Abstract CN06-03: Regulation of breast cancer stem cells by cytokine networks.

Abstract

Abstract Many cancers, including breast cancer are maintained by a subpopulation of cells that display stem cell properties, mediate metastasis and contribute to treatment resistance. These cancer stem cells are regulated by the interaction of cell intrinsic pathways as well as extracellular signals originating from the tumor microenvironment. Developing tumors recruit a diverse collection of cells that make up the tumor microenvironment and through iterative interactions both the tumor cell and its microenvironment co-evolve. The tumor microenvironment is composed of multiple cell types including mesenchymal cells, fibroblasts, endothelial cells and immune cells. We have utilized in vitro and mouse xenograft models to examine the interaction between breast cancer stem cells and cells within the microenvironment. We previously demonstrated that bone marrow derived mesenchymal stem cells like tumor stem cells are hierarchically organized and are recruited to the growing sites of breast cancers via cytokines such as interlukin-6 (IL-6). Mesenchymal stem cells interact with cancer stem cells forming “niches” which influences the growth and differentiation of both cellular compartments. Both IL-8 and IL-6 play seminal roles in the regulation of breast cancer stem cells. IL-6 also plays an important role in mediating resistance of breast cancer stem cells to a variety of therapeutic agents. These include development of resistance of HER2 overexpressing breast cancers to trastuzumab-targeted therapy. Although inactivation of the PTEN gene has been implicated in the development of resistance to HER2 targeting antibody trastuzumab, the mechanisms mediating this resistance have remained elusive. We have found that development of trastuzumab resistance in PTEN deleted cells is mediated by activation of an IL-6 inflammatory loop leading to expansion of the cancer stem cell population. Interestingly, long term trastuzumab treatment generates highly enriched cancer stem cells with an epithelial mesenchymal (EMT) phenotype which secrete over 100-fold more IL-6 than parental cells. The IL-6 receptor antibody tociluzumab was able to interrupt this inflammatory loop reducing the cancer stem cell population resulting in decreased tumor growth and metastasis in mouse xenografts. These studies demonstrate that trastuzumab resistance may be mediated by an IL-6 inflammatory loop and suggests that blocking this loop represents a novel strategy to overcome trastuzumab resistance. Another inflammatory cytokine intimately involved in breast cancer stem cell regulation is IL-8. The IL-8 receptor CXCR1 is selectively over expressed in breast cancer stem cell populations. Recombinant IL-8 stimulates breast cancer self-renewal and a small molecule CXCR1 inhibitor, reparaxin is able to block this signaling pathway. Reparaxin is able to target breast cancer stem cells in mouse xenograft models reducing tumor growth and metastasis. Based on these preclinical models a clinical trial utilizing reparaxin in combination with chemotherapy for the treatment of women with advanced breast cancers is currently being planned. Together, these studies suggest that strategies aimed at blocking the interaction of breast cancer stem cells with the microenvironment may prove an effective strategy to target this important cell population.