Abstract
Intratumoral heterogeneity helps drive the selection for diverse therapy-resistant cell populations. In this study, we demonstrate the coexistence of two therapy-resistant populations with distinct properties that are reproducibly enriched under conditions that characterize tumor pathophysiology. Breast cancer cells that survived chemotherapy or hypoxia were enriched for cells expressing the major hyaluronic acid receptor CD44. However, only CD44(hi) cells that survived chemotherapy exhibited cancer stem cell (CSC) phenotypes based on growth potential and gene expression signatures that represent oncogenic signaling and metastatic prowess. Strikingly, we identified TGFβ2 as a key growth promoter of CD44(hi) cells that survived chemotherapy but also as a growth inhibitor of cells that survived hypoxia. Expression of the TGFβ receptor TGFβR1 and its effector molecule SMAD4 was required for enrichment of CD44(hi) cells exposed to the chemotherapeutic drug epirubicin, which suggests a feed-forward loop to enrich for and enhance the function of surviving CSCs. Our results reveal context-dependent effects of TGFβ2 signaling in the same tumor at the same time. The emergence of distinct resistant tumor cell populations as a consequence of prior therapeutic intervention or microenvironmental cues has significant implications for the responsiveness of recurring tumors to therapy.
Highlights
Tumor cells that are resistant to therapy can fuel disease relapse and constitute a major barrier to achieving sustained clinical responses
Chemotherapy and hypoxia enrich for a CD44hi population Cultured SKBR3 breast cancer cells and tumor xenografts established from them exhibit low expression of CD44, but when tumor-bearing animals were treated with epirubicin, a cytotoxic chemotherapy, the relapsed tumors exhibited high CD44 expression [27]
Because CD44 did not mark a cancer stem cell (CSC)-specific population after hypoxia, we examined whether another CSC marker defined a population that could regrow after exposure to low oxygen
Summary
Tumor cells that are resistant to therapy can fuel disease relapse and constitute a major barrier to achieving sustained clinical responses. Intratumoral heterogeneity may generate a diversity of resistance mechanisms that coexist within the same tumor. Sources of this heterogeneity include genetic and epigenetic changes, cellular plasticity, tumor microenvironment factors such as hypoxia, immune cell infiltration, exposure to therapeutic compounds, and stochastic changes in signal transduction and gene expression [1,2,3,4]. The cancer stem cell (CSC) model provides a mechanistic basis for intratumoral heterogeneity based on measurable phenotypes and constitutes a useful framework for studying therapeutic resistance. CSCs can be resistant to cytotoxic chemotherapies [1, 7] and have been observed adjacent to hypoxic regions of tumors, for Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, New York
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