Enumeration of circulating tumor cells (CTCs) in the bloodstream can predict prognosis and survival in cancer patients. However, CTC rarity and heterogeneity pose challenges in using them as biomarkers. Recent publications have reported new classes of circulating, non-cancerous tumor-derived cells present in cancer patients but not in healthy controls; these include cancer-associated macrophages, tumor-endothelial clusters (TECs), and cancer-associated fibroblasts (CAFs). Well-established marker-dependent CTC enrichment technologies will miss this group of circulating cells. To maximize our chance of finding useful circulating biomarkers in cancer patients, we propose the use of size-based enrichment technologies to isolate both cancerous and non-cancerous cells in circulation. We review their biological properties and discuss device features to consider in their enrichment.
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