Date of Award

January 2014

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Marcus W. Bosenberg

Subject Area(s)

Medicine, Oncology

Abstract

Phenotypic and functional variability between cancer cells within the same tumor is known to exist, yet is poorly characterized. It has been hypothesized that a small subset of cells within a cancer are uniquely capable of reforming tumors following therapy and for establishing metastases. The characteristics and functions of these cells capable of propagating tumors and other cancer cell subsets remains controversial. Prior research has established that in mouse models of melanoma, three phenotypically distinct cellular subsets could be identified. CD34+ cells are capable of forming tumors at a high rate following engraftment of a single tumor cell in mice. Melanoma cells lacking CD34 and the p75 nerve growth factor receptor (double negative; DN) are capable of forming tumors at a lower rate, but also retain greater plasticity to form other cellular subsets. The p75+ subset is generally not tumorigenic, yet comprises a sizeable proportion of cells within a given mouse melanoma. The phenotypic characteristics of these melanoma cellular subsets are well-characterized and serve as an ideal platform in which to study how these populations are established as a function of tumor growth and what expression differences define the different subsets. Using immunohistochemical analyses of different time points during melanoma growth we have determined the subset that predominates during early melanoma growth. In addition, functional characteristics of the different cellular subsets were determined using gene set enrichment analysis (GSEA) of transcript differences. These findings have implications on functional interactions of heterogenous tumor cells that are likely required for tumor growth, metastasis, and resistance to oncologic therapies.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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