Unlocking the crucial role of cancer-associated fibroblasts in tumor metastasis: Mechanisms and therapeutic prospects

Abstract

Background: Tumor metastasis represents a stepwise progression and stands as a principal determinant of unfavorable prognoses among cancer patients. Consequently, an in-depth exploration of its mechanisms holds paramount clinical significance. Cancer-associated fibroblasts (CAFs), constituting the most abundant stromal cell population within the tumor microenvironment (TME), have garnered robust evidence support for their pivotal regulatory roles in tumor metastasis.

Aim of review: This review systematically explores the roles of CAFs at eight critical stages of tumorigenic dissemination: 1) extracellular matrix (ECM) remodeling, 2) epithelial-mesenchymal transition (EMT), 3) angiogenesis, 4) tumor metabolism, 5) perivascular migration, 6) immune escape, 7) dormancy, and 8) premetastatic niche (PMN) formation. Additionally, we provide a compendium of extant strategies aimed at targeting CAFs in cancer therapy.

Key scientific concepts of review: This review delineates a structured framework for the interplay between CAFs and tumor metastasis while furnishing insights for the potential therapeutic developments. It contributes to a deeper understanding of cancer metastasis within the TME, facilitating the utilization of CAF-targeting therapies in anti-metastatic approaches.

Keywords: Cancer-associated fibroblasts; Metastasis; Therapy; Tumor microenvironment.

Graphical abstract

Fig. 1

Multiple cell sources of CAFs. Normal fibroblasts, cancer stem cells, mesenchymal stem cells, pericytes, mesothelial cells, macrophages, adipocytes, endothelial cells, epithelial cells, and stellate cells are the cell sources of CAFs. Figure created with BioRender (https://www.biorender.com).

Fig. 2

Mechanism of the involvement of CAFs in major aspects of tumor metastasis: 1. ECM remodeling; 2. EMT; 3. angiogenesis; 4. metabolism. Figure created with BioRender (https://www.biorender.com).

Fig. 3

Mechanism of the involvement of CAFs in major aspects of tumor metastasis: 5. immune escape; 6. perivascular migration; 7. dormancy; 8. premetastasic niche (PMN) formation. Figure created with BioRender (https://www.biorender.com).

Fig. 4

Key processes in which CAFs are involved in tumor metastasis: 1. ECM remodeling; 2. EMT; 3. angiogenesis; 4. metabolism; 5. immune escape; 6. perivascular migration; 7. dormancy; 8. premetastasic niche (PMN) formation. Figure created with BioRender (https://www.biorender.com).

Fig. 5

Antimetastatic strategies targeting CAFs. Specific elimination of CAFs through FAP inhibition, induction of quiescent fibroblast states from activated CAFs, and inhibition of prometastatic signaling pathways within CAFs are three main approaches antimetastatic strategies targeting CAFs. Figure created with BioRender (https://www.biorender.com).