Abstract
Abstract Accumulating evidence suggests that tumor growth, recurrence and metastasis are driven by a subset of highly tumorigenic cells referred to as cancer stem cells (CSCs) or tumor initiating cells. Several investigators have demonstrated that CSCs are relatively resistant to chemotherapy and that tumor recurrence and the development of drug resistance after chemotherapy are mediated by residual cancer stem cells. Furthermore, it has been demonstrated that the process of epithelial-to-mesenchymal transition (EMT) contributes to drug resistance and results in cells with CSC-like characteristics. We previously demonstrated that targeting Notch signaling pathway by a novel anti-DLL4 antibody inhibited tumor growth and decreased cancer stem cell frequency. Using patient-derived breast cancer and pancreatic cancer xenograft tumors we found that residual tumors after conventional chemotherapy (paclitaxel for breast cancer and gemcitabine for pancreatic cancer) were enriched with cancer stem cells. Gene expression analysis of cell populations enriched for CSCs revealed that several mesenchymal-associated genes were up-regulated, whereas epithelial gene was down-regulated. As shown by in vivo limiting dilution analyses, treatment with anti-DLL4 antibody decreased cancer stem cell frequency. Anti-DLL4 reversed chemotherapy-induced mesenchymal gene expression and delayed tumor recurrence. The residual tumor cells treated with conventional therapy eventually developed acquired drug resistance following repeated treatment. Compared to the parental xenograft, the resistant tumors had increased cancer stem cell frequency and tumorigenic ability. Treatment with anti-DLL4 antibody inhibited growth of these resistant tumors and re-sensitized them to the chemotherapeutic agent. This effect was in part due to the ability of the antibody to decrease cancer stem cell frequency in resistant tumors. The combination of antibody and chemotherapeutic agent further decreased cancer stem cell frequency compared to the parental tumor. Gene expression analysis demonstrated that resistant tumors had increased expression of many genes associated with EMT, multidrug resistance, DNA repair, and the Notch and Wnt pathways. Importantly, treatment with anti-DLL4 suppressed many gene expression changes in chemo-resistant tumors and resulted in a gene expression profile more like the original (drug sensitive) tumor. Immunohistochemical analysis indicated that anti-DLL4 mediated anti-tumor effect was associated with inhibition of EMT and induction of differentiation markers. Our findings provide a rationale to target cancer stem cells through interference with Notch pathway as a therapeutic approach in patients who are refractory to chemotherapeutic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3357. doi:1538-7445.AM2012-3357
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