Date of Award

1-1-2013

Document Type

Open Access Dissertation

Department

Biological Sciences

First Advisor

Maria M Pena

Second Advisor

Franklin G Berger

Abstract

Tumors have come to be known as independently functioning complex organs consisting of cancer cells coexisting with a heterogeneous mixture of host-derived non-neoplastic cells that form the tumor stroma. Tumor survival, progression, and metastasis depend on multiple close interactions between the cancer cells and the tumor stromal cells. These tumor stromal cells are mainly bone marrow derived cells (BMDCs) that are recruited to the primary tumor and sites of metastasis by a variety of signals secreted by the cancer cells. Because of the close interaction between the tumor and the tumor stroma, we propose that tumor stromal cells play an important role in tumor response to systemic treatment with chemotherapeutic agents and that tumor response will reflect that of the tumor stroma. By also targeting the tumor stroma with chemotherapy, we can potentially enhance drug efficacy and specificity. In this study, we used ApcMin/+ mice that are predisposed to the development of spontaneous adenomatous tumors in the small intestine and colon, and a Balb/c orthotopic mouse model that were subcutaneously implanted with CT26 colon carcinoma cells. Using these murine models, we identified and quantitated the myeloid derived suppressor cells (MDSCs), mast cells, and T-regulatory cells (T-regs) in the tumor stromal compartment. We then determined if these BMDCs were direct cellular targets of thymidylate synthase (TS) inhibitors in the tumor stroma by studying the kinetics of their response to the drug 5-fluorouracil (5-FU). We validated the impact of TS inhibitors on these target cells in chimeric ApcMin/+ mice that were generated by transplanting genetically modified bone marrow cells, such that the sensitivity of tumor stromal cells to systemic drug treatment was distinct from that of the tumor cells. The results showed that MDSCs are selectively sensitive and are direct targets of 5-FU, mast cells are resistant and are recruited the tumor bed in response to 5-FU, while Tregs are largely unaffected by 5-FU. We examined the mechanisms underlying the differential effects of 5-FU on MDSCs, mast cells, and T-regs. The results will lay the foundation for our ultimate goal of developing a strategy to target TS specifically in the tumor and tumor associated stromal cells using a single agent while protecting normal, healthy actively dividing cells from the detrimental effects of these inhibitors.

Rights

© 2013, Grishma Acharya

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