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

SIMPLE SUMMARY: Circulating tumor cell clusters (CTC clusters) seem to play a primary role in the metastatic spread of cancer, the main cause of death associated with this disease. The metastatic potential of CTCs can be enhanced by the presence within the clusters of cancer-associated fibroblast (CAFs), known to promote cancer invasion and dissemination. In this review, the authors summarize the role of CTC clusters and CAFs on the metastatic process and the current knowledge about the contribution of CAFs to the genesis and metastasis initiating ability of CTC clusters. In addition, they discuss the potential of therapeutically interfering with the CAFs within CTC clusters, as a strategy to reduce their metastatic competency. Lastly, the authors highlight some relevant questions about the biology of these clusters that need to be answered in order to fully understand and be able to limit their contribution to metastasis. 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.