Biology of Perlecan in Cancer

描述（由申请人提供）：本竞争项目的长期目标 格兰特是为了了解串珠素的生物学，串珠素是一种多功能的乙酰肝素。 硫酸化蛋白聚糖具有广泛组织分布和功能活性， 并了解其在肿瘤发生中的确切作用。核心假设是 串珠素的异常表达有助于肿瘤的促进， 入侵，一个工作理论的基础上几个关键的意见：[a] 在人结肠癌的细胞周围基质中表达升高， 黑色素瘤，[B]这种基因产物的大量沉积发生在黑色素瘤中及其周围。 新形成的肿瘤血管，[c]转化细胞具有高的 增殖指数过度产生串珠素，[d]串珠素直接参与 血管生成生长因子的储存，[e]串珠蛋白核心结合FGF 7 并调节其促有丝分裂活性，[f]串珠蛋白核心相互作用 FGF结合蛋白（FGF-BP），一种也与肿瘤相关的蛋白质， 形成和血管生成。最后两个发现是在P.I.的 实验室的赞助下，这项赠款，并指出，各种模块 的串珠素可以与生物活性蛋白协同作用， 调节肿瘤生长。 在接下来的五年里，我们计划：（1）研究串珠素在 通过检测废除或诱导的癌细胞的行为， 串珠素在同源宿主中的表达，（2）深入研究串珠素在宿主中的表达， 串珠素与FGF-BP相互作用;（3）鉴定细胞表面蛋白 利用表达克隆和酵母双杂交技术研究串珠素的相互作用 系统 这些协调一致的研究路线将提供信息，不仅在 哺乳动物串珠素在肿瘤发生中的功能作用，但也将确定 可以直接影响串珠蛋白功能的新型生物伴侣。的 预期的结果可能会导致未来的癌症预防方法， 针对阻碍该蛋白聚糖表达的治疗， 使肿瘤细胞失去一种必需的大分子。

DESCRIPTION (provided by applicant): The long-term objective of this competing grant is to understand the biology of perlecan, a multifunctional heparan sulfate proteoglycan with wide tissue distribution and functional activities, and to discern its precise role in tumorigenesis. The central hypothesis is that the aberrant expression of perlecan contributes to tumor promotion and invasion, a working theory based on several key observations: [a] Perlecan expression is elevated in the pericellular matrix of human colon cancer and melanomas, [b] Abundant deposition of this gene product occurs in and around the newly-formed tumor blood vessels, [c] Transformed cells with a high proliferative index overproduce perlecan, [d] Perlecan is directly involved in the storing of angiogenic growth factors, [e] Perlecan protein core binds FGF7 and modulates its mitogenic activity, and [f] Perlecan protein core interacts with FGF- binding protein (FGF-BP), a protein that is also implicated in tumor formation and angiogenesis. The last two discoveries were made in the P.I.'s laboratory under the auspices of this grant and indicate that various modules of perlecan may act synergistically with biologically active proteins in modulating tumor growth. Over the next five years we plan to: (1) Investigate the role of perlecan in tumorigenesis by testing the behavior of cancer cells with abrogated or induced expression of perlecan in syngeneic hosts, (2) Investigate in depth the interaction between perlecan and FGF-BP, and (3) Identify cell surface proteins interacting with perlecan using expression cloning and the yeast two hybrid system. These concerted research lines will provide information, not only on the functional roles of mammalian perlecan in tumorigenesis, but will also identify novel biological partners that could directly affect perlecan's functions. The expected results could lead to future approaches of cancer prevention and treatment directed at hindering the expression of this proteoglycan thereby depriving the tumor cells of an essential macromolecule.