5.3. Circulating tumor cell cluster

5.3. Circulating tumor cell clustersCTC clusters have been observed in a number of studies, and their relationshipto stemness, EMT, and tumor progression is under investigation(Molnar et al., 2001; Paris et al., 2009; Friedlander et al., in press). Amajor challenge in the study of CTC clusters is the fact that many CTCisolation platforms disrupt cell–cell contact and presumably lead tothe breakdown of these clusters into individual cells. Similarly, there isdispute over whether clusters are an artifact of the CTC isolation procedure.Therefore, comparatively less is known currently about thephenomenon of CTC clusters.The study of CTC clusters is warranted though, as their observationraises the possibility that conglomerates of tumor emboli either shedby the primary tumor or formed/aggregated in circulation becomelodged in distant sites and are able to survive and proliferate, in contrastto the hypothesis that solitary EMT or stem-like cells are responsible fordistal spread of tumors. The notion that tumor cell clusters play a role inmetastasis is supported by the observation that tumor emboli are capableof forming metastases in multiple preclinical models (Watanabe,1954; Fidler, 1973) and by the fact that there may be less autolysis inclusters as evidenced by relative hematoxylin and eosin stainingintensities (Zheng et al., 2007; Z. Zhang et al., 2008), suggesting thatcluster formation may serve to protect CTCs fromthe stresses of circulation.Recent work has shown that E-cadherin is overexpressed inlymphovascular emboli and that E-cadherin cleavage may directly mediatethe formation of these clusters and promote tumor cell survival(Ye et al., 2012). Interestingly, in a recent study (M. Yu et al., 2013)