Mechanisms of the hypoxic response underlying tumor progression

描述（由申请人提供）：我们的长期目标是在分子水平上了解肿瘤微环境如何决定肿瘤的生长和进展。几十年的癌症研究已经得出结论，癌症本质上是一种遗传疾病，在基因组中发生了动态变化。人类癌症的发展需要一系列复杂的基因改变，赋予细胞选择性生长优势。这些基因变化导致致癌基因的激活和肿瘤抑制基因的失活。各种DNA修复机制通过纠正由各种类型的损伤引起的突变来保护正常细胞中的基因组完整性。DNA修复基因的种系突变与多种类型的遗传性癌症有关。然而，通常没有发现这种突变与散发性癌症的发展有关。除了肿瘤本身，肿瘤微环境，特别是缺氧，与癌症遗传不稳定性增加有关，可能归因于肿瘤进展和对化疗和放疗的耐药性，尽管其潜在机制尚不清楚。我们最近发现，缺氧诱导因子1a （HIF-1a）是缺氧反应的中心转录因子，通过一种新的HIF-1a-c- myc途径抑制DNA修复基因表达，从而诱导遗传不稳定，这表明DNA修复的功能损伤参与了肿瘤的发生和进展。尽管HIF-1a的异构体HIF-2a与肿瘤生长和血管生成密切相关，但由于苏氨酸磷酸化，HIF-2a不能抑制DNA修复。在本提案中，我们研究了HIF-1a和HIF-2a在肿瘤发生和进展中的作用。特异性Aim 1和特异性Aim 2验证了一种假设，即通过激活HIF-1a-Myc途径诱导遗传不稳定性，从而赋予肿瘤细胞诸如体外培养的侵袭性和肿瘤异种移植模型中的致瘤性、局部侵袭性和转移等恶性性状。特异性目标3在细胞培养和小鼠模型中研究了磷酸化对HIF-2a活性和肿瘤生长的要求。我们相信这一提议解决了肿瘤生长和进展动态性质的基本机制，并将为开发新的治疗方法奠定分子基础。从本质上讲，癌症是一种在基因组中发生动态变化的遗传疾病。这一建议解决了癌细胞遗传不稳定的模糊机制，这是与癌症作斗争中无法克服的问题。我们期望这项研究将有助于确定新疗法发展的分子基础。

DESCRIPTION (provided by applicant): Our long-term objective of this proposal is to gain an understanding at the molecular level of how the tumor microenvironment determines tumor growth and progression. Decades of cancer research has come to a conclusion that cancer is essentially a genetic disease acquiring dynamic changes in the genome. The development of cancer in humans requires a complex succession of genetic alterations over time, conferring selective growth advantage on cells undergoing progressive transformation. These genetic changes result in activation of oncogenes and inactivation of tumor-suppressor genes for tumor development. Various DNA repair mechanisms safeguard the genomic integrity in normal cells by correcting mutations arising from myriad types of damage. Germline mutations of DNA repair genes have been linked to diverse types of hereditary cancers. However, no such mutations are generally found to be responsible for the development of sporadic cancers. Apart from tumor itself, the tumor microenvironment, hypoxia in particular, has been associated with increased genetic instability in cancers, presumably attributable to tumor progression and resistance to chemotherapy and radiotherapy, even though the underlying mechanisms remain obscure. We have recently shown that the hypoxia-inducible factor 1a (HIF-1a), a central transcription factor of the hypoxic response, induces genetic instability by inhibiting DNA repair gene expression via a novel HIF-1a-c-Myc pathway, suggesting the involvement of functional impairment of DNA repair in tumor development and progression. Despite the heavy implication in tumor growth and angiogenesis, HIF-2a, an isoform of HIF-1a, fails to inhibit DNA repair because of threonine phosphorylation. In this proposal, we study the role of HIF-1a and HIF-2a in tumor development and progression. Specific Aim 1 and Specific Aim 2 test the hypothesis that the induction of genetic instability through activation of HIF-1a-Myc pathway confers malignant traits such as invasion on cultured tumor cells in vitro and tumorigenicity, local invasion, and metastasis in tumor xenograft models. Specific Aim 3 investigates the requirement of phosphorylation for HIF-2a activities and in turn tumor growth in both cell culture and mouse models We believe that this proposal addresses the fundamental mechanisms underlying the dynamic nature of tumor growth and progression and will build a molecular basis for the development of novel therapeutics. PUBLIC HEALTH RELEVANCE Cancer is, in essence, a genetic disease acquiring dynamic changes in the genome. This proposal tackles the obscure mechanisms underlying genetic instability of cancer cells, an insurmountable problem in the fight against cancer. We anticipate this study will help define the molecular basis for the development of novel therapeutics.