Type of Document Dissertation Author Nandana, Srinivas Rao Author's Email Address firstname.lastname@example.org URN etd-07122010-111539 Title Mouse Models of Prostate Cancer Progression and Bone Metastasis Degree PhD Department Cancer Biology Advisory Committee
Advisor Name Title Dr.'s Robert Matusik, Vito Quaranta, Neil Bhowmick Committee Member Keywords
Date of Defense 2010-04-23 Availability unrestricted AbstractCANCER BIOLOGY
MOUSE MODELS OF PROSTATE CANCER PROGRESSION AND BONE METASTASIS
Srinivas Rao Nandana
Dissertation under the direction of Robert J. Matusik, PhD
Prostate cancer is the second leading cause of deaths due to cancer in men in the United States. The American Cancer Society has projected that 192,280 new cases and 27,360 deaths will occur in the year 2009. Mostly, men over the age of 50 are afflicted by the disease and more than 70% of the men diagnosed with prostate cancer are over the age of 65. Most of the patients who suffer from prostate cancer do not die due to the tumor at the primary site but rather due to complications when the tumor has spread to the bone. It is estimated that each year, about 350,000 people die of bone metastasis in the United States. The causative tumor becomes incurable once the bone has been invaded and only 25% of prostate cancer patients are able to live 5 years subsequent to their diagnosis of bone metastasis. The interaction between prostate cancer cells and the bone creates a vicious cycle of bone formation and bone destruction thereby destabilizing the inherently delicate homeostasis within the bone. In prostate cancer, this process leads to metastatic lesions that are predominantly osteoblastic. However within the background of bone formation, several groups have reported that bone resorption is an integral part of prostate cancer bone lesions. Therefore, early detection and treatment before the tumor metastasizes is critical for the survival of the patient.
Creating and characterizing mouse models that better mimic the progression in human prostate cancer is a powerful tool to study and delineate the various steps in tumor progression. Most of the currently available mouse models of prostate cancer successfully recapitulate the early steps of tumor progression in the primary site but fail to metastasize to other organs especially to the bone. Amongst the existing ones, transgenic models that are created by dysregulating a gene that is widely known to be altered in human prostate cancer are considered to be more reflective of the human disease. This is in contrast to transgenic mouse models that overexpress the small t and large T antigens that despite the phenotype they produce, are considered to have little physiological significance.
This first part of the thesis describes the creation and characterization of the hepsin/myc bigenic model that develops adenocarcinoma in the primary site. The second part of the thesis describes a model that delineates the interactions between prostate cancer cells and the bone microenvironment. This is approached by dysregulating the T-box transcription factor Tbx2 in PC3 human prostate cancer cells and looking at the effect of this dysregulation on the interaction of the cells with the bone microenvironment.
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