Isolation and phenotypic characterization of colorectal cancer stem cells with organ-specific metastatic potential

Abstract

Background & aims: Migrating cancer stem cells (MCSCs) are believed to form metastases. We sought to identify markers of MCSCs from human colorectal cancers (CRCs) and determine their roles in organ-specific metastasis.

Methods: To identify colorectal MCSCs that contribute to organ-specific metastasis, we developed a model of liver or lung metastasis using primary tumor cells from patients with CRC who had liver and lung metastases. Distinct organ-specific metastatic cells were isolated by 6 cycles of selecting for cells that formed liver and lung tumors after subcutaneous injection into mice. Microarray analysis was used to identify markers of the organ-specific MCSCs. We then measured levels of these markers in CRC cell lines and 128 CRC samples. We characterized the functional roles of these markers in organ-specific metastasis.

Results: We identified CD110 and CDCP1 as cell surface markers of MCSCs from human colorectal tumors that metastasized to liver and lung. We observed a distinct pattern of CD110 and CDCP1 in a panel of primary colorectal tumor samples and their matched liver or pulmonary metastases, indicating that these proteins might serve as biomarkers of organ-specific metastasis. Functional studies showed that thrombopoietin attracts CD110(+) CSCs and increases their self-renewal to promote formation of liver metastases. CDCP1 promoted adhesion of CRC cells to the lung endothelium.

Conclusions: We isolated MCSCs from primary human CRCs and found that the CD110(+) and CDCP1(+) subpopulations mediate organ-specific metastasis. These findings might be used to aid in selection of patients for postoperative adjuvant therapy.

Keywords: 5-FU; 5-fluoropyrimidine; CRC; CRLM; CRPM; CSC; Colon Cancer; GFP; Initiation; MCSC; PCR; Prognosis; TPO; Tumor Progression; cancer stem cell; colorectal cancer; colorectal liver metastases; colorectal pulmonary metastases; green fluorescent protein; migrating cancer stem cell; polymerase chain reaction; thrombopoietin.