Abstract
The presence of circulating tumor cells (CTCs) and CTC clusters, also known as tumor microemboli, in biological fluids has long been described. Intensive research on single CTCs has made a significant contribution in understanding tumor invasion, metastasis tropism, and intra-tumor heterogeneity. Moreover, their being minimally invasive biomarkers has positioned them for diagnosis, prognosis, and recurrence monitoring tools. Initially, CTC clusters were out of focus, but major recent advances in the knowledge of their biogenesis and dissemination reposition them as critical actors in the pathophysiology of cancer, especially metastasis. Increasing evidence suggests that “united” CTCs, organized in clusters, resist better and carry stronger metastatic capacities than “divided” single CTCs. This review gathers recent insight on CTC cluster origin and dissemination. We will focus on their distinct molecular package necessary to resist multiple cell deaths that all circulating cells normally face. We will describe the molecular basis of their increased metastatic potential as compared to single CTCs. We will consider their clinical relevance as prognostic biomarkers. Finally, we will propose future directions for research and clinical applications in this promising topic in cancer.
Highlights
Since the first observation of circulating tumor cells (CTCs) in the mid-nineteenth century by Thomas Arsthworth, it took over a century to better characterize them because of many shortcomings, the major one being their rarity
The dogma positioning single circulating cells as stemming metastasis based on their capacity to achieve epithelial to mesenchymal transition (EMT) did not propose CTC clusters as important actors of cancer dissemination
By artificially modulating EMT, Beerling et al showed the existence of epithelial-mesenchymal plasticity minimizing any differences in stemness between epithelial and mesenchymal states. This plasticity positions epithelial or mesenchymal circulating tumor cell to potential metastasis growth [5]. This is in agreement with the fact that no difference in EMT score was found in CTC clusters as compared to single CTCs originating from triple-negative breast cancer patient derived xenografts (PDXs) [6]
Summary
Since the first observation of circulating tumor cells (CTCs) in the mid-nineteenth century by Thomas Arsthworth, it took over a century to better characterize them because of many shortcomings, the major one being their rarity. 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]). By artificially modulating EMT, Beerling et al showed the existence of epithelial-mesenchymal plasticity minimizing any differences in stemness between epithelial and mesenchymal states This plasticity positions epithelial or mesenchymal circulating tumor cell to potential metastasis growth [5]. This is in agreement with the fact that no difference in EMT score was found in CTC clusters as compared to single CTCs originating from triple-negative breast cancer patient derived xenografts (PDXs) [6]. We will explore recent literature on CTC clusters and realize that their implication in cancer aggressiveness should not be neglected, as well as that they may even represent a valuable access to therapeutic optic
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