Promotion Of Metastatic Processes By Laminin And Peptide

层粘连蛋白和肽促进转移过程

• 批准号: 6503221
• 负责人: HYNDA K KLEINMAN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6503221
• 关键词: basement membrane; breast neoplasms; human tissue; laminin; melanoma; metastasis; neoplasm /cancer invasiveness; prostate neoplasms; salivary gland neoplasms; synthetic peptide; tissue /cell culture

Studies are conducted to define the mechanisms involved in tumor growth and metastasis and to develop new animal models of human cancers. We have found that a basement membrane extract (Matrigel) when premixed with human tumor cells (which do not grow well in mice) promotes their incidence and growth. We have been able to culture new highly differentiated human tumor cell lines from the tumors grown in mice including certain colon and prostate cell lines. Laminin, a major basement membrane component, has been found to promote the malignant phenotype. Laminin adherent cells are more malignant than either the non-adherent cells or the parental cells. Various biologically active laminin-derived synthetic peptides have been identified. One, YIGSR (tyr-ile-gly-ser-arg) reduces tumor growth, metastases, and angiogenesis whereas IKVAV increases these activities. Another peptide LQVQLSIR increases metastases but a mechanism has not yet been defined. Our goal is to define the molecular mechanisms involved in tumor growth and metastases. Our approach is to (1) select for and isolate highly malignant cells, (2) define their cellular laminin receptors, (3) identify additional sequences on laminin which promote or reduce the malignant phenotype, (4) identify genes involved in malignancy and (5) define molecules in bone responsible for prostate and breast cancer organ-specific metastases. We work with several models including B16F10 melanoma cells, breast, prostate and salivary gland tumor cells. We hope to define regulatory events involved in metastases and develop therapeutic and diagnostic reagents.

研究旨在确定肿瘤生长和转移的机制，并开发新的人类癌症动物模型。我们发现基底膜提取物（Matrigel）与人类肿瘤细胞（在小鼠中生长不好）预混时，可以促进肿瘤的发生和生长。我们已经能够从小鼠肿瘤中培养出新的高度分化的人类肿瘤细胞系，包括某些结肠和前列腺细胞系。层粘连蛋白，一个主要的基底膜成分，已被发现促进恶性表型。层粘连蛋白贴壁细胞比非贴壁细胞或亲本细胞更恶性。各种生物活性层粘连蛋白衍生的合成肽已被确定。第一，YIGSR （tyr1 -ile-gly-ser-arg）抑制肿瘤生长、转移和血管生成，而IKVAV则增加这些活性。另一种肽LQVQLSIR增加转移，但其机制尚未明确。我们的目标是确定参与肿瘤生长和转移的分子机制。我们的方法是：(1)选择并分离高度恶性细胞，(2)确定它们的细胞层粘连蛋白受体，(3)确定层粘连蛋白上促进或减少恶性表型的额外序列，(4)确定与恶性肿瘤有关的基因，(5)确定骨中负责前列腺癌和乳腺癌器官特异性转移的分子。我们研究了几种模型，包括B16F10黑色素瘤细胞、乳腺、前列腺和唾液腺肿瘤细胞。我们希望确定转移的调控事件，并开发治疗和诊断试剂。