ORAL MELANOMA: ALPHA V BETA 3 EXPRESSION AND METASTASIS

描述（改编自研究者摘要）： 口腔几乎总是致命的拟议的工作重点是两个阶段 在黑色素瘤进展中：侵袭和转移，在此期间，黑色素瘤细胞 主要通过整合素受体与细胞外基质相互作用。 玻连蛋白受体α v β 3由垂直侵袭性细胞表达， 转移性皮肤黑色素瘤，但缺乏浅表扩散性黑色素瘤 和正常的黑素细胞。在鼠K1735黑色素瘤中，高转移性 细胞表达α v β 3，但不表达α v β 5玻连蛋白受体， 转移性差的细胞表达α v β 5而不表达α v β 3。粘附 α v β 3，而不是α v β 5，与玻连蛋白的结合导致 FAK、c-Src和pMAP激酶信号传导分子参与细胞运动， 基因表达-和基质金属蛋白酶-2的表达增加 （MMP-2）。本研究探讨了以下问题：1）表达 alphavbeta 3或alphavbeta 5与口腔黑色素瘤转移相关？人类 活检标本将通过免疫组织化学和原位 用于表达α v β 3或α v β 5杂交。2)做表情 与鼠黑色素瘤细胞的转移潜能相关？ 具有不同转移潜能的K1735细胞将用于产生 通过经口和后胁腹注射来治疗额外的转移性变体。的 将评价所得肿瘤和变异细胞系的表达， α v β 3和激活FAK、pMAP激酶和表达MMP-2。第三章 α v β 3的过表达是否会使转移性表型变得不好 转移性黑素瘤细胞表达β 3的转移性差的细胞， 将评价逆转录病毒转导的侵袭和转移行为。 表达组成型活性Src对转移的影响也将被研究。 评估。4)降低α v β 3受体表达，或抑制 它的功能，改变黑色素瘤细胞的侵袭和转移潜力？ 在高转移性细胞中β 3的表达将被两种反义寡核苷酸 和显性消极策略。此外，人类β 3将在低水平表达。 侵袭性黑色素瘤细胞及其功能被功能阻断抑制 人β 3抗体。最后，显性否定的表达是否 将确定高转移性细胞系中的c-Src降低转移。 了解β 3在口腔黑色素瘤侵袭和转移中的作用， 导致新预后指标和新治疗的发展 战略布局

DESCRIPTION (Adapted from the Investigator's Abstract): Malignant melanoma of the oral cavity is almost always fatal. The proposed work focuses on two stages in melanoma progression: invasion and metastasis, during which melanoma cells interact with the extracellular matrix primarily through integrin receptors. The vitronectin receptor alphavbeta3 is expressed by vertically invasive and metastatic cutaneous melanoma but is absent from superficial spreading melanoma and normal melanocytes in vivo. In the murine K1735 melanoma, highly metastatic cells express alphavbeta3, but not the alphavbeta5 vitronectin receptor, while poorly metastatic cells express alphavbeta5 but not alphavbeta3. Adhesion of alphavbeta3, but not alphavbeta5, to vitronectin results in the activation of FAK, c-Src, and pMAP kinase-signaling molecules implicated in cell motility and gene expression - and in increased expression of matrix metalloproteinase-2 (MMP-2). This study addresses the following questions: 1) Does expression of alphavbeta3 or alphaVbeta5 correlate with oral melanoma metastasis? Human biopsy specimens will be evaluated by immunohistochemistry and in situ hybridization for expression of alphavbeta3 or alphavbeta5. 2) Does expression of alphavbeta3 correlate with metastatic potential in murine melanoma cells? K1735 cells with differing metastatic potential will be used to generate additional metastatic variants by both transoral and hind-flank injection. The resulting tumors and variant cell lines will be evaluated for expression of alphavbeta3 and for activation of FAK, pMAP kinase, and expression of MMP-2. 3) Will overexpression of alphavbeta3 confer the metastatic phenotype to poorly metastatic melanoma cells? Poorly metastatic cells expressing beta3 by retroviral transduction will be evaluated for invasive and metastatic behavior. The effect on metastasis of expressing a constitutively active Src will also be evaluated. 4) Will decreasing alphavbeta3 receptor expression, or suppressing its function, alter the invasive and metastatic potential of melanoma cells? beta3 expression in highly metastatic cells will be reduced by both antisense and dominant negative strategies. Also, human beta3 will be expressed in poorly invasive melanoma cells, and its function suppressed by function-blocking antibody to human beta3. Finally, whether expression of a dominant-negative c-Src in a highly metastatic cell line decreases metastasis will be determined. Understanding the role beta3 plays in oral melanoma invasion and metastasis may lead to novel prognostic indicators and development of new treatment strategies.