Mechanical regulation of the microenvironmental niche in skin tumorigenesis

皮肤肿瘤发生中微环境生态位的机械调节

• 批准号: 8938176
• 负责人: Kandice Tanner
• 金额: $ 31.39万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/8938176
• 关键词: Aging; Atypia; BRAF gene; Basement membrane; Benign; Cells; Cellular Morphology; Chemicals; Clinical; Dermis; Dysplastic Nevus; Epidermis; Etiology; Evolution; Extracellular Matrix; Fibroblasts; Histologic; Immune; Individual; Indolent; Lesion; Location; Malignant - descriptor; Mechanics; Melanins; Melanocytic nevus; Metastatic Melanoma; Motion; Mutation; Neoplasm Metastasis; Neoplasms; Nevus; Normal Cell; Outcome; Precancerous melanosis; Property; Radial; Radial Growth Phase; Regulation; Role; Signal Pathway; Signal Transduction; Skin; Solid Neoplasm; Staging; Subcutaneous Tissue; Testing; Tissues; Tumor Suppressor Proteins; Vertical Growth Phase; base; biophysical properties; cell motility; cell type; chemical property; keratinocyte; melanocyte; melanoma; morphogens; neoplastic cell; tumor; tumorigenesis

Melanomas are histologically classified according to their location and stage of progression ranging from the congenital nevi without dysplastic changes to metastatic melanoma. The presumed precursors; benign and dysplastic nevi are characterized by the architectural disruption of the epidermal melanin unit. BRAF mutations have been implicated as a crucial step in the initiation of melanocytic neoplasia. However, melanocytic nevi can be relatively indolent for decades despite the presence of activating BRAF mutations. The role of the microenvironment is emerging as critical for malignant progression, metastasis and tumor etiology. The interactions between tumor cells and the extracellular matrix (ECM), normal cells and immune cells remain elusive. In solid tumors, dysplastic lesions remain local aberrations as long as the specialized, ECM, basement membrane (BM) remains intact. So why are some lesions quiescent while others progress rapidly to metastasis? Do tumor cells force their way through or do the structural properties of the BM simply degrade during aging? Can we determine the mechanical regulation of this motion and understand the role of the mechanical properties of the microenvironment in regulating progression to full metastatic potential?

黑色素瘤根据其位置和进展阶段进行组织学分类，范围从没有异常增生性改变的先天性痣到转移性黑色素瘤。推测的前体；良性和发育不良的痣以表皮黑色素单位的结构破坏为特征。BRAF基因突变被认为是黑素细胞肿瘤发生的关键步骤。然而，尽管存在激活的BRAF突变，黑色素细胞痣可能会相对迟钝数十年。微环境在恶性进展、转移和肿瘤病因学中的作用日益显现。肿瘤细胞与细胞外基质(ECM)、正常细胞和免疫细胞之间的相互作用仍然难以捉摸。在实体瘤中，只要特化的ECM基底膜(BM)保持完好，发育不良的病变仍然是局部的异常。那么，为什么有些病变是静止的，而另一些病变进展得很快呢？是肿瘤细胞强行通过，还是骨髓的结构特性在老化过程中退化？我们能否确定这一运动的机械调节，并了解微环境的机械特性在调节进展至完全转移潜能方面的作用？