Growth factors in tumor/stroma interactions during melanoma progression

黑色素瘤进展过程中肿瘤/基质相互作用的生长因子

• 批准号: 6594572
• 负责人: Meenhard F Herlyn
• 金额: $ 31.28万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6594572
• 关键词: SCID mouse; cellular oncology; fibroblast growth factor; fibroblasts; growth factor; human tissue; melanoma; metastasis; mitogens; mixed tissue /cell culture; neoplastic cell; neoplastic process; neoplastic transformation; platelet derived growth factor; tissue /cell culture; vascular endothelial growth factors; vascular endothelium

Human melanoma can develop in a sequence of steps from benign proliferative lesions. Melanocytes isolated and cultured from normal skin and lesions representing each step have been characterized for growth requirements, synthesis of growth factors, and expression of cell surface tumor associated antigens. Still, little is known about the molecular events leading to tumor development and progression towards an aggressive phenotype. Two models have now been established to provide tools for in- depth experimental investigations with a focus on the early stages of melanoma. The first model consists of full-thickness human skin, nevi or primary melanomas of the radial (non-tumorigenic) growth phase that are transplanted to immunodeficient SCID mice and treated in two-step and one- step carcinogenesis protocols for induction of human melanocytic lesions. The protocols involve treatments with the chemical carcinogen DMBA and ultraviolet (UV) light in the UV-B range which are applied alone or in combination. Developing melanocytic lesions will be characterized for expression of growth factors, adhesion receptors, and aberrations in oncogene and suppressor gene expression. The second model aims at 'reconstructing" melanocytic lesions by overexpressing a cell-cell adhesion receptor (MUC18) in melanocytes for induction of "nevi" and two angiogenic growth factors (pleiotrophin and PDGF-B) in biologically early (non- tumorigenic) melanomas for induction of tumorigenic lesions. Overexpression is achieved by gene transfer with adenovirus vectors. To investigate the biological properties of transduced cells, they are incorporated into three-dimensional epidermal and dermal equivalents that resemble normal human skin and that can also be grafted to SCID mice, thus allowing cell-cell contracts between normal and malignant human cells under in vivo experimental conditions. The two experimental models provide excellent tools for a better understanding of the molecular events leading to melanoma development and progression.

人类黑色素瘤可以从良性增殖性黑色素瘤发展为恶性黑色素瘤。 病变 从正常皮肤和病变中分离和培养黑素细胞 代表每一步都已经被表征为生长要求， 生长因子的合成和细胞表面肿瘤的表达 相关抗原。 尽管如此，人们对这些分子事件知之甚少 导致肿瘤发展和进展， 表型 现在已经建立了两个模型，为信息技术提供工具- 深入的实验研究，重点是早期阶段， 黑素瘤 第一个模型由全层人类皮肤、痣或 放射状（非致瘤性）生长期的原发性黑素瘤， 移植到免疫缺陷的SCID小鼠，并在两步和一步治疗， 诱导人黑素细胞损伤的分步致癌方案。 该方案涉及用化学致癌物DMBA进行治疗， 在UV-B范围内的紫外（UV）光，其单独或组合应用。 组合. 发展中的黑素细胞病变将被表征为 生长因子、粘附受体和畸变的表达， 癌基因和抑制基因表达。 第二种模式旨在 通过过度表达a细胞-细胞粘附“重建”黑素细胞损伤 黑素细胞中的MUC 18受体，用于诱导“痣”和两种血管生成 生长因子（多效生长因子和PDGF-B）在生物学早期（非 致瘤性）黑素瘤，用于诱导致瘤性损伤。 通过用腺病毒载体进行基因转移来实现过表达。 到 研究转导细胞的生物学特性，它们是 结合到三维表皮和真皮等同物中， 类似于正常的人类皮肤，也可以移植到SCID小鼠身上， 允许正常和恶性人类细胞之间的细胞-细胞收缩， 体内实验条件。 两个实验模型提供了 这是一个很好的工具，可以更好地理解导致 黑色素瘤的发生和发展