Hypoxia: Impact on Src Signaling and Prostate Cancer

 描述（由申请人提供）：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;导致预后差和死亡率高。低氧是包括前列腺癌在内的大多数实体瘤的共同特征，长期以来一直与转移增强和患者预后不良相关。肿瘤中出现缺氧是因为肿瘤细胞的侵袭性生长和促血管生成因子的相关过度表达导致异常的血管网络，其不能充分递送营养物和去除废物。因此，肿瘤细胞可能在氧扩散的极限（慢性或扩散限制性缺氧）或由于间歇性血流波动（急性或灌注限制性缺氧）而经历氧剥夺。两者都与增强的肿瘤细胞扩散有关，尽管它们的相对重要性尚未明确解决。有证据表明，肿瘤中的氧缺乏可直接影响对转移表型至关重要的关键肿瘤细胞功能，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HIF 1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）是在人类癌症中经常过度活化的非受体酪氨酸激酶家族。在前列腺癌中，它们有助于增加侵袭性，并与激素不敏感性和转移有关。Src信号不仅促进侵袭性肿瘤细胞表型，而且增强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信号传导，这是一个不太被认可的发现。本提案的目的是（i）确定急性和慢性低氧暴露对SFK活性和前列腺癌细胞体外和体内转移潜力的相对影响，（ii）检查低氧介导的HIF 1-Src信号通路，和（iii）评估临床使用的小分子Src抑制剂损害低氧诱导的转移的能力。我们认为，治疗方案，如Src靶向策略，干扰转移的过程将有显着的影响癌症治疗的结果和相关的死亡率。由于转移在临床和实验上都与缺氧有关，因此更好地了解实体瘤中可能发生的不同缺氧如何影响转移相关的信号传导和行为，最终将导致未来开发新的治疗方案。

 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.