Circulating Tumor Cells: Come Together, Right Now, Over Metastasis

Abstract

Circulating tumor cells (CTC) are the source of metastases, but only an infinitesimal fraction of them eventually succeed in colonizing a distant organ. New results show that CD44-dependent aggregation in the circulation provides CTCs with cancer stem cell-like characteristics, suggesting an explanation for the low metastatic efficiency of CTCs, but also avenues for therapeutic intervention.See related article by Liu et al., p. 96.

Figure 1. Circulating tumor cell clusters display enhanced metastatic fitness.

(A) Cancer cells can leave the primary tumor either as individual cells or as clusters, entering the circulation directly or via the lymphatic system. Spatially and temporally proximal intravasation events can lead to cluster formation also within the vasculature. Most CTCs are eliminated and do not form clinically significant metastases. However, both pre-formed and de novo CTC clusters have a survival advantage over individual CTCs and they display enhanced cancer stem cell phenotypes, consequently leading to more efficient metastasis formation in secondary organs. (B) CTC clusters with high expression of either plakoglobin or keratin 14 can originate from collective migration or passive shedding of the primary tumor. These factors and their downstream effectors increase survival and metastatic potential. (C) Individual migrating tumor cells can aggregate in the blood forming CTC clusters in a CD44-dependent manner. CD44-CD44 homophilic interactions stabilize these CTC clusters, leading to the activation of PAK2-signaling. This improves stemness, survival and metastatic growth of CTC clusters. (D) Preventing CTC cluster formation or targeting CTC clusters in circulation is challenging due to the narrow window of therapeutic opportunity. If CD44-dependent signaling supports cancer cell clusters also at the early stages of metastatic colonization, targeting CD44-CD44 interaction with antibodies or PAK2 activation with small molecule inhibitors could reduce the viability of disseminated CTC clusters and consequently help reduce the likelihood of clinical metastases in the adjuvant setting.