Abstract
The quantitative evaluation of circulating EpCAM+ tumor cells (CTCs) in the peripheral blood of breast cancer patients provides an independent predictor of risk of progression in patients with metastatic disease. The present study investigated the tumorigenic potential of CTCs from cryopreserved mobilized leukapheresis products obtained from three metastatic breast cancer patients in remission. Cells were immunomagnetically separated if they expressed either the epithelial cell surface marker EpCAM, or CD90, a mesenchymal stromal cell marker associated with tumorigenic stem-like cancer cells. Cells were injected into the mammary fat pads of NOD-scid Il2rgnull mice. The injection of very large numbers of CTCs (0.3–1.5×106 CTCs per site, 20 sites per sample) in an optimized xenograft model did not result in the establishment of human-derived tumor xenografts. Four orders of magnitude fewer cells of the same CD90+ phenotype, but obtained from metastatic breast cancer pleural effusions, were highly tumorigenic in the same model system. These results favor the interpretation that circulating tumor cell load does not directly bear on metastatic potential, and that tumorigenic circulating breast cancer cells in patients with metastatic breast cancer are exceedingly rare. Furthermore, the CD44+/CD90+ phenotypic signature indicative of tumorigenicity in cells separated from metastatic or primary breast tumors does not have the same significance in circulating tumor cells.
Highlights
The metastatic spread of a primary tumor through the dissemination, seeding, and spreading of metastasis-inducing cells to a new anatomical site[1] is the leading cause of cancer-related deaths in the United States.[2]
The present study demonstrates that viable circulating EpCAM+ tumor cells (CTCs) were abundant in leukapheresis products collected from late-stage breast cancer patients in remission
Abbreviation: ASC, adipose stromal cells. a6 Months after injection. bBoth tumors were of lymphoid morphology and confirmed to be of murine origin. cOne animal was not evaluable due to early death unrelated to tumor injection. d6 Weeks after injection. ePreviously published data (Zimmerlin et al, Tissue Engineering Part A, 2011); PE16 and PE30 were unpassaged FACSorted breast cancer metastatic pleural effusions
Summary
The metastatic spread of a primary tumor through the dissemination, seeding, and spreading of metastasis-inducing cells to a new anatomical site[1] is the leading cause of cancer-related deaths in the United States.[2]. 5 CTC/7.5 ml blood is considered an indicator of poor prognosis in patients with metastatic breast cancer.[3] As all samples were obtained from patients with preexisting metastatic disease, the results could well be interpreted to suggest that metastatic lesions in a small proportion of these patients (~2.7%) shed tumorigenic cells of uncharacterized phenotype into the blood. This must not be confused with the scenario in which a primary tumor sheds cells capable of metastatic spread. Cells were injected into the mammary fat pads of NOD-scid
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