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Pathogenesis of Osteoblastic metastasis in Prostate Cancer: Role of Animal Models

Thudi, Nanda Kumar
http://rave.ohiolink.edu/etdc/view?acc_num=osu1244042766

Abstract Details

2009, Doctor of Philosophy, Ohio State University, Veterinary Biosciences.
Prostate cancer (PCa) is the most commonly diagnosed cancer in men accounting for 25% of the new cases every year in the USA. PCa is the second leading cause of cancer-related deaths due to the development of serious skeletal complications in advanced stages of the disease. Bone metastases in PCa are predominantly osteoblastic characterized by formation of excessive low quality woven bone leading to spinal cord compression, paralysis, pathological fractures and severe pain eventually resulting in a poor quality of life. Therefore, bone metastasis represents a major clinical and research interest to investigate and develop therapeutic strategies.Previously, our lab established a canine PCa cell line (Ace-1) that metastasized to bone and caused mixed osteoblastic and osteolytic lesions in nude mice similar to that observed in human patients. We utilized this animal model to investigate the molecular pathogenesis of bone metastasis. First, we investigated the role of osteolytic activity in the development of bone metastasis by inhibiting bone resorption with the bisphosphosphonate, zoledronic acid. We showed that zoledronic acid significantly inhibited osteolysis in this model, but did not affect the PCa growth, incidence and the osteoblastic phenotype of the metastases. These data demonstrated that PCa bone metastases were independent of osteolysis and that PCa secreted factors that directly regulated bone metastasis. To explore the molecular mechanisms involved in metastasis, we investigated the role of Wnt signaling that plays an important role in oncogenesis and osteogenesis in the progression of prostate cancer growth, and incidence and osteoblastic phenotype of bone metastases. Antagonizing Wnt signaling using Dickkopf-1 (Dkk-1) in our model resulted in increased tumor growth although it significantly decreased new woven bone formation in the metastases. In conclusion, these investigations demonstrated PCa secrete factors that induce bone metastasis. Importantly, Wnt signaling in PCa was important for the induction of the osteoblastic phenotype in bone metastases which was inhibited by Dkk-1. Therefore, investigating the factors responsible for prostate cancer-induced bone induction in bone metastases will be useful to design novel therapeutics.
Thomas Rosol, PhD (Advisor)
268 p.
Biomedical Research
Prostate cancer; ACe-1; Bone metastasis; Osteoblastic; osteolytic zoledronic acid; Dkk-1; Wnts

Recommended Citations

Citations

  • Thudi, N. K. (2009). Pathogenesis of Osteoblastic metastasis in Prostate Cancer: Role of Animal Models [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1244042766

    APA Style (7th edition)

  • Thudi, Nanda. Pathogenesis of Osteoblastic metastasis in Prostate Cancer: Role of Animal Models. 2009. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1244042766.

    MLA Style (8th edition)

  • Thudi, Nanda. "Pathogenesis of Osteoblastic metastasis in Prostate Cancer: Role of Animal Models." Doctoral dissertation, Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1244042766

    Chicago Manual of Style (17th edition)

osu1244042766
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© 2009, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.