Dangerous Liaisons: Circulating Tumor Cells (CTCs) and Cancer-Associated Fibroblasts (CAFs)

Abstract

The crosstalk between cancer cells and the tumor microenvironment (TME) is a key determinant of cancer metastasis. Cancer-associated fibroblasts (CAFs), one of the main cellular components of TME, promote cancer cell invasion and dissemination through mechanisms including cell-cell interactions and the paracrine secretion of growth factors, cytokines and chemokines. During metastasis, circulating tumor cells (CTCs) are shed from the primary tumor to the bloodstream, where they can be detected as single cells or clusters. The current knowledge about the biology of CTC clusters positions them as key actors in metastasis formation. It also indicates that CTCs do not act alone and that they may be aided by stromal and immune cells, which seem to shape their metastatic potential. Among these cells, CAFs are found associated with CTCs in heterotypic CTC clusters, and their presence seems to increase their metastatic efficiency. In this review, we summarize the current knowledge on the role that CAFs play on metastasis and we discuss their implication on the biogenesis, metastasis-initiating capacity of CTC clusters, and clinical implications. Moreover, we speculate about possible therapeutic strategies aimed to limit the metastatic potential of CTC clusters involving the targeting of CAFs as well as their difficulties and limitations.

Keywords: CTC clusters; cancer-associated fibroblasts (CAFs); circulating tumor cells (CTCs); liquid biopsy; metastasis.

Figure 1

Role of CAFs on the formation of CTC clusters. CAFs can contribute to the formation of CTC clusters by at least three mechanisms. (A) CAFs secreted factors can reprogram cancer cells, inducing epithelial/mesenchymal plasticity, which endows an invasive phenotype. (B) CAFs exert mechanical forces on cancer cells that direct collective migration through the establishment of heterotypic cell-to-cell interactions. (C) CAFs trigger structural modifications of the ECM, by generating ECM tracks or by applying mechanical pulling forces on ECM fibers that favor collective cancer cell invasion.

Figure 2

Pro-metastatic effects exerted by CAFs within heterotypic CTC clusters and at the secondary site. In circulation, CAFs enhance the metastatic potential of CTCs by conferring to them shear stress resistance through the establishment of strong cellular adhesions. Moreover, CAFs protect CTCs from apoptosis by activating cell survival pathways and maintaining CTC proliferation. At the metastatic site, CAF-secreted factors and tumor-derived exosomes create an appropriate environment for CTC growth, also supported by CAF-mediated immunosuppression. Additionally, circulating CAFs can be recruited to secondary sites and contribute to the establishment of the metastatic niche.