Integrin Signaling Pathways in Prostate Cancer

描述（由申请人提供）：整联蛋白包括一个大家族的细胞表面受体，在癌细胞增殖、侵袭和转移潜能中具有关键作用。在上一个资助周期进行的实验已经发现了一种由α v β 6整合素介导的前列腺癌进展的新途径。我们发现，6在人和小鼠正常前列腺中不表达，但在肿瘤前病变、前列腺腺癌（AdCa）和骨转移中显著上调。从机制上讲，α v β 6表达通过JNK介导的途径导致雄激素受体（AR）活性上调。我们的研究结果首次表明，整合素调节AR活性。在这一途径中，我们已经确定了生存素，一种细胞分裂和细胞凋亡抑制剂的双功能调节剂，作为一种关键的下游效应分子，在表达av？6的细胞中上调。 我们的体内数据表明，与不同的α v整联蛋白α v β 3相比，α v β 6的表达导致肿瘤生长和转移性播散增强。av <$6的表达也会引起肿瘤介导的骨质溶解，这是前列腺癌转移的关键步骤。由于av？3已被证明可促进前列腺癌转移病灶的骨获得，我们假设骨病灶形成的程度受av <$6和av <$3的相对表达水平控制。最后，我们表明，这些整合素的表达是由两个不同的转录因子激活TGF <$：av <$6是通过Smad 3激活诱导，而av <$3的表达是由Runx 2介导的。 我们已经形成了一个统一的假设，即α v β 6整合素作为多种信号通路的整合剂，促进前列腺癌进展的早期和晚期。在本续期申请中，将通过以下目的对这一假设进行检验。在目标1中，将研究av？6激活AR的分子机制。在目标2中，我们将在前列腺癌小鼠模型中研究体内av <$6在前列腺癌进展中的作用;为此目的，我们将使用前列腺特异性Pten缺失小鼠模型，其发展PIN、癌症和转移。在目的3中，为了证明α v整联蛋白作为前列腺癌骨病变治疗中的分子靶点，我们将剖析α v整联蛋白6和α v整联蛋白3在体内促进骨疾病的途径。我们的长期目标是利用这一新产生的知识，开发新的前列腺癌进展的分子拮抗剂。 公共卫生相关性：在最后一个周期进行的研究揭示了α v β 6整合素在前列腺癌进展的“早期”和“晚期”阶段的关键作用。在本申请中，我们将剖析α v β 6增强肿瘤发生和转移性骨疾病的途径。与此同时，我们计划进行一项体内研究，以调查是否av <$6抗体抑制前列腺癌小鼠模型Ptenpc-/-中的肿瘤进展。这项在Ptenpc-/-小鼠中进行的临床前研究如果成功，将为临床研究铺平道路，该研究可能有助于选择具有PTEN突变的患者（约占美国前列腺癌患者的50%）作为av 6抑制剂的目标患者人群。 本申请中描述的途径与人类疾病相关，因为前列腺癌在美国占显著的癌症负担，其中在2008年，预计其导致超过28，000例死亡和超过180，000例新病例。我们对疾病进展的理解仍然存在很大的差距，这阻碍了更有效药物的开发。晚期前列腺癌迫切需要新的治疗方法，利用前列腺肿瘤中常见的分子缺陷，如Pten缺陷，可能会提供创新的治疗机会。 通过抑制av？6依赖的信号通路，我们将确定关键的新方法，适用于治疗干预和铺平道路的个性化治疗前列腺癌。我们还将深入了解促进骨转移的机制，骨转移在前列腺癌患者中非常常见，并导致严重的骨痛，高钙血症，神经压迫和病理性骨折。目前的治疗，化疗，放疗和双膦酸盐都改善了疾病的组成部分，但并不完全有效。 我们的长期目标是利用我们的机制研究来帮助开发抑制人类前列腺癌进展的新分子策略。

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. PUBLIC HEALTH RELEVANCE: Studies carried out during the last cycle have uncovered a key role of the av¿6 integrin in "early" and "late" stages of prostate cancer progression. We will dissect in the present application the pathways by which av¿6 enhance tumorigenesis and metastatic bone disease. In parallel, we plan to perform an in vivo study to investigate whether an antibody to av¿6 inhibits tumor progression in a mouse model of prostate cancer, Ptenpc-/-. This preclinical study in Ptenpc-/- mice, if successful, will pave the way for a clinical study which may help selecting patients with PTEN mutations {which represent approximately 50% of prostate cancer patients in the US} as the target patient population for av¿6 inhibitors. The pathways described in the present application are relevant to the human disease since prostate cancer accounts for a significant cancer burden in USA, where in 2008 it was projected to result in over 28,000 deaths and more than 180,000 new cases. Large gaps still exist in our understanding of disease progression, and this has hampered the development of more effective drugs. New therapeutic approaches in advanced prostate cancer are urgently needed, and harnessing the frequent molecular defects in prostate tumors, such as Pten deficiency, may provide innovative therapeutic opportunities. By inhibiting av¿6 - dependent signaling pathways, we will identify critical new approaches suitable for therapeutic intervention and pave the way for personalized therapies of prostate cancer. We will also gain insights in the mechanisms that promote bone metastasis, which is very frequent in prostate cancer patients and which results in severe bone pain, hypercalcemia, nerve compression and pathological fractures. Current treatments, chemotherapies, radiation and bisphosphonates all ameliorate components of the disease, but are not completely effective. Our long-term goal is to take advantage of our mechanistic studies to help develop novel molecular strategies for inhibition of prostate cancer progression in humans.