ADHESION AND PROLIFERATION IN ORAL CANCER PROGRESSION

口腔癌的特点是无休止的生长和侵袭，经常导致远处转移。虽然在确定癌症的临床和组织病理学特征方面已经取得了重大进展，但肿瘤进展的分子机制仍然知之甚少。拟议计划项目的主要重点是进一步确定从正常粘膜到口腔不典型增生，最后到浸润性鳞状细胞癌的逐步转化过程中发生的变化。该项目由加州大学旧金山分校的四个互动研究实验室组成。在定义与肿瘤进展相关的分子方面有相当丰富的经验，包括肿瘤标记分析、生长因子和黏附受体功能、信号转导和分子遗传学。此外，该小组已经开始着手分析与表征肿瘤进展的顺序过程有关的复杂问题。项目I阐述了转化生长因子-α的处理机制及其在肿瘤发展过程中通过细胞内信号通路的调节。项目二将研究α类整合素受体在调节细胞生长和侵袭中的重要性，该受体结合细胞外基质配体和潜在的转化生长因子-β形式。项目III将确定特定的细胞黏附系统在调节正常和恶性口腔角质形成细胞的存活、凋亡和生长方面的重要性。项目四将分析人类乳头瘤病毒和MRP-8/14在口腔癌发病机制中的作用。此外，该计划将支持年轻研究人员在肿瘤内寻找种子，提出口腔癌的基础和临床研究项目。这两个最初的试点项目将检验(1)p14/ARF状态作为口腔癌发展的分子预测因子，以及(2)纤维连接蛋白及其受体在调节口腔鳞状细胞癌侵袭和生长中的作用。这些互动研究和可行性项目将得到行政核心、细胞培养/动物模型核心和组织病理学核心的支持。新成立的加州大学旧金山分校综合癌症中心的专门核心将提供额外的基础设施支持。

Oral cancer is characterized by relentless growth and invasion, frequently resulting in distant metastasis. While significant progress has been made in defining the clinical and histopathological characteristics of cancer, the molecular mechanisms of tumor progression remain poorly understood. The major focus of the proposed Program Project is to further define the alterations that occur during the stepwise conversion of normal mucosa to oral dysplasia, and finally to invasive squamous cell carcinoma. The project comprises four interactive research laboratories at the University of California San Francisco. That have considerable experience in defining molecules related to tumor progression, including tumor marked analysis, growth factor and adhesion receptor function, signal transduction, and molecular genetics. Moreover, this group has already initiated approaches to the analysis of the complex issues related to the sequential processes characterizing tumor progression. Project I addresses the mechanism of TGF-alpha processing and its regulation by intracellular signaling pathways during carcinoma development. Project II will examine the importance of he alphav class of integrin receptors, which bind extracellular matrix ligands as well as the latent form of TGF- beta, in regulating cell growth and invasion. Project III will define the importance of specific cell adhesion systems in regulating survival, apoptosis and growth in normal and malignant oral keratinocytes. Project IV will analyze the role of human papillomavirus and MRP-8/14 in oral cancer pathogenesis. In addition, the Program will support intratumoral seed finding of young investigators proposing basic and clinical research projects in oral cancer. The two initial pilot projects will examine (1) p14/ARF status as a molecular predictor of oral cancer development, and (2) the role of fibronectin and its receptors in regulating invasion and growth of oral squamous cell carcinoma. These interactive research and feasibility projects will be supported by an administrative core, a cell culture/animal model core, and a histopathology core. Additional infrastructure support will be provided by the specialized cores of the newly established UCSF Comprehensive Cancer Center.