PILOT--INVASION REGULATED BY FIBRONECTIN AND RECEPTORS

细胞外基质是肿瘤细胞侵袭和迁移的重要调节成分。特别是，纤维连接蛋白(FN)的选择性剪接的V区对于这些进展是重要的，因为只有含有该区域的FN微蛋白(V+H和V+H-)在体外诱导鳞状细胞癌(SCC)细胞的侵袭和迁移增加。相反，原代正常角质形成细胞和成纤维细胞在用V+H-FN蛋白处理时会发生凋亡。在成纤维细胞中，这一机制是由硫酸软骨素蛋白多糖介导的，可能是通过α4整合素，通过涉及caspase-1和-3的caspase级联，通过p53和c-myc的改变，以及伴随的pp125FAK的减少。这些数据表明，致瘤性使SCC细胞能够绕过凋亡途径，转而呈现侵袭性和迁移性表型，以响应V+H蛋白。这是假设，SCC细胞经历了更多的迁移表型对V+H-蛋白的反应。假设鳞癌细胞通过细胞表面蛋白多糖和整合素受体选择性剪接FN的V区而发生侵袭和迁移的增加，从而启动了不同于原始未转化受体的信号转导途径，该信号转导途径不同于原始非表面受体(S)，参与了含V的FN片段诱导的侵袭和迁移的增加。具体地说，确定Condroitin硫酸蛋白多糖和α4整合素是否参与了这种侵袭和迁移机制，因为这些受体调控着含V的FN片段在成纤维细胞中触发的凋亡途径。(2)检测在介导含V的FN片段诱导的迁移和侵袭增加中所涉及的SCC细胞信号反应。具体地说，确定P53和c-myc是否像在原代细胞中一样被调制。这些研究将有助于解释细胞-基质相互作用的一些基本机制，以及调节肿瘤细胞生物学的信号机制。此外，由于鳞状细胞癌是最常见的口腔恶性肿瘤类型，占与口腔癌相关的死亡的主要部分，这些研究可能为治疗干预提供潜在的有用途径。

The extracellular matrix is an important regulatory component of tumor cell invasion and migration. Specifically, the alternatively spliced V region of fibronectin (FN) is important to these progresses since only FN miniproteins (V+H and V+H-) containing this region induce increased invasion and migration of squamous cell carcinoma (SCC) cells in vitro. In contrast, primary normal keratinocytes and fibroblasts undergo apoptosis when treated with the V+H-FN protein. In fibroblasts, this mechanism is mediated by chondroitin sulfate proteoglycans, possibly by the alpha 4 integrin, by a caspase cascade involving caspase-1 and -3, by alterations in p53 and c-myc, and by a concomitant decrease in pp125 FAK. These data suggest that tumorigenicity has enabled SCC cells to bypass the apoptotic pathway and instead take on an invasive and migratory phenotype in response to the V+H- protein. It is hypothesized that SCC cells undergo increased migratory phenotype in response to the V+H- protein. It is hypothesized that SCC cells undergo increased invasion and migration in response to the alternatively spliced V region of FN via cell surface proteoglycan and integrin receptors, which initiate a signal transduction pathway that differs from that in primary non- transformed receptors, which initiate a signal transduction pathway that differs from that in primary non-surface receptor(s) involved in mediating increased migration and invasion induced by the V-containing FN fragments. Specifically, determine whether condroitin sulfate proteoglycans and the alpha4 integrin are involved in this mechanism of invasion and migration, since these receptors regulate the apoptotic pathway triggered by the V-containing FN fragment in fibroblasts. (2) Examine the SCC cell signaling response involved in mediating increased migration and invasion induced by the V-containing FN fragments. Specifically, determine whether p53 and c-myc are modulated as in the primary cells. These studies will help explain some of the basic mechanisms underlying the cell-matrix interactions and signaling mechanism that regulate tumor cell biology. In addition, since squamous cell carcinoma is the most common type of malignant oral neoplasm, accounting for a major portion of deaths related to oral cancer, these studies may provide potentially useful avenues for therapeutic intervention.