Abstract
Conventional circulating tumor cell (CTC) detection technologies are restricted to large tumor cells (> white blood cells (WBCs)), or those unique carcinoma cells with double positive expression of surface epithelial cell adhesion molecule (EpCAM) for isolation, and intracellular structural protein cytokeratins (CKs) for identification. With respect to detecting the full spectrum of highly heterogeneous circulating rare cells (CRCs), including CTCs and circulating endothelial cells (CECs), it is imperative to develop a strategy systematically coordinating all tri-elements of nucleic acids, biomarker proteins, and cellular morphology, to effectively enrich and comprehensively identify CRCs. Accordingly, a novel strategy integrating subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH), independent of cell size variation and free of hypotonic damage as well as anti-EpCAM perturbing, has been demonstrated to enable in situ phenotyping multi-protein expression, karyotyping chromosome aneuploidy, and detecting cytogenetic rearrangements of the ALK gene in non-hematologic CRCs. Symbolic non-synonymous single nucleotide variants (SNVs) of both the TP53 gene (P33R) in each single aneuploid CTCs, and the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor suppressor gene in each examined aneuploid CECs, were identified for the first time across patients with diverse carcinomas. Comprehensive co-detecting observable aneuploid CTCs and CECs by SE-iFISH, along with applicable genomic and/or proteomic single cell molecular profiling, are anticipated to facilitate elucidating how those disparate categories of aneuploid CTCs and CECs cross-talk and functionally interplay with tumor angiogenesis, therapeutic drug resistance, tumor progression, and cancer metastasis.
Highlights
Circulating tumor cells (CTCs) are cancer cells shed from primary or metastatic solid tumors into peripheral blood, whereas circulating endothelial cells (CECs) are derived from endothelial cells (ECs) of blood vessels into circulation
In addition to aneuploid cancer cells and aneuploid endothelial cells localized in tumor tissues, existence of aneuploid CTCs and CECs in peripheral blood has been recently reported [8]
CTCs and CECs constitute the principal entity of non-hematologic circulating rare cells in circulation
Summary
Circulating tumor cells (CTCs) are cancer cells shed from primary or metastatic solid tumors into peripheral blood, whereas circulating endothelial cells (CECs) are derived from endothelial cells (ECs) of blood vessels into circulation. Clinical relevance of CTCs in tumor metastasis and prognosis [1,2,3], CECs in tumor angiogenesis [4], and CEC clusters in carcinoma [5] have been substantially discussed elsewhere. In addition to aneuploid cancer cells and aneuploid endothelial cells localized in tumor tissues, existence of aneuploid CTCs and CECs in peripheral blood has been recently reported [8]. How those diverse types of aneuploid malignant cells cross-talk and inter-play in tumor formation and metastasis remains to be further investigated. In the present short review, conventional CTC detection strategies, and a novel integrated SE-iFISH platform, applied to examine cytogenetic gene rearrangements in cancer cells, and to co-detect, characterize, molecularly profile aneuploid CTCs as well as CECs, are discussed
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