Promotion Of Metastatic Processes By Laminin And Laminin

层粘连蛋白和层粘连蛋白促进转移过程

• 批准号: 6673976
• 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/6673976
• 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.

进行研究是为了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（在小鼠体内生长不佳）预混合时会促进其发生和生长。我们已经能够从小鼠体内生长的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。层粘连蛋白是一种主要的基底膜成分，已被发现可促进恶性表型。层粘连蛋白贴壁细胞比非贴壁细胞或亲代细胞更恶性。已鉴定出多种具有生物活性的层粘连蛋白衍生的合成肽。第一，YIGSR（tyr-ile-gly-ser-arg）可减少肿瘤生长、转移和血管生成，而 IKVAV 可增加这些活性。另一种肽 LQVQLSIR 会增加转移，但其机制尚未明确。我们的目标是确定肿瘤生长和转移所涉及的分子机制。我们的方法是（1）选择和分离高度恶性细胞，（2）定义其细胞层粘连蛋白受体，（3）识别层粘连蛋白上促进或减少恶性表型的其他序列，（4）识别与恶性肿瘤有关的基因，以及（5）定义骨中负责前列腺癌和乳腺癌器官特异性转移的分子。我们使用多种模型，包括 B16F10 黑色素瘤细胞、乳腺癌、前列腺和唾液腺肿瘤细胞。我们希望定义与转移有关的监管事件并开发治疗和诊断试剂。