Integrin Signaling Pathways in Prostate Cancer

描述（由申请人提供）：整合素包括一个大家族的细胞表面受体，在癌细胞增殖、侵袭和转移潜能中起关键作用。在上一个资助周期中进行的实验发现了由av¿6整合素介导的前列腺癌进展的新途径。我们发现av¿6在人和小鼠正常前列腺中不表达，但在癌前病变、前列腺腺癌（AdCa）和骨转移中显著上调。在机制上，av¿6的表达通过jnk介导的途径导致雄激素受体（AR）活性的上调。我们的研究结果首次表明，整合素可以调节AR活性。在这一途径中，我们已经确定了survivin，一种细胞分裂和凋亡的双功能调节剂，作为关键的下游效应分子之一，在表达av的细胞中上调。我们的体内数据表明，与另一种av整合素av¿3相比，av¿6的表达可促进肿瘤生长和转移性传播。av¿6的表达也导致肿瘤介导的骨溶解，这是前列腺癌转移的关键步骤。由于av¿3已被证明可以促进前列腺癌转移灶的骨增重，我们假设骨病变形成的程度是由av¿6和av¿3的相对表达水平控制的。最后，我们发现这些整合素的表达受TGF激活的两种不同转录因子的调控：av¿6是通过Smad3激活诱导的，而av¿3是由Runx2介导的。我们已经制定了一个统一的假设，即av - 6整合素作为多种信号通路的整合者，促进前列腺癌的早期和晚期进展。这一假设将在目前的更新申请中通过以下目的进行检验。在Aim 1中，将研究av - 6激活AR的分子机制。在Aim 2中，我们将在前列腺癌小鼠模型中研究av¿6在前列腺癌进展中的体内作用；为此，我们将使用前列腺特异性pten缺失小鼠模型，该模型会发生PIN，癌症和转移。在Aim 3中，为了证明av整合素是前列腺癌骨病变治疗的分子靶点，我们将剖析av¿6和av¿3在体内促进骨病的途径。我们的长期目标是利用这些新产生的知识来开发前列腺癌进展的新型分子拮抗剂。

DESCRIPTION (provided by applicant): Integrins comprise a large family of cell surface receptors with critical roles in cancer cell proliferation, invasion and metastatic potential. Experiments carried out during the last funding cycle have uncovered a novel pathway of prostate cancer progression mediated by the av¿6 integrin. We have found that av¿6 is not expressed in human and mouse normal prostate but becomes significantly upregulated in preneoplastic lesions, prostatic adenocarcinoma (AdCa) and bone metastasis. Mechanistically, av¿6 expression results in upregulation of androgen receptor (AR) activity via a JNK-mediated pathway. Our findings show, for the first time, that integrins modulate AR activity. In this pathway, we have identified survivin, a bifunctional regulator of cell division and inhibitor of apoptosis, as one of the critical downstream effector molecule which becomes upregulated in cells expressing av¿6. Our in vivo data demonstrate that expression of av¿6 results in enhanced tumor growth and metastatic dissemination as compared to a different av integrin, av¿3. Expression of av¿6 also causes tumor-mediated osteolysis, a crucial step in prostate cancer metastasis. Since av¿3 has been shown to promote bone gain in prostate cancer metastatic lesions, we hypothesize that the extent of bone-lesion formation is controlled by the relative expression levels of av¿6 and av¿3. Finally, we show that these integrins' expression is regulated by two different transcription factors activated by TGF¿: av¿6 is induced via Smad3 activation, whereas av¿3 expression is mediated by Runx2. We have formulated a unifying hypothesis that av¿6 integrin functions as an integrator of multiple signaling pathways to promote early and late phases of prostate cancer progression. This hypothesis will be tested in the present renewal application by the following aims. In Aim 1, the molecular mechanisms by which av¿6 activates AR will be investigated. In Aim 2, we will investigate in vivo the role of av¿6 in prostate cancer progression in a mouse model of prostate cancer; for this purpose, we will use the prostate specific Pten-null mouse model which develops PIN, cancer and metastasis. In Aim 3, to credential av integrins as molecular targets in prostate cancer bone lesion therapies, we will dissect the pathways by which av¿6 and av¿3 contribute to bone disease in vivo. Our long-term objective is to take advantage of this newly generated knowledge to develop novel molecular antagonists of prostate cancer progression.