Circulating tumor microemboli: Progress in molecular understanding and enrichment technologies

Abstract

Circulating tumor cells (CTCs) and their clusters, also known as circulating tumor microemboli (CTM), have emerged as valuable tool that can provide mechanistic insights into the tumor heterogeneity, clonal evolution, and stochastic events within the metastatic cascade. However, recent investigations have hinted that CTM may not be mere aggregates of tumor cells but cells comprising CTM exhibit distinct phenotypic and molecular characteristics in comparison to single CTCs. Moreover, in many cases CTM demonstrated higher metastatic potential and resistance to apoptosis as compared to their single cell counterparts. Thus, their evaluation and enumeration may provide a new dimension to our understanding of cancer biology and metastatic cancer spread as well as offer novel theranostic biomarkers. Most of the existing technologies for isolation of hematogenous tumor cells largely favor single CTCs, hence there is a need to devise new approaches, or re-configure the existing ones, for specific and efficient CTM isolation. Here we review existing knowledge and insights on CTM biology. Furthermore, a critical commentary on current and emerging trends in CTM enrichment and characterization along with recently developed ex-vivo CTC expansion methodologies is presented with the aim to facilitate researchers to identify further avenues of research and development.

Circulating Tumor Cell Clusters: United We Stand Divided We Fall

“…About 10 years earlier, Virchow had detected tumor emboli entrapped in vasculature and proposed the first explanation of cancer dissemination by metastases. These clusters of cells were further described from the 1950s, with strong focus on their metastatic potential as compared to single circulating tumor cells (review in Reference [1]). There is already substantial literature on the molecular mechanisms linked with CTCs generation (review in Reference [2]), involving, for example, major cellular pathways effectors, like Erythroblastosis oncogene B (ERBB) family receptors [3].…”

The Role of Circulating Tumor Cells in the Metastatic Cascade: Biology, Technical Challenges, and Clinical Relevance

“…This hypothesis is supported by multicolor lineage-tracing experiments in a mouse model of pancreatic cancer [37]. Moreover, intravascular CTC aggregation might be inhibited by the shear forces generated in the bloodstream [38].…”

Tubular membranes extended between monolayer cells, from solid spheroids, and from clustered hollow spheroids in Ishikawa endometrial cell cultures can carry chromatin granules and mitonucleons

“…The characteristics of a unique structure of clustered hollow spheroids is described for the first time in this paper. An obvious question is whether anything like it has already been seen in vivo , an inquiry that turns up a surprisingly rich history of research on tumor cell clusters mostly isolated from blood, and stretching back more than 50 years (Hong et al2016;Umer et al,2018). Almost consistently, starting with Watanabe in 1954, researchers have concluded that tumor cell clusters are more likely to contribute to metastases than single tumor cells.…”

“…The relevance of tumor cell clusters in metastases was recently reviewed by Cheung & Ewald (2016) with a model of metastatic dissemination that highlights the activities of clusters of tumor cells that retain epithelial properties. Overall, there appears to be recognition that at least some tumor cell clusters may be more than the sum of their parts relating perhaps to discussions about the distinct phenotypic and molecular characteristics of cells in tumor clusters or microemboli in comparison with single cancer tumor cells (Umer et al,2018).…”