Regulation of Invasion and Metastasis by HIF-1 Oral Squamous Cell Carcinoma

HIF-1对口腔鳞状细胞癌侵袭和转移的调控

• 批准号: 7289879
• 负责人: STEPHEN Y LAI
• 金额: $ 12.62万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-22 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7289879
• 关键词: Address; Behavior; Biochemical; Biological Markers; Candidate Disease Gene; Cell Death; Cell division; Cells; Cervical lymph node group; Commit; Condition; Development; Diagnostic; Disease Progression; Distant; Distant Metastasis; Fostering; Gene Targeting; Genomics; Glycolysis; Goals; Growth; Growth Factor; Head and Neck Cancer; Head and neck structure; Homeostasis; Human; Hypoglycemia; Hypoxia; In Vitro; Institution; Lead; Local Tumor Spread; Malignant - descriptor; Malignant Epithelial Cell; Mediating; Mentors; Metabolism; Molecular; Monitor; Morbidity - disease rate; Neoplasm Metastasis; Nutrient; Oropharyngeal Neoplasms; Oxygen; Patients; Pattern; Play; Proliferating; Radiation therapy; Regulation; Research; Research Personnel; Research Project Grants; Resistance; Resources; Role; Signal Pathway; Signal Transduction; Site; Stimulus; Surgical Oncologist; System; Testing; Therapeutic Intervention; Time; Translating; Treatment Protocols; angiogenesis; base; cancer type; career; chemotherapy; design; extracellular; head and neck cancer patient; hypoxia inducible factor 1; improved; insight; mortality; mouth squamous cell carcinoma; mutant; neoplastic cell; novel; novel therapeutics; outcome forecast; prevent; research study; therapy design; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): Project Summary: Resistance to treatment has been a vexing challenge for oral squamous cell carcinoma (OSCC). Within the tumor microenvironment, OSCC cells rapidly expend oxygen and nutrients supplied by the local vasculature. Although hypoxia may inhibit new cell division or increase cell death, those cells most capable of adapting to hypoxia and hypoglycemia may have a selective advantage leading to increased malignant behavior. Indeed, studies have demonstrated a relationship between tumor hypoxia and increased resistance to radiation therapy and chemotherapy. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor that plays an essential role in regulating oxygen homeostasis. Expression and activity of the HIF-1 a subunit is influenced by cellular oxygen concentration, as well as numerous growth factors and signaling pathways. Over 70 HIF-1 target genes have been identified that are crucial for angiogenesis, glycolysis and other adaptive mechanisms. Increased HIF-1 expression within oropharyngeal tumors is correlated with worse patient prognosis. This research project is focused upon the role of HIF-1 in modulating OSCC invasion and metastasis. In Specific Aim 1, we will elucidate the function of HIF-1 in OSCC invasion and metastasis. We will characterize the contribution of HIF-1 to the regulation of candidate genes that mediate invasion and metastasis in OSCC in Specific Aim 2. Understanding the biochemical and molecular basis for the altered regulation of HIF-1 in OSCC could lead to opportunities for new therapeutic interventions to limit OSCC invasion and metastasis and improve patient survival. The candidate is a head and neck oncologic surgeon with a research background in signal transduction and head and neck cancer. His career goal is to translate advances in the understanding of OSCC metastasis and invasion into novel and effective therapeutic interventions for head and neck cancer patients. His institution is committed to this goal and has provided the necessary space, protected time and resources. He has assembled a team of mentors and consultants who will not only provide extensive scientific guidance, but also foster his development as an independent investigator. Relevance: Morbidity and mortality due to head and neck cancers is often related to tumor spread by local invasion and distant metastasis. Understanding the role of HIF-1 in OSCC invasion and metastasis may identify new targets for the development of diagnostic biomarkers and therapies designed to monitor and prevent tumor spread. These studies will directly benefit patients with head and neck cancer and may provide valuable insight into the regulation of tumor spread in other types of cancer.

描述（由申请人提供）：项目摘要：对治疗的抵抗一直是口服鳞状细胞癌（OSCC）的挑战。在肿瘤微环境中，OSCC细胞迅速消耗局部脉管系统提供的氧气和营养。尽管缺氧可能会抑制新的细胞分裂或增加细胞死亡，但最能够适应低氧和低血糖的细胞可能具有选择性的优势，从而导致恶性行为增加。实际上，研究表明，肿瘤缺氧与对放射治疗和化疗的耐药性增加之间存在关系。低氧诱导因子1（HIF-1）是一种异二聚体转录因子，在调节氧气稳态中起着至关重要的作用。 HIF-1 A亚基的表达和活性受细胞氧浓度以及许多生长因子和信号通路的影响。已经确定了超过70个HIF-1靶基因，这些基因对于血管生成，糖酵解和其他适应性机制至关重要。口咽肿瘤中HIF-1表达的增加与患者预后较差有关。该研究项目的重点是HIF-1在调节OSCC入侵和转移中的作用。在特定目标1中，我们将阐明HIF-1在OSCC侵袭和转移中的功能。我们将表征HIF-1对特定目标中介导OSCC中侵袭和转移的候选基因的调节的贡献。了解HIF-1在OSCC中改变调节的生化和分子基础可能会导致新的治疗干预措施限制OSCC入侵和转移的机会，并提高患者的生存。 候选人是一名头颈肿瘤外科医生，具有信号转导和头颈癌的研究背景。他的职业目标是将了解OSCC转移和入侵的进步转化为针对头颈癌患者的新颖有效的治疗干预措施。他的机构致力于这一目标，并提供了必要的空间，受保护的时间和资源。他召集了一个导师和顾问团队，他们不仅会提供广泛的科学指导，而且还促进了他作为独立调查员的发展。 相关性：由于局部侵袭和遥远的转移，头部和颈部癌引起的发病率和死亡率通常与肿瘤扩散有关。了解HIF-1在OSCC侵袭和转移中的作用可能会确定诊断生物标志物和旨在监测和预防肿瘤扩散的诊断生物标志物和疗法的新靶标。这些研究将直接使头颈癌患者受益，并可能对其他类型的癌症的肿瘤扩散调节有价值。