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Models and Mechanisms of Prostate Cancer Bone Metastasis

Simmons, Jessica Kelly
http://rave.ohiolink.edu/etdc/view?acc_num=osu1397636660

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Veterinary Biosciences.
It is estimated that over 238,000 men were diagnosed with prostate cancer in 2013. Prostate cancer death is typically secondary to metastatic disease. The most common site of metastasis is bone. These metastases are typically osteoblastic and result in increased morbidity and mortality through debilitating pain, pathologic fracture, spinal cord compression and paralysis. Therefore, the pathogenesis of prostate cancer bone metastasis represents a major clinical and research interest to investigate and develop therapeutic strategies. The purpose of this body of work was to develop and characterize a model of osteoblastic prostate cancer bone metastasis and to investigate the molecular pathogenesis of these metastasis. In order to research prostate cancer, animal models that closely recapitulate the disease in man must be developed. To date, there is no complete animal model; instead, each model focuses on one or more phases of prostate cancer progression. The majority of the animal models of prostate cancer that develop bone metastases do not recapitulate the osteoblastic nature of metastases found in men. The first objective of this work was to characterize a naturally occurring model of osteoblastic prostate cancer metastasis in dogs. This model, the Probasco cell line, grew well in vitro and in vivo and formed dramatically osteoblastic metastases after intra-tibial or intra-cardiac injection. The Probasco prostate cancer cell line will be a valuable model to investigate the mechanisms of prostate cancer pathogenesis and osteoblastic bone metastases. The second objective was to investigate the molecular pathways important in the pathogenesis of prostate cancer bone metastases in relevant in vitro and in vivo models. In prostate cancer cells expressing parathyroid hormone-related peptide (PTHrP), increased tumor growth and a shift to a more bone resorptive phenotype was evident in both in vitro and in vivo models. Since bone resorption is known to release factors that can stimulate tumor cell proliferation, the existence of a vicious cycle between prostate cancer growth and osteoclastic bone resorption may be playing a role in the increased tumor size. The final objective was to expand upon our previous work detailing the significance of Wnt signaling in prostate cancer bone metastasis. Previously, our lab established a canine prostate cancer cell line (Ace-1) that metastasized to bone and caused mixed osteoblastic and osteolytic lesions in nude mice. We had previously found that Ace-1 cells expressing Dickkopf-1 (Dkk-1), an antagonize of canonical Wnt signaling and an enhancer of non-canonical Wnt/JNK signaling, resulted in increased tumor growth and number of metastases while decreasing new woven bone formation in the metastases. In this study, we confirmed enhanced Wnt/JNK signaling in vitro and how modulation of this pathway could alter gene expression and result in the increased cell growth and metastasis seen in vivo. These studies support the role of PTHrP and Wnt signaling in the pathogenesis of prostate cancer bone metastasis. Additionally, a novel experimental model of osteoblastic prostate cancer bone metastasis was developed for the advancement of prostate cancer research.
Thomas Rosol (Advisor)
Ramiro Toribio (Committee Member)
Ahmad Shabsigh (Committee Member)
159 p.
Comparative; Molecular Biology; Oncology
prostate cancer; bone metastasis; animals models

Recommended Citations

Citations

  • Simmons, J. K. (2014). Models and Mechanisms of Prostate Cancer Bone Metastasis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397636660

    APA Style (7th edition)

  • Simmons, Jessica. Models and Mechanisms of Prostate Cancer Bone Metastasis. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1397636660.

    MLA Style (8th edition)

  • Simmons, Jessica. "Models and Mechanisms of Prostate Cancer Bone Metastasis." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397636660

    Chicago Manual of Style (17th edition)

osu1397636660
191
© 2014, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.