Abstract
ObjectiveCirculating rare cells (CRCs) are known as a crucial nucleated cellular response to pathological conditions, yet the landscape of cell types across a wide variety of diseases lacks comprehensive understanding. This study aimed at detecting and presenting a full spectrum of highly heterogeneous CRCs in clinical practice and further explored the characterization of CRC subtypes in distinct biomarker combinations and aneuploid chromosomes among various disease groups.MethodsPeripheral blood was obtained from 2,360 patients with different cancers and non-neoplastic diseases. CRC capture and identification were accomplished using a novel platform integrating subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) strategy with a high-throughput automated image scanning system, on which hemocyte, tumor, epithelial, endothelial, mesenchymal, and stemness biomarkers were immunostained and displayed simultaneously. Double chromosome enumeration probe (CEP8 and CEP12) co-detection was performed on isolated CRCs from an extended trial for two chromosome ploidy patterns.ResultsA comprehensive atlas categorizing the diverse CRCs into 71 subtypes outlining was mapped out. The presence of epithelial–mesenchymal transition (EMT) or endothelial–mesenchymal transition (EndoMT), the cells with progenitor property, hematologic CRCs expressing multiple biomarkers, CRCs at “naked nuclei” status, and the rarely reported aneuploid mesenchymal epithelial–endothelial fusion cluster were described. Circulating tumor cells (CTCs) were detected in 2,157 (91.4%) patients; the total numbers of CTCs and circulating tumor-derived endothelial cells (CTECs) were relatively higher in several digestive system cancer types and non-neoplastic infectious diseases (p < 0.05). Co-detection combining CEP8 and CEP12 showed a higher diagnostic specificity on account of 57.27% false negativity of CRC detection through a single probe of CEP8.ConclusionsThe alternative biomarkers and chromosomes to be targeted by SE-iFISH and the image scanning platform, along with the comprehensive atlas, offer insight into the heterogeneity of CRCs and reveal potential contributions to specific disease diagnosis and therapeutic target cell discovery.
Highlights
In today’s comprehensive oncology era, clarification of abnormal cell landscapes of individual patients’ peripheral circulation is crucial to early diagnosis, therapeutic guidance, prognostic monitoring, and alertness for the emergence of treatment resistance, tumor metastasis, and disease relapse
Apart from the existence of conventional circulating tumor cells (CTCs) and CTECs characterized by the criteria mentioned above, diverse circulating rare cells, including cells with size variation and heterogeneous expression of surface anchor molecules, were enriched and comprehensively identified by the SE-iFISH and image scanning platform in varieties of cancer and non-neoplastic patients
A total of 71 subtypes of circulating rare cells (CRCs) were classified according to cell size taking the average diameter of WBCs as the boundary, phenotyping of multiple cellular protein expression, and karyotyping of chromosome 8 ploidy (Figure 2)
Summary
In today’s comprehensive oncology era, clarification of abnormal cell landscapes of individual patients’ peripheral circulation is crucial to early diagnosis, therapeutic guidance, prognostic monitoring, and alertness for the emergence of treatment resistance, tumor metastasis, and disease relapse. Considering the challenges of biopsy acquisition, the tumor evolution during disease progression, and especially the temporal and spatial heterogeneity of the tumor cells [1], there is a strong need for an accessible method implying minimally invasive procedures and allowing real-time monitoring of patients’ tumor cell alterations [2]. In the case of blood circulation, CTCs are a population of cells that accompany primary tumor cell invasion into the bloodstream, escape anoikis, evade destruction by the immune system, survive and settle in secondary or remote organs [5], and play a critical role in cancer relapse and metastasis and the management of advanced diseases. A variety of cell-based liquid biopsies have been explored to find the appropriate CTC enrichment and identification technologies, and most of the current detection strategies rely on physical cellular properties or cell surface molecules for isolation, and immunostaining of cellular proteins for identification [6]
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