Abstract
The realization that many cancers, including breast cancer, are driven by cells which display stem cell properties has significant clinical implications. Furthermore, the demonstrated role of these cells in mediating tumor metastasis and treatment resistance suggests the need to develop strategies to specifically target CSC populations. Cancer stem cell self-renewal and survival pathways represent potential therapeutic targets. These self-renewal pathways are regulated by an interacting network of cell intrinsic pathways, as well as extrinsic factors from the tumor microenvironment. These mircroenvironmental factors include cytokines such as IL-6, IL-8 and TGFb. CSCs maintain the plasticity to transition between epithelial-like MET and mesenchymal-like EMT states, a process regulated by the tumor microenvironment through microRNA circuits. We have demonstrated that previously identified cancer stem cell markers are cancer stem cell state specific. CD44+/CD24- CSCs represent mesenchymal-like stem cells capable of tissue invasion which are largely quiescent. In contrast, Aldehyde dehydrogenase expression identifies a more epithelial-like cancer stem cell state associated with self-renewal. Reversible EMT/MET transitions play a crucial role in mediating tumor metastasis.
Preclinical breast cancer models predict that the greatest efficacy of CSC targeting therapeutics will occur when they are used in the adjuvant setting, a concept supported by preclinical models and clinical trials. Tumor regression may reflect effects on bulk cell populations explaining the lack of correlation between tumor shrinkage and patient survival. In contrast, recurrence following adjuvant therapy may be mediated by CSCs, which possesses sufficient self-renewal to form clinically significant metastasies. The important role of HER2 signaling in regulating breast cancer stem cell self-renewal may account for the remarkable clinical efficacy of targeting HER2 in the adjuvant setting. Furthermore, the clinical benefit of such therapies in classically defined HER2-negative breast cancers may be due to selective expression of HER2 in CSCs in the absence of HER2 gene amplification. The clinical benefit of adjuvant trastuzumab in women whose breast cancers are currently classified as HER2-negative is currently being assessed in the randomized national clinical trial B47. These studies may demonstrate the need for reevaluating currently used clinical endpoints and clinical trial designs. Promising new technologies including the isolation and molecular characterization of circulating cancer stem cells may provide the opportunity for real time assessment of the efficacy of CSC targeting agents. A number of agents regulating BCSCs have entered early phase clinical trials which will determine whether effective targeting of CSCs improves patient outcome.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr BS01-2.
Volume 73, Issue 24 Supplement
