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（由适用提供）：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热衰竭的主要原因。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瘤的常见特征，长期以来一直与增强的转移和患者预后不良有关。缺氧是在肿瘤中出现的，因为肿瘤细胞的侵略性生长以及促血管生成因子的过表达导致异常的血管网络，这些血管网络无法充分提供营养和去除废物。因此，肿瘤细胞可以在氧扩散极限（慢性或扩散限制的缺氧）或由于间歇性血流波动（急性或灌注限制的缺氧）上经历氧气剥夺。两者都与增强的肿瘤细胞扩散相关，尽管它们的相对重要性尚未明确解决。证据表明，肿瘤中的氧缺陷会直接影响关键肿瘤细胞对转移表型至关重要的功能，包括增殖，生存，侵袭和血管生成的诱导。关键缺氧调节的转录因子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）是一个非受体酪氨酸激酶的家族，在人类癌症中经常过度激活。在前列腺癌中，它们有助于提高侵略性，并与马酮不敏感和转移有关。 SRC信号不仅促进侵入性肿瘤细胞表型，还可以增强骨转移的血管生成和形成。有趣的是，我们的初步证据表明，缺氧能够促进SRC信号传导，这是一个不太认可的发现。该建议的目标是（i）确定急性和慢性缺氧暴露对SFK活性和前列腺癌细胞在体外和体内的转移潜力的相对影响，（ii）检查缺乏介导的HIF1-SRC信号传导途径，以及（iii）（III）评估临床上就业的小型分解剂量的症状症状症状症状。我们认为，诸如干扰转移过程的SRC靶向策略之类的治疗方案将对癌症治疗结果和相关死亡率产生重大影响。由于转移已在临床和实验上与缺氧有关，因此可以更好地了解在实体瘤中可能发生的氧气剥夺如何影响转移相关的信号传导和行为，最终应最终导致未来新型治疗方案的发展。