Cell-Cell Communication During Melanoma Development

黑色素瘤发育过程中的细胞间通讯

• 批准号: 7779986
• 负责人: Meenhard F Herlyn
• 金额: $ 27.63万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-05 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7779986
• 关键词: Adhesions; Adult; B-Lymphocytes; Basement membrane; Biological Models; Cadherins; Cell Communication; Cell Line; Cell Lineage; Cell Shape; Cell surface; Cells; Cessation of life; Characteristics; Code; Collagen; Commit; Dermis; Development; Differentiation and Growth; E-Cadherin; Environment; Epidermis; Epithelial Cells; Equilibrium; Fibroblasts; Funding; Genes; Growth; Hair; Hair follicle structure; Homeostasis; Human; Integrins; Invaded; Lead; Lesion; MS4A1 gene; Malignant Neoplasms; Mediating; Melanoma Cell; Mesenchymal; Metastatic Melanoma; Minor; Neoplasm Metastasis; Oligonucleotides; Oncogenes; Organ; Pathway interactions; Patients; Phenotype; Pigments; Play; Population; Positioning Attribute; Production; Proliferating; Property; Proteins; Research Personnel; Role; Signal Transduction; Simulate; Skin; Source; Stem cells; Testing; Tumor Suppressor Genes; Tumorigenicity; United States National Institutes of Health; WA01 cell line; WA09 Cell Line; Work; adhesion receptor; base; cancer cell; embryonic stem cell; human embryonic stem cell; in vivo; intercellular communication; keratinocyte; melanoblast; melanocyte; melanoma; morphogens; notch protein; osteogenic; precursor cell; progenitor; programs; receptor; self-renewal; stem cell differentiation; stem cell division; stem cell population; three-dimensional modeling; tumor; tumorigenic

In normal human skin, melanocytes are tightly regulated by surrounding keratinocytes, which determine melanocyte growth, expression of cell surface molecules, and cell shape. This dominance of keratinocytes over the melanocytes is lost during transformation, allowing melanoma cells to invade into the dermis. By studying cell-cell communication between normal melanocytes and keratinocytes, we are beginning to understand how melanoma cells have escaped from keratinocytes' control. We now expand for normal human skin the homeostatic concept of growth, differentiation, and survival or death and include stem cells as a continuing source for differentiated, pigment-producing melanocytes. As model systems we use melanocytes differentiated from human embryonic stem cells (NIH cell line codes WA01 and WA09) and progenitor cells of the human hair follicle. The working hypothesis in the first aim is that cadherin-mediated cell-cell interactions determine self-renewal of multi-potent progenitor, oligo-potent precursor and committed melanocyte stem cells whereas cell-matrix interactions drive differentiation. Using a three-dimensional model of normal human skin with a 'dermis' of fibroblasts embedded in collagen and an 'epidermis' with melanocytes and multi-layered keratinocytes, we will determine whether proper positioning of mature melanocytes at the basement membrane is controlled by integrin D6B1 and matricellular protein CCN3 and whether improper activation of cell-cell signaling genes such as Notchl leads to transformation. Our hypothesis is that melanocyte precursor and stem cells are more prone to transformation than mature, pigment-producing melanocytes. Using culture conditions developed for human embryonic stem cells, we have for aim 2 isolated melanoma cells from patients' lesions that have stem cell-like characteristics and differentiate into melanogenic, adipogenic, chondrogenic, and osteogenic cell lineages. These 'melanoma stem cells' represent a minor tumorigenic population and are characterized by the expression of the B cell marker CD20. We will determine whether and how cell-cell and cell-matrix interactions regulate the CD20- defined melanoma stem cell population and how CD20 can be optimally targeted for melanoma therapy. These studies will demonstrate how dysregulation of homeostasis results in tumor formation and targeting subpopulations of malignant cells leads to successful therapy.

在正常的人皮肤中，黑素细胞受周围的角质形成细胞的严格调节，这决定了 黑素细胞生长，细胞表面分子的表达和细胞形状。角质形成细胞的这种优势 在转化过程中，黑色素细胞上丢失，使黑色素瘤细胞侵入真皮。经过 研究正常黑色素细胞和角质形成细胞之间的细胞细胞通信，我们开始 了解黑色素瘤细胞如何从角质形成细胞的控制中逸出。我们现在扩展正常 人皮肤的生长，分化和生存或死亡的体内平衡概念，并将干细胞包括在内 持续的分化，产生色素的黑素细胞的来源。作为模型系统，我们使用 黑色素细胞与人类胚胎干细胞（NIH细胞系代码WA01和WA09）和 人毛囊的祖细胞。第一个目的的工作假设是钙粘蛋白介导 细胞细胞相互作用决定了多功能祖细胞，寡素的前体的自我更新和效力 黑色素细胞干细胞，而细胞矩阵相互作用驱动分化。使用三维模型 正常的人皮肤，带有胶原蛋白中的成纤维细胞的“真皮”和一个“表皮” 黑色素细胞和多层角质形成细胞，我们将确定是否正确定位成熟 地下膜的黑素细胞由整合素D6B1和矩阵蛋白CCN3和 细胞 - 细胞信号基因（如Notchl）的激活是否会导致转化。我们的 假设是黑素细胞前体和干细胞更容易转化，而不是成熟， 产生色素的黑素细胞。使用为人类胚胎干细胞开发的培养条件，我们 具有AIM 2来自具有干细胞样特征的患者病变和 分化为黑色素生成，成脂，软骨和成骨细胞谱系。这些“黑色素瘤” 干细胞的代表较小的肿瘤种群，其特征是B细胞的表达 标记CD20。我们将确定是否以及如何以及如何调节CD20- 确定的黑色素瘤干细胞群以及如何最佳地靶向CD20用于黑色素瘤治疗。 这些研究将证明体内平衡失调如何导致肿瘤形成和靶向 恶性细胞的亚群会成功治疗。