The role of beta integrins in epidermal tumor progression

描述（由申请人提供）：上皮恶性肿瘤代表了绝大多数人类癌症。肿瘤的一个共同特征是肿瘤细胞通过基底膜侵入，为局部和远处转移奠定了基础，这是患者发病和死亡的主要原因。在早期人类肿瘤进展过程中，基底膜上发生的关键肿瘤-基质相互作用尚未得到充分表征。本研究的重点是整合素亚基¿1和¿4以及整合素相关的局灶黏附激酶（FAK）在介导早期表皮肿瘤进展中的作用。首先，我们计划扩展最近的研究结果，即¿1和¿4整合素及其多个整合素伙伴是人类表皮肿瘤进展中细胞外基质中心基因表达网络的关键组成部分。靶向整合素可适度减轻表皮肿瘤异种移植模型的肿瘤进展(1)。我们设计了一个实验，使用阻断抗体和RNA干扰，在3-D人体表皮组织模型中靶向¿1和¿4整合素，以进一步表征它们在肿瘤基底膜侵袭中的作用。将研究¿1和¿4整合素在早期表皮肿瘤进展中的协同作用的可能性。这些研究旨在描述整合素在早期表皮肿瘤发生中的作用。其次，我们将描述FAK激活在人类表皮肿瘤模型中的作用。据报道，FAK在人类鳞状细胞癌中表达增加(2)。初步实验将确定整合素阻断对表皮肿瘤发生过程中FAK磷酸化的影响，作为FAK活性的替代。随后，我们将测试FAK的表达是否能克服整合素阻断对表皮肿瘤进展的影响。最后，我们计划描述我们最近在人类皮肤鳞状细胞癌中发现的FAK激酶结构域突变的功能意义。突变体FAK将在诱导表皮瘤变模型中表达，以确定其对肿瘤基底膜侵袭的影响。这些研究旨在确定FAK在介导表皮肿瘤进展中的作用。在拟议的资助期结束时，我们希望能够确定¿1和¿4整合素亚基以及下游信号激酶FAK在早期表皮肿瘤进展中的作用。结果可能确定治疗上皮癌的治疗策略。

DESCRIPTION (provided by applicant): Epithelial malignancies represent the vast majority of human cancers. A common feature of carcinomas is the invasion of neoplastic cells through the basement membrane that sets the stage for local and distant metastases, the major cause of morbidity and mortality in patients. The critical tumor-stroma interactions occurring at the basement membrane during early human tumor progression have yet to be fully characterized. This proposal focuses on the role of the ¿1 and ¿4 integrin subunits as well as the integrin associated focal adhesion kinase (FAK) in mediating early epidermal tumor progression. First, we plan to extend recent findings that ¿1 and ¿4 integrin and their multiple ¿ integrin partners are key components of an extracellular matrix-centric gene expression network in human epidermal tumor progression. Targeting of ¿1 integrin modestly attenuated neoplastic progression in an epidermal tumor xenograft model(1). We have designed experiments using blocking antibodies and RNA interference to target ¿1 and ¿4 integrin in a 3-D human epidermal tissue model to further characterize their role in neoplastic basement membrane invasion. The possibility of a cooperative role of ¿1 and ¿4 integrins in early epidermal tumor progression will be investigated. These studies are designed to characterize the role of ¿ integrins in early epidermal tumorigenesis. Second, we will characterize the role of FAK activation in the human epidermal neoplasia model. Increased expression of FAK has been reported in human squamous cell carcinomas(2). Initial experiments will determine the effect of integrin blockade on FAK phosphorylation as a surrogate of FAK activity during epidermal tumorigenesis. Subsequently, we will test if expression of FAK can overcome the effect of ¿ integrin blockade on epidermal tumor progression. Finally, we plan to characterize the functional significance of a FAK kinase domain mutation that we recently identified in a human cutaneous squamous cell carcinoma. The mutant FAK will be expressed in the inducible epidermal neoplasia model to determine its effect on neoplastic basement membrane invasion. These studies are designed to define the role of FAK in mediating epidermal neoplastic progression. At the end of the proposed funding period, we hope to have characterized the role of the ¿1 and ¿4 integrin subunits as well as the downstream signaling kinase FAK during early epidermal tumor progression. The results may identify therapeutic strategies to treat epithelial cancers. PUBLIC HEALTH RELEVANCE: This proposal aims to further characterize how cancer cells invade through their surrounding connective tissue to invade locally and eventually metastasize to distant organs. The ultimate goal is to identify potential therapeutic targets for the preventio and treatment of human cancers.