Beta1 Integrins and IGF-I Receptor in Prostate Cancer

描述(申请人提供)：整合素控制癌细胞增殖、存活和黏附的能力在肿瘤进展中起着重要作用。PI的最新发现揭开了β1整合素亚家族成员与IGF-IR(胰岛素样生长因子受体)之间的新的分子界面，IGF-IR是一种已知在前列腺癌中显著上调的激酶受体。PI描述了一种控制前列腺癌细胞功能的新机制，该机制通过β1整合素对IGF-IR信号的选择性调节来响应IGF刺激。通过将信号复合体差异化地募集到其选择性剪接的细胞质结构域，PI发现Beta1A与IGF-IR的关联促进了IGF-IR刺激的细胞增殖，并阻止了IGF介导的细胞与基底膜蛋白的黏附，从而可能允许肿瘤肿块扩张和侵袭。相反，β1C细胞质整合素变异体拮抗这些效应，抑制IGF-IR刺激的细胞增殖，并促进与基底膜蛋白的牢固黏附。β1整合素细胞结构域通过差异募集到IGF-IR下游效应器的质膜，从而差异化地调节前列腺癌细胞对IGF的反应功能。与这些发现一致的还有观察到，在前列腺癌小鼠模型的肿瘤转化的早期阶段，Beta1和IGF-IR同时上调。根据上述发现，在本申请中要检验的假设是，β1整合素在前列腺癌进展中调节IGF-IR信号和功能。在目标1中，专门计划在体外剖析Beta1A-IGF-IR复合体和Beta1C在调节前列腺癌细胞功能中的作用。在目标2中，PI计划研究Beta1A-IGF-IR复合体的定位，特定底物对该复合体活性的调节，以及Beta1A-IGF-IR复合体和Beta1C下游的信号通路。在目标3中，PI将在体内分析Beta1整合素和IGF-IR以及Beta1A-IGF-IR复合体在前列腺癌进展中的作用。这项研究旨在阐明前列腺癌中整合素和生长因子受体之间的新的分子相互作用，并将使前列腺癌治疗的新靶点得到验证。

DESCRIPTION (provided by applicant): Integrins' ability to control cancer cell proliferation, survival and adhesion plays an important role in tumor progression. Recent findings by the PI have unraveled a novel molecular interface between members of the beta1 integrin subfamily and IGF-IR (Insulin-like Growth Factor Receptor), a kinase receptor known to be significantly upregulated in prostate cancer. The PI describes a novel mechanism that controls prostate cancer cell functions and occurs via a selective modulation of IGF-IR signaling by beta1 integrins in response to IGF-stimulation. Through differential recruitment of signaling complexes to their alternatively spliced cytoplasmic domains, the PI found that the association of beta1A with IGF-IR promotes IGF-IR - stimulated cell proliferation and prevents IGF-mediated cell adhesion to basement membrane proteins, thus presumably allowing the tumor mass to expand and invade. In contrast, the beta1C cytoplasmic integrin variant antagonizes these effects, suppresses IGF-IR - stimulated cell proliferation and promotes firm adhesion to basement membrane proteins. The mechanism by which the beta1 integrin cytodomain differentially modulates prostate cancer cell functions in response to IGF occurs via differential recruitment to the plasma membrane of IGF-IR downstream effectors. Consistent with these findings is also the observation that both beta1 and IGF-IR are concurrently upregulated in the early stages of neoplastic transformation in a mouse model of prostate cancer. The hypothesis to be tested in the present application, based on the findings described above, is that beta1 integrins modulate IGF-IR signaling and functions in prostate cancer progression. It is specifically planned, in Aim 1, to dissect in vitro the role of the beta1A-IGF-IR complex and of beta1C in modulating prostate cancer cell functions. In Aim 2, the PI plans to study the localization of the beta1A-IGF-IR complex, the modulation of the activity of the complex by specific substrates as well as the signaling pathways downstream of the beta1A-IGF-IR complex and of beta1C. In Aim 3, the PI will analyze in vivo the role of beta1 integrins and IGF-IR and of the beta1A-IGF-IR complex in prostate cancer progression. This study is designed to elucidate novel molecular interactions between integrins and growth factor receptors in prostate cancer and will allow new target validation in prostate cancer therapy.