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Said PhD dissertation 2017 new.pdf (6.84 MB)

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Pathogenesis and Treatment of Canine Prostate Cancer

Elshafae, Said Mohammed Abbas
http://orcid.org/0000-0001-6285-5483
http://rave.ohiolink.edu/etdc/view?acc_num=osu1492081831172341

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Comparative and Veterinary Medicine.
Prostate cancer (PCa) is the most common malignant neoplasm among men in Western countries and the second leading cause of cancer mortalities after lung cancer. It is expected that by 2016, 180,890 men will be diagnosed with prostate cancer and 26,120 will die due to the disease. One of the most frequent complications of prostate cancer in patients is bone metastasis. Osteoblastic bone metastasis is the predominant finding at sites of skeletal metastases. Understanding the pathogenesis of prostate cancer progression and bone metastasis and targeting these processes are very important to control this aggressive disease. The main objectives of this work were to identify the role of signaling pathways that have shown to be upregulated in prostate cancer, evaluate a histone deacetylase inhibitor in treatment of prostate cancer metastasis and develop an osteoblastic PCa model for further understanding the molecular mechanisms of bone metastases. Intensive studies have been performed for better understanding the role of various signaling pathways in PCa progression and metastasis. Importantly, gastrin-releasing peptide receptor (GRPr) signaling was shown to be upregulated in human prostatic intraepithelial neoplasia (PIN), invasive prostatic carcinoma and related skeletal metastases. Our objective in this study was to determine the importance of this signaling in the pathogenesis of PCa progression. By activation of GRPr signaling using bombesin (BBN), there was an increase in proliferation and migration of canine prostate cancer cells. GRPR signaling also modulated the expression level of genes that are implicated in epithelial-mesenchymal transition (EMT), growth, invasion and metastasis of PCa. Histone deacetylase inhibitors (HDACi) are a class of therapeutics that can prevent tumor growth and induce differentiation and apoptosis in a wide group of cancers. AR-42, a HDACi, was shown to be efficient against multiple myeloma, lung cancer and hepatocellular carcinoma. In this study, we evaluated AR-42 as an anti-metastatic drug against canine prostate cancer. AR-42 decreased the mRNA expression level of anoikis resistance and osteomimicry genes in vitro. AR-42 declined the incidence of xenograft bone metastases and tumor growth and increased apoptosis and stemness of metastatic tumors. Osteoblastic bone metastasis is very common finding in PCa patients. During PCa progression, cancer cells acquire osteomimicry properties that facilitate their metastasis and support their proliferation and survival in the bone microenvironment. The pathogenesis of osteoblastic bone metastasis and osteomimicry is still not well understood. For this reason, we developed and characterized a novel canine prostatic cancer cell line (LuMa) that had osteomimicry properties and induced osteoblastic bone metastasis in vivo. The predominant sites of LuMa cells metastasis were bone, brain and adrenal glands.
Thomas Rosol (Advisor)
James DeWille (Committee Member)
Beth Lee (Committee Member)
Ahmad Shabsigh (Committee Member)
143 p.
Animal Diseases; Animal Sciences; Biology; Medicine; Molecular Biology; Oncology; Pathology; Toxicology; Veterinary Services
Canine Prostate Cancer, Metastasis, Osteoblast Bone Metastasis, HDACi, AR-42, EMT, GRPR

Recommended Citations

Citations

  • Elshafae, S. M. A. (2017). Pathogenesis and Treatment of Canine Prostate Cancer [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492081831172341

    APA Style (7th edition)

  • Elshafae, Said. Pathogenesis and Treatment of Canine Prostate Cancer. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1492081831172341.

    MLA Style (8th edition)

  • Elshafae, Said. "Pathogenesis and Treatment of Canine Prostate Cancer." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492081831172341

    Chicago Manual of Style (17th edition)

osu1492081831172341
933
© 2017, some rights reserved.Creative Commons License Pathogenesis and Treatment of Canine Prostate Cancer by Said Mohammed Abbas Elshafae is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.