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MATRIX REMODELING IN ORAL SQUAMOUS CELL CARCINOMA

口腔鳞状细胞癌的基质重塑

基本信息

批准号：
6176024
负责人：
DANIEL M RAMOS
金额：
$ 0.32万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-01 至 2000-09-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6176024
关键词：
athymic mouse biological signal transduction disease /disorder model extracellular matrix proteins gene expression gene induction /repression glycoproteins immunocytochemistry integrins laboratory mouse neoplastic process oral pharyngeal neoplasm protein structure function squamous cell carcinoma tetracyclines western blottings

项目摘要

Squamous cell carcinoma (SCC), a highly metastatic lesion, accounts for approximately 96 percent of all oral cancers. Tumor metastasis requires multiple interactions with the extracellular matrix (ECM), including cell migration, invasion and matrix remodeling. Our group has shown that the ECM molecule tenascin-C (TN-C) and its integrin receptor, alphavbeta6, are neo-expressed in oral SCC. TN-C, a hexameric glycoprotein containing antiadhesive domains, reportedly promotes cell motility. The alphav integrin subfamily has also been reported to mediate cell motility. Coexpression of TN-C and alphavbeta6 thus provides a permissive environment for tumor cell invasion. Recently, others showed that a transmembrane molecule found on the surface of some tumor cells, extracellular matrix metalloproteinase inducer (EMMPRIN), stimulates matrix metalloproteinase (MMP) secretion by peritumor fibroblasts. Using human biopsy specimens, we observed an increase in staining for EMMPRIN in both oral dysplasia and oral SCC when compared with normal oral mucosa. We also identified a novel role for EMMPRIN as a modulator of TN-C matrix deposition. In the presence of antibodies to EMMPRIN, the deposition of TN-C matrices by cocultures of SCC cells and peritumor fibroblasts was inhibited, and their secretion of the latent forms of both MMP-2 and MMP-9 was increased. Anti-EMMPRIN antibodies also perturbed oral SCC cell motility in vitro. We hypothesize that TN-C, EMMPRIN, and alphavbeta6 influence oral cancer by acting as interdependent stimulatory modulators of tumor cell invasion and gene expression. Specific aims 1 and 2 were put forth in the funded R-29DE11930-02A grant and should be completed within the 5 years as originally proposed. The new specific aims (boldface) represent additional work to be done in years 6 and 7. The specific aims of this proposal are: (1) To determine whether alterations in the expression of alphavbeta6 will modify the invasive behavior of oral SCC cells. (2) To evaluate different stages of tumor invasion, using an animal model, for differential expression of TN-C and alphabeta6. (3) To investigate EMMPRIN's role in TN-C matrix deposition by determining the effects of anti-EMMPRIN antibodies on MMPs that may interact with TN-C. (4) To evaluate the effects of overexpressing EMMPRIN in poorly invasive oral SCC cells. These experiments should help us understand the mechanisms underlying ECM remodeling in oral cancer.

鳞状细胞癌（SCC）是一种高度转移性病变，约占所有口腔癌的96%。肿瘤转移需要与细胞外基质（ECM）的多种相互作用，包括细胞迁移、侵袭和基质重塑。我们的研究小组已经表明，ECM分子腱生蛋白-C（TN-C）及其整合素受体α v β 6在口腔SCC中新表达。 TN-C是一种含有抗粘附结构域的六聚体糖蛋白，据报道可促进细胞运动。还报道了α v整联蛋白亚家族介导细胞运动。 TN-C和α v β 6的共表达因此为肿瘤细胞侵袭提供了一个允许的环境。最近，其他研究表明，在一些肿瘤细胞表面发现的跨膜分子，细胞外基质金属蛋白酶诱导剂（EMMPRIN），刺激肿瘤周围成纤维细胞分泌基质金属蛋白酶（MMP）。使用人类活检标本，我们观察到与正常口腔粘膜相比，EMMPRIN在口腔异型增生和口腔SCC中的染色增加。我们还确定了EMMPRIN作为TN-C基质沉积调节剂的新作用。在EMMPRIN抗体的存在下，SCC细胞和瘤周成纤维细胞的共培养物的TN-C基质的沉积被抑制，并且它们的MMP-2和MMP-9的潜伏形式的分泌增加。抗EMMPRIN抗体也干扰口腔SCC细胞在体外的运动。我们假设TN-C、EMMPRIN和α v β 6通过作为肿瘤细胞侵袭和基因表达的相互依赖的刺激调节剂影响口腔癌。具体目标1和2在R-29 DE 11930 - 02 A资助中提出，应在最初提议的5年内完成。新的具体目标（黑体字）表示第六和第七年要做的额外工作。本研究的具体目的是：（1）确定α v β 6表达的改变是否会改变口腔SCC细胞的侵袭行为。 (2)使用动物模型评估肿瘤侵袭的不同阶段的TN-C和TN 6的差异表达。 (3)通过测定抗EMMPRIN抗体对可能与TN-C相互作用的MMP的影响，研究EMMPRIN在TN-C基质沉积中的作用。 (4)探讨EMMPRIN过表达对低侵袭性口腔鳞癌细胞的影响。这些实验有助于我们了解口腔癌中ECM重塑的机制。