Date of Award

2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell Biology, Neurobiology and Anatomy

Abstract

Thoracic malignancies are one of the deadliest of all cancers, being the leading cause of cancer death in the Western world. Thoracic malignancies arise from different tissues; however the most common are of epithelial (commonly referred to as non-small cell lung cancer, or NSCLC), neuroendocrine (small cell lung cancer, or SCLC) and mesothelial origin (malignant mesothelioma, or MM). The DNA oncogenic virus Simian Virus 40 (SV40) has been shown to cooperate with environmental oncogenic fibers in the onset of MM. Insulin like growth factor-1 (IGF-1) signaling plays a central role in all thoracic malignancies and in the process of SV40-mediated malignant transformation of human cells. We have found that in SV40-transformed human mesothelial cells (HM) the Large T antigen (Tag), p53, pRb and p300 function in a multi-protein complex to promote transcription of the IGF1 gene. Depletion of p53 in these cells causes growth arrest because of lack of IGF-1 synthesis. These results provide a novel mechanistic and biological interpretation of the p53/Tag complexes and of DNA tumor virus transformation in general. It was generally believed that one of the major functions of Tag was to bind and inactivate the tumor suppressor p53. Our data, instead, support a model in which the Tag/p53 complexes are not inert, but rather play an active, essential role in the process of SV40-mediated transformation of HM, hence in the pathogenesis of MM.

Aside from the well-established role played by the IGF-1/Akt-1 axis in thoracic malignancies, we focused our research on the role of Notch signaling in cancers of the thorax. Notch-1 signaling has been shown to be required for the growth of SV40-transformed HM. We therefore expanded the studies of the role of Notch signaling in MM and NSCLC. We have found that, under hypoxia, the condition that best recapitulates solid tumors microenvironment, both MM and NSCLC cells have an elevated Notch signaling pathway as compared to normal human mesothelial (HM) and lung bronchioalveolar cells. Genetic and chemical modulation of the Notch pathway indicated that these tumor cells are dependent on Notch signaling. More specifically, MM and NSCLC cell survival was Notch-1 dependent. Notch-1 through its negative regulation of phosphatase and tensin homolog (PTEN) and positive regulation of the IGF-1 receptor (IGF-1R) expression causes activation of the pro-survival IGF-1/Akt-1 signaling pathway. These results provide new insight into the role of Notch in MM and lung cancer, and strongly implicate that Notch pathway inhibitors may be useful in the treatment of those deadly diseases. Our data indicate that targeting Notch-1 signaling using γ-secretase inhibitors (GSI) may represent a novel, promising therapeutic approach for thoracic malignancies treatment, by specifically targeting hypoxic tumor microenvironment. This is especially important because hypoxic tumor microenvironment is responsible for poor response to standard anticancer treatment, tumor recurrence and ultimately death. These results also identify additional molecular targets that may synergize with Notch-1 inhibition.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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