DOI: 10.1038/s41467-020-18916-5. View

Arina A, Idel C, Hyjek E, Alegre M, Wang Y, Bindokas V . Tumor-associated fibroblasts predominantly come from local and not circulating precursors. Proc Natl Acad Sci U S A. 2016; 113(27):7551-6. PMC: 4941507. DOI: 10.1073/pnas.1600363113. View

Mukherjee S, Sakpal A, Mehrotra M, Phadte P, Rekhi B, Ray P . Homo and Heterotypic Cellular Cross-Talk in Epithelial Ovarian Cancer Impart Pro-Tumorigenic Properties through Differential Activation of the Notch3 Pathway. Cancers (Basel). 2022; 14(14). PMC: 9319742. DOI: 10.3390/cancers14143365. 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

Kudo D, Suto A, Hakamada K . The Development of a Novel Therapeutic Strategy to Target Hyaluronan in the Extracellular Matrix of Pancreatic Ductal Adenocarcinoma. Int J Mol Sci. 2017; 18(3). PMC: 5372616. DOI: 10.3390/ijms18030600. View

Liu Z, Wang H, He J, Yuan X, Sun W . Rictor ablation in BMSCs inhibits bone metastasis of TM40D cells by attenuating osteolytic destruction and CAF formation. Int J Biol Sci. 2019; 15(11):2448-2460. PMC: 6775318. DOI: 10.7150/ijbs.37241. View

Muchlinska A, Nagel A, Popeda M, Szade J, Niemira M, Zielinski J . Alpha-smooth muscle actin-positive cancer-associated fibroblasts secreting osteopontin promote growth of luminal breast cancer. Cell Mol Biol Lett. 2022; 27(1):45. PMC: 9188043. DOI: 10.1186/s11658-022-00351-7. View

10.

Xia S, Liu Z, Cai J, Ren H, Li Q, Zhang H . Liver fibrosis therapy based on biomimetic nanoparticles which deplete activated hepatic stellate cells. J Control Release. 2023; 355:54-67. DOI: 10.1016/j.jconrel.2023.01.052. View

11.

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

12.

Gertych A, Walts A, Cheng K, Liu M, John J, Lester J . Dynamic Changes in the Extracellular Matrix in Primary, Metastatic, and Recurrent Ovarian Cancers. Cells. 2022; 11(23). PMC: 9736731. DOI: 10.3390/cells11233769. View

13.

Haider M, Smit D, Taipaleenmaki H . The Endosteal Niche in Breast Cancer Bone Metastasis. Front Oncol. 2020; 10:335. PMC: 7082928. DOI: 10.3389/fonc.2020.00335. View

14.

Alsayed R, Khan A, Ahmad F, Ansari A, Alam M, Buddenkotte J . Epigenetic regulation of CXCR4 signaling in cancer pathogenesis and progression. Semin Cancer Biol. 2022; 86(Pt 2):697-708. DOI: 10.1016/j.semcancer.2022.03.019. View

15.

Minchinton A, Tannock I . Drug penetration in solid tumours. Nat Rev Cancer. 2006; 6(8):583-92. DOI: 10.1038/nrc1893. View

16.

Altmann A, Haberkorn U, Siveke J . The Latest Developments in Imaging of Fibroblast Activation Protein. J Nucl Med. 2020; 62(2):160-167. DOI: 10.2967/jnumed.120.244806. View

17.

OHara S, LaRusso N . Portal fibroblasts: A renewable source of liver myofibroblasts. Hepatology. 2022; 76(5):1240-1242. DOI: 10.1002/hep.32528. View

18.

Mukaida N, Zhang D, Sasaki S . Emergence of Cancer-Associated Fibroblasts as an Indispensable Cellular Player in Bone Metastasis Process. Cancers (Basel). 2020; 12(10). PMC: 7600711. DOI: 10.3390/cancers12102896. View

19.

Bielczyk-Maczynska E . White Adipocyte Plasticity in Physiology and Disease. Cells. 2019; 8(12). PMC: 6953026. DOI: 10.3390/cells8121507. View

20.

Maehira H, Miyake T, Iida H, Tokuda A, Mori H, Yasukawa D . Vimentin Expression in Tumor Microenvironment Predicts Survival in Pancreatic Ductal Adenocarcinoma: Heterogeneity in Fibroblast Population. Ann Surg Oncol. 2019; 26(13):4791-4804. DOI: 10.1245/s10434-019-07891-x. View