Wnt Signaling and Prostate Cancer Bone Metastasis

Wnt 信号转导与前列腺癌骨转移

• 批准号: 8254847
• 负责人: Jessica Kelly Simmons
• 金额: $ 5.13万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8254847
• 关键词: American Cancer Society; Bone Resorption; Bone Surface; Calvaria; Canis familiaris; Cause of Death; Cell Adhesion; Cell Line; Cell Mobility; Cell Polarity; Cell Proliferation; Cell physiology; Cells; Coculture Techniques; Development; Disease; Epithelial; Fellowship; Gene Expression; Gene Targeting; Genetic Transcription; Growth; In Vitro; Laboratories; Lead; Ligands; Link; MAPK8 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mesenchymal; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modeling; Morbidity - disease rate; Mus; Neonatal; Neoplasm Metastasis; Nude Mice; Osteoblasts; Osteoclasts; Osteogenesis; Osteolytic; Pain; Pathogenesis; Pathway interactions; Phenotype; Prevention; Production; Prostate; Prostate carcinoma; Prostatic Neoplasms; Regulation; Reporting; Research; Research Project Grants; Research Training; Role; Scientist; Signal Pathway; Signal Transduction; Site; Testing; Transcription Factor AP-1; Transforming Growth Factors; Translational Research; Tumor necrosis factor receptor 11b; Up-Regulation; Vertebral column; autocrine; bone; bone invasion; cancer cell; career development; cofactor; design; experience; human disease; implantation; in vivo; in vivo Model; inhibitor/antagonist; interest; long bone; men; mortality; mouse model; new therapeutic target; osteoclastogenesis; paracrine; receptor; receptor activator of NF-kappa B; release factor 3; research study; spine bone structure; tumor; tumor growth

DESCRIPTION (provided by applicant): The American Cancer Society estimated that in 2010 over 32,000 men have died of prostate cancer.1 Metastasis is the primary cause of death due to prostate cancer, and the most common site is bone.2 Bone metastases are incurable and associated with significant pain and morbidity. The mechanisms by which prostate cancer cells metastasize and grow in bone are not fully understood, but we hypothesize that the Wnt signaling pathways are essential.3-8 While Wnt signaling in prostate cancer bone metastases has been shown to stimulate epithelial-mesenchymal transition (EMT) and the typical osteoblastic phenotype of the metastases, its role is still unclear.9-11 Understanding the role of Wnt signaling will lead to new therapeutic targets in the prevention or treatment of bone metastasis in prostate cancer and will decrease its morbidity and mortality. This project is designed to test the central hypothesis that the Wnt signaling pathways and DKK-1 (an inhibitor of canonical and stimulator of noncanonical Wnt signaling) are important for regulation of prostate cancer proliferation, progression, and metastasis to bone. The three aims are designed to test whether: 1) Autocrine non-canonical Wnt signaling by prostate cancer increases tumor growth; 2) Paracrine canonical Wnt signaling by prostate cancer induces osteoblastic metastases; and 3) Factors released by bone resorption, in cooperation with the noncanonical Wnt pathway, promote prostate cancer growth and metastasis. We have developed a unique mouse model of prostate cancer using the canine Ace-1 prostate cancer cells to test the hypotheses. Ace-1 cells metastasize exclusively to long bones and the spine and induce osteoblastic bone metastases. In addition, the hypotheses will be tested using two-compartment in vitro co-cultures of mouse calvaria and prostate cancer cells and vossicle (neonatal mouse vertebrae)/prostate cancer co-implantation in nude mice. The proposed F32 fellowship research training plan will provide a strong basic-translational science research experience for Jessica Simmons, DVM. Dr. Simmons is an aspiring scientist whose research interests are focused in investigating the pathogenesis of prostate cancer metastases in the bone. The F32 fellowship will support Dr. Simmons' research studies as well as augment her career development. PUBLIC HEALTH RELEVANCE: Wnt signaling modulates the bone microenvironment in both development and disease. Unraveling the dialogue between of Wnt signaling between metastatic prostate cancer cells and the bone microenvironment will help elucidate new treatment targets. The results of our specific aims will be relevant to the understanding the pathogenesis of prostate cancer metastasis and discovery of new therapeutic targets for the prevention or inhibition of bone metastasis.

描述（由申请人提供）：美国癌症协会估计，2010年有超过32,000名男性死于前列腺癌转移是前列腺癌死亡的主要原因，最常见的转移部位是骨骨转移是无法治愈的，并伴有明显的疼痛和发病率。前列腺癌细胞在骨内转移和生长的机制尚不完全清楚，但我们假设Wnt信号通路是必不可少的。3-8虽然Wnt信号在前列腺癌骨转移中已被证明可刺激上皮-间质转化（EMT）和转移的典型成骨细胞表型，但其作用尚不清楚。9-11了解Wnt信号的作用将为预防或治疗前列腺癌骨转移提供新的治疗靶点，并将降低其发病率和死亡率。该项目旨在验证Wnt信号通路和DKK-1（典型Wnt信号的抑制剂和非典型Wnt信号的刺激剂）在前列腺癌增殖、进展和骨转移的调节中起重要作用的中心假设。这三个目的旨在测试：1)前列腺癌自分泌非典型Wnt信号是否会促进肿瘤生长；2)前列腺癌旁分泌典型Wnt信号诱导成骨细胞转移；3)骨吸收释放的因子与非典型Wnt通路共同促进前列腺癌的生长和转移。我们已经开发了一种独特的前列腺癌小鼠模型，使用犬Ace-1前列腺癌细胞来测试假设。Ace-1细胞只转移到长骨和脊柱，并诱导成骨细胞骨转移。此外，这些假设将通过小鼠颅骨和前列腺癌细胞的双室体外共培养和裸鼠的小泡（新生小鼠椎骨）/前列腺癌共植入来验证。拟议的F32奖学金研究培训计划将为Jessica Simmons， DVM提供强大的基础转化科学研究经验。Simmons博士是一位有抱负的科学家，他的研究兴趣集中在研究前列腺癌骨转移的发病机制。F32奖学金将支持Simmons博士的研究以及促进她的职业发展。