The propensity of invasive circulating tumor cells (iCTCs) in metastatic progression and therapeutic responsiveness

Abstract

Circulating tumor cells (CTCs) are important clinical indicators of metastatic progression and treatment efficacy. However, because of their low number and heterogeneity, reliable patient‐derived CTC models are not readily available. We report here the isolation and characterization of the invasive population of CTCs, iCTCs, from blood of 10 patients with epithelial ovarian cancer (EOC) and one pancreatic cancer patient based on the avidity of tumor cells toward an artificial collagen‐based adhesion matrix (CAM), in comparison with tumor progenitor (TP) cells isolated from tumor cell lines, tumors and ascites from EOC patients. CAM‐avid cells identified to be iCTCs were indistinguishable with TP cells using either functional CAM uptake or surface markers (seprase and CD44). In addition, iCTCs were characterized using peritoneal and spontaneous metastasis models in vivo to evaluate their metastatic propensity and therapeutic response. TP cells and iCTCs had a doubling time of about 34‐42 hours. TP cells were rare (<3.5%) in most patient‐derived specimens, however, iCTCs emigrated into blood, at a high frequency, 64.2% (n = 49). Approximately 500 patient‐derived iCTCs recapitulated formation of iCTCs in mouse blood and formed micrometastases in the liver and/or lung, a degree of metastatic spread equivalent to the inoculation of 5 × 10 5 bulk tumor cells isolated from ascites and tumors. iCTCs were shown to be novel therapeutic targets for blocking metastasis using the reduced formation of iCTCs and micrometastases by RNAi, peptides, and monoclonal antibodies against seprase.

Extracellular vesicle-miRNAs as liquid biopsy biomarkers for disease identification and prognosis in metastatic colorectal cancer patients

“…During the last 20 years, CTCs have become an stronger marker for prognosis and response to the treatment 39,40 . CTCs are implicated in disease dissemination and they have been proposed as indicators of minimal residual disease 41 , which cannot be detected by standard imaging methodologies in the clinical practice 42,43 . miRNAs profiles have been related to the metastatic spread of the tumour, characterized by the presence of CTCs 44 .…”

Recent Advances in Methods for Circulating Tumor Cell Detection

“…CAM invasion assay kits are sold under the Vita assay TM brand (Applied DNA Sciences, Stony Brook, NY, USA). These kits include 6-well plates in which the bottom of each well is coated with a CAM layer that may be fluorescently labeled [ 22 , 58 ]. The methods mentioned in this section are summarized in Table 1 .…”

Circulating Tumor Cells Adhesion: Application in Biosensors

“…Circulating tumor cells (CTCs) refer to a population of cells that have detached from the tumor and are circulating in the peripheral blood and/or lymphatic system. They are found in almost all solid malignant tumors and play a crucial role in the metastatic process [ 5 , 6 , 7 ]. Furthermore, recent studies have indicated that tumor cells can disseminate even in the early stages of tumor progression [ 8 , 9 , 10 ].…”