The RET/PTC3 Oncogene: Antigenic and Inflammatory Properties

描述（由申请人提供）：甲状腺乳头状癌（PTC）是一种相对良性的肿瘤，在尸检时可在普通人群中发现高达10%的隐匿病变。我们认为这是由于RET/PTC癌基因不仅增加了增殖和生存能力，而且还驱动了自身反应性抗肿瘤反应。事实上，RET/PTC驱动的PTC和桥本甲状腺炎（HT）是非常巧合的，同时存在这两种情况的个体比没有自身免疫特征的恶性未分化甲状腺癌患者预后更好。我们对RET/PTC中最常见的RET/PTC蛋白之一RET/ pt3 （RP3）进行了初步的研究，指出了其潜在的机制基础：首先，RP3本身可以通过断点区、下游靶点的异常自磷酸化和磷酸化，以及可能通过调节抗原加工的构象效应提供抗原性（“信号1”）。其次，RP3已被证明可以诱导多种有效的炎症介质（“信号2”），从而为有效的适应性反应提供所需的共同刺激。这种情况与炎症促进癌症发展和扩散的流行观点形成了对比。利用生物化学、体外和体内方法的结合，我们将探索这些活动及其对PTC进化的影响，在两年的时间里，两个主要并行执行的特定目标。这些研究将为转基因模型的发展奠定基础，使我们能够更有力地解剖癌症与宿主防御系统之间的相互作用。此外，它们可能指出加强癌症免疫治疗的一般策略。

DESCRIPTION (provided by applicant): Papillary thyroid carcinoma (PTC) is a relatively benign neoplasia, with occult lesions found in up to 10% of the general population at time of autopsy. We propose that this is attributable to the RET/PTC oncogenes that not only increase proliferation and viability, but also drive an autoreactive anti-tumor response. Indeed, RET/PTC-driven PTC and Hashimoto's thyroiditis (HT) are strongly coincidental and individuals who present with both conditions have a better prognosis than patients with malignant undifferentiated thyroid carcinomas without features of autoimmunity. Our established and preliminary studies focused upon one of the most common RET/PTC proteins, RET/PTC3 (RP3), point to a potential mechanistic basis: First, RP3 itself can provide antigenicity ("signal 1") via the breakpoint region, aberrant autophosphorylation and phosphorylation of downstream targets, and possibly through conformational effects that modulate antigen processing. Second, RP3 has been shown to induce a wide array of potent inflammatory mediators ("signal 2"), thereby providing the co-stimulation required for an effective adaptive response. This scenario provides contrast to the popular notion that inflammation encourages the development and spread of cancer. Using a combination of biochemical, in vitro and in vivo approaches, we will explore these activities and their impact on the evolution of PTC in two specific aims executed mainly in parallel over the two year period. These studies will set the stage for the development of transgenic models that allow for more powerful dissection of the interplay between cancer and the host defense system. In addition, they may point to general strategies for enhancing cancer immunotherapy.