Abstract
SummaryCancer stem cells (CSCs) are defined by their ability to regenerate a tumor upon transplantation. However, it is not yet clear whether tumors contain a single CSC population or different subsets of cells with mixed capacities for initiating primary and secondary tumors. Using two different identification strategies, we studied the overlap between metastatic stem cells and tumor-initiating cells (TICs) in the MMTV-PyMT model. Our results show that in the MMTV-PyMT model, Lin−CD90−ALDHhigh cells retained a high tumor-initiating potential (TIP) in orthotopic transplants, in contrast to Lin−CD24+CD90+, which retained higher metastatic capacity. Interestingly, suppression of TGFβ signaling increased TIC numbers. We here describe the existence of distinct populations of CSCs with differing capacities to initiate tumors in the primary or the secondary site. Inhibiting TGFβ signaling shifts the balance toward the former, which may have unanticipated implications for the therapeutic use of TGFβ/TGFBR1 inhibitors.
Highlights
The cancer stem cell (CSC) hypothesis proposes that, to what happens in normal tissues, heterogeneity within tumors is the consequence of their hierarchical organization, i.e., that many tumors are organized as a pyramid with Cancer stem cells (CSCs) at its apex
CD90ÀALDHhigh Cells Are Lineage-Committed CSCs The ability of cancer cells to form metastasis in the lungs is typically tested in intravenous injections in the tail vein
Our results show that Tgfbr1 expression is higher in LinÀCD24+CD90+ and LinÀ CD90ÀALDHlow cells when compared with LinÀCD24+ CD90À and LinÀCD90ÀALDHhigh cells, respectively (Figures 3C and 3D), which indicates that these subsets may be more sensitive to TGFBR1 inhibition
Summary
The cancer stem cell (CSC) hypothesis proposes that, to what happens in normal tissues, heterogeneity within tumors is the consequence of their hierarchical organization, i.e., that many tumors are organized as a pyramid with CSCs at its apex. In many tumor types such as breast cancer, this subset of cells is known to sustain tumor growth and, as we and others have shown, to lead metastatic colonization (Malanchi et al, 2012). The latter is important since over 90% of cancer-related deaths are due to metastatic disease. CSCs are defined as tumor-derived cells that have the exclusive ability to regenerate a tumor upon transplantation— with all its full complexity and heterogeneity. The lack of universal CSC markers poses a serious problem in understanding how homogeneous the CSC pool is
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