Gene expression changes induced upon Beta3 integrin expression in human melanoma metastasis

转移性黑色素瘤的诊断和预后标记物对于更好地了解这种癌症的发展是必不可少的。到目前为止发现的与肿瘤细胞侵袭性相关的最有效的标记之一，因此与黑色素瘤的致命性相关，是β3整合素分子。当这种蛋白在早期黑色素瘤细胞的表面表达时，这些细胞本身不能形成转移肿瘤，它们向细胞传递了从皮肤表面生长(径向生长期)到允许它们侵入皮肤(垂直生长期)的能力。目前尚不清楚Beta 3的表达如何允许这种生长状态的变化，该研究计划旨在测试Beta 3是否是介导转移转化的基因表达变化的直接原因。为了深入了解表达Beta3蛋白的黑色素瘤细胞中诱导的基因变化，将对在Beta3存在下被激活或抑制的基因进行筛选。非转移性黑色素瘤细胞将被转导Beta 3基因，并将一种分子技术应用于这些细胞，以识别遗传差异，从而克隆差异表达的基因。识别出的基因片段将首先提供线索，说明哪些基因可能被开启或关闭，从而使肿瘤在皮肤下生长。它们还将形成转移性黑色素瘤基因PanelO的基础，可以测试其对肿瘤的诊断价值。该基因小组的实用性和重复性将通过测试黑色素瘤细胞系和肿瘤组织来证实。这些实验应该会导致更好地诊断转移性黑色素瘤，也可能找到新的途径来开发这种疾病的治疗方法。

Diagnostic and prognostic markers for metastatic melanoma are essential to better understand the development of this cancer. One of the most effective markers so far found to correlate with invasiveness of tumour cells, and hence lethality of melanoma, is the Beta3 integrin molecule. When this protein is expressed on the surface of early stage melanoma cells, that in themselves are not able to form metastatic tumours, they convey upon the cells the ability to proceed from growing on the surface of the skin (radial growth phase) to allowing them to invade the skin (vertical growth phase). It is not clear how expression of Beta 3 allows this change in growth state to occur and this research program is designed to test if Beta 3 is the direct cause of gene expression changes mediating the metastatic transformation. To provide insight into the genetic changes induced in melanoma cells expressing the Beta3 protein a screen for genes that are either activated or repressed in the presence of Beta3 will be performed. Non-metastatic melanoma cells will be transduced with the Beta 3 gene and a molecular technique applied to these cells that can identify genetic differences which will allow the cloning of differentially expressed genes. The gene fragments that are identified will first provide clues as to what the genes are that maybe switched on or off to allow the tumour to grow beneath the skin. They will also form the basis of a Ometastatic melanoma gene panelO that can be tested for its diagnostic value of tumours. The utility and reproducibility of the gene panel will be confirmed by testing melanoma cell lines and tumour tissue. These experiments should lead to better diagnosis of metastatic melanoma and also possible new avenues to develop therapies for the disease.