The Role of Cancer-Associated Fibroblasts in Ovarian Cancer

Abstract

Ovarian cancer is a lethal gynecologic tumor and is generally resistant to conventional treatments. Stable cancer-associated fibroblasts (CAFs) are important cellular components in the ovarian cancer tumor microenvironment and may provide novel resources for future treatment strategies. Different subtypes of CAFs display specific functions in tumor pathogenesis and various CAF markers suggest potential treatment targets, such as FAP and GPR77. Both autocrine and paracrine cytokines play important roles in the CAF activation process and regulate tumor progression. Downstream mediators and pathways, including IL-6, TGF-β, NF-κB, mitogen-activated protein kinase (MAPK), and AKT/mTOR/(p70S6K), play important roles in the initiation, proliferation, invasiveness, and metastasis of ovarian cancer cells and also participate in angiogenesis, therapeutic resistance, and other biological processes. Several clinical or preclinical trials have targeted stromal fibroblasts and focused on the properties of CAFs to enhance ovarian cancer treatment outcomes. This review concentrates on the origins, subtypes, and activation of CAFs, as well as specific roles of CAFs in regulating tumor development and drug resistance, and aims to provide potential and prospective targets for improving the therapeutic efficacy of ovarian cancer treatment.

Keywords: cancer-associated fibroblasts; ovarian cancer; stroma; tumor microenvironment.

Figure 1

Origins of ovarian cancer-associated fibroblasts. CAFs are important components in the tumor microenvironment and may potentially derive from several cellular sources, including normal fibroblasts (which can convert into CAFs via activation), epithelial cells (through EMT), smooth muscle cells (through trans-differentiation), adipocytes (through trans-differentiation), endothelial cells (EndMT), and bone marrow MSCs (through EMT, recruitment, and activation), among other cells. Image created with BioRender.com (accessed on 19 April 2022). CAFs: cancer-associated fibroblasts; EMT: epithelial-to-mesenchymal transition; EndMT: endothelial-to-mesenchymal transition; MSCs: mesenchymal stem cells.

Figure 2

Pathways and mediators associated with CAFs activation. Quiescent fibroblasts can be transformed into an activated state through inflammatory cytokines and several pathways. Based on the different expressions of surface markers, including α-SMA, FAP, CD29, PDGFRβ, FSP1, and CAV1, CAFs are classified into four subsets in some cancers. Single-cell sequencing analysis of CAF-S1 in ovarian cancer has identified two subsets, iCAFs and myCAFs. Image created with BioRender.com (accessed on 25 May 2022).

Figure 3

Mechanisms of CAFs in ovarian cancer progression and dissemination. CAFs can regulate the growth, proliferation, and metastasis of ovarian cancer in different ways, including (a) secreting cytokines, (b) shaping the immune microenvironment, and (c) establishing metabolic crosstalk. Image created with BioRender.com (accessed on 24 April 2022).

Figure 4

Therapeutic strategies of CAFs in ovarian cancer. Three aspects of strategies targeting CAFs in TME include: (a) Depletion of CAFs via specific surface markers; (b) conversion of activated CAFs to the quiescent state by inhibitors; and (c) targeting significant downstream effectors of CAFs. Image created with BioRender.com (accessed on 23 May 2022). CAFs: cancer-associated fibroblasts; TME: tumor microenvironment.