The role of beta integrins in epidermal tumor progression

描述（由申请方提供）：上皮恶性肿瘤代表了绝大多数人类癌症。癌的一个共同特征是肿瘤细胞通过基底膜侵入，这为局部和远处转移奠定了基础，这是患者发病率和死亡率的主要原因。在早期人类肿瘤进展过程中发生在基底膜上的关键肿瘤-间质相互作用尚未完全表征。该建议的重点是<$1和<$4整合素亚基以及整合素相关的粘着斑激酶（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。在表皮肿瘤异种移植模型中，靶向1整合素适度减弱肿瘤进展（1）。我们设计了使用阻断抗体和RNA干扰的实验，在3-D人类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协同作用的可能性。这些研究旨在表征整合素在早期表皮肿瘤发生中的作用。其次，我们将描述FAK激活在人表皮肿瘤模型中的作用。已报道人鳞状细胞癌中FAK表达增加（2）。最初的实验将确定整联蛋白阻断对FAK磷酸化的影响，作为表皮肿瘤发生过程中FAK活性的替代。随后，我们将测试FAK的表达是否可以克服整合素阻断对表皮肿瘤进展的影响。最后，我们计划对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进行表征。突变FAK将在诱导型表皮瘤形成模型中表达，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。在建议的资助期结束时，我们希望能够表征整合素1和整合素4亚基以及下游信号激酶FAK在早期表皮肿瘤进展中的作用。这些结果可能会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.