Hypoxia: Impact on Src Signaling and Prostate Cancer

缺氧：对 Src 信号传导和前列腺癌的影响

• 批准号: 9298599
• 负责人: DIETMAR W SIEMANN
• 金额: $ 34.41万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-16 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9298599
• 关键词: Acute; Adhesions; Affect; Angiogenic Factor; Behavior; Blood Vessels; Blood flow; Cancer Etiology; Cancer Patient; Cell physiology; Cessation of life; Chronic; Clinical; Clinical Trials; Dasatinib; Development; Diffusion; Disease Progression; Extravasation; Failure; Family; Future; Genes; Goals; Hormones; Human; Hypoxia; Hypoxia Inducible Factor; Impairment; In Vitro; Individual; Lead; Link; Location; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Metastatic to; Molecular; Neoplasm Metastasis; Neoplasms; North America; Nutrient; Osteogenesis; Oxygen; Pathway interactions; Patient-Focused Outcomes; Patients; Perfusion; Phenotype; Process; Regulation; Role; Secondary to; Signal Pathway; Signal Transduction; Site; Solid Neoplasm; Therapeutic; Tissue Sample; Treatment Protocols; Waste Products; angiogenesis; antitumor effect; base; cancer cell; cancer diagnosis; cancer therapy; castration resistant prostate cancer; cell growth; chemotherapy; clinical application; deprivation; effective therapy; experience; experimental study; hypoxia inducible factor 1; in vivo; inhibitor/antagonist; kinase inhibitor; men; migration; molecular marker; mortality; neoplastic cell; novel; outcome forecast; overexpression; phase III trial; potential biomarker; pre-clinical; prostate cancer cell; prostate cancer model; public health relevance; radiation resistance; small molecule; src-Family Kinases; targeted agent; therapy outcome; transcription factor; treatment strategy; tumor

 DESCRIPTION (provided by applicant): Prostate cancer is the most commonly diagnosed cancer in North America and the leading cause of cancer death in men. Metastasis is the primary cause of therapeutic failure in prostate cancer patients; resulting in poor prognosis and high mortality. Hypoxia, a common feature of most solid tumors including prostate cancer, has long been associated with enhanced metastasis and poor patient outcome. Hypoxia arises in tumors because the aggressive growth of neoplastic cells and associated over-expression of pro-angiogenic factors leads to aberrant vascular networks that are incapable of adequately delivering nutrients and removing waste products. As a consequence tumor cells can experience oxygen deprivation at the limit of oxygen diffusion (chronic or diffusion-limited hypoxia) or due to intermittent blood flow fluctuations (acute or perfusion-limited hypoxia). Both have been linked to enhanced tumor cell spread though their relative importance has not been unequivocally resolved. Evidence indicates that oxygen deficiencies in tumors can directly impact critical tumor cell functions critical to the metastatic phenotype including proliferation, survival, invasion, and induction of angiogenesis. The key hypoxia-regulated transcriptional factor HIF1 drives expression of many of the genes associated with these cancer cell functions. The Src family kinases (SFKs) are a family of non-receptor tyrosine kinases that are frequently hyper-activated in human cancers. In prostate cancer they contribute to increased aggressiveness and are associated with hormone insensitivity and metastasis. Src signaling promotes not only an invasive tumor cell phenotype but also enhances angiogenesis and formation of bone metastases. Interestingly, our preliminary evidence indicates that hypoxia is able to promote Src signaling, a less well-recognized finding. The goals of this proposal are to (i) determine the relative impact of acute and chronic hypoxic exposures on SFK activity and metastatic potential of prostate cancer cells in vitro and in vivo, (ii) examine the hypoxia-mediated HIF1-Src signaling pathways, and (iii) assess the ability of clinically employed small molecule Src inhibitors to impair hypoxia-induced metastasis. We believe that treatment options such as Src targeting strategies that interfere with the process of metastasis will have significan impact on cancer therapy outcomes and related mortality. Since metastasis has been linked both clinically and experimentally to hypoxia gaining a better understanding of how the varying oxygen deprivations that can occur in solid tumors impact metastasis-associated signaling and behavior should ultimately lead to the development of novel treatment options in the future.

 描述(申请人提供)：前列腺癌是北美最常见的癌症，也是男性癌症死亡的主要原因。转移是前列腺癌患者治疗失败的主要原因，导致预后不良和高死亡率。缺氧是包括前列腺癌在内的大多数实体肿瘤的共同特征，长期以来一直与转移增加和患者预后不良有关。肿瘤中出现缺氧是因为肿瘤细胞的侵袭性生长和相关的促血管生成因子的过度表达导致血管网络异常，无法充分输送营养物质和清除废物。其结果是，肿瘤细胞可能在氧气扩散极限(慢性或扩散受限缺氧)或由于血流间歇性波动(急性或灌注受限缺氧)而经历缺氧。两者都与促进肿瘤细胞扩散有关，尽管它们的相对重要性尚未得到明确解决。有证据表明，肿瘤中的缺氧可以直接影响对转移表型至关重要的肿瘤细胞功能，包括增殖、存活、侵袭和诱导血管生成。关键的低氧调节转录因子HIF1驱动与这些癌细胞功能相关的许多基因的表达。Src家族激酶(SFK)是一类非受体酪氨酸激酶家族，在人类癌症中经常被过度激活。在前列腺癌中，它们有助于增加侵袭性，并与激素不敏感和转移有关。SRC信号不仅促进侵袭性肿瘤细胞表型，而且促进血管生成和骨转移的形成。有趣的是，我们的初步证据表明，缺氧能够促进Src信号转导，这是一个不太被认可的发现。本研究的目的是(I)确定急性和慢性低氧暴露对体外和体内前列腺癌细胞SFK活性和转移潜能的相对影响，(Ii)研究低氧介导的HIF1-Src信号通路，以及(Iii)评估临床使用的小分子Src抑制剂对低氧诱导的转移的影响。我们相信，干扰转移过程的治疗选择，如src靶向策略，将对癌症治疗结果和相关死亡率产生重大影响。由于转移在临床和实验上都与缺氧有关，对实体瘤中可能发生的不同的氧剥夺如何影响转移相关的信号和行为有了更好的了解，这最终将导致未来新的治疗方案的发展。