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，在尸检时发现高达10%的一般人群存在隐匿性病变。我们认为，这是由于RET/PTC癌基因，不仅增加增殖和活力，但也驱动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，患有这两种疾病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。我们建立和初步的研究集中在一个最常见的RET/PTC蛋白，RET/PTC 3（RP 3），指出了一个潜在的机制基础：首先，RP 3本身可以提供抗原性（“信号1”）通过断点区域，异常自磷酸化和磷酸化的下游目标，并可能通过构象效应，调节抗原加工。第二，RP 3已经显示出诱导多种有效的炎症介质（“信号2”），从而提供有效适应性反应所需的共刺激。这种情况与炎症促进癌症发展和扩散的流行观念形成了鲜明对比。使用生物化学，体外和体内的方法相结合，我们将探讨这些活动及其对PTC的演变在两个特定的目标主要是在两年内平行执行的影响。这些研究将为转基因模型的开发奠定基础，从而更有力地剖析癌症与宿主防御系统之间的相互作用。此外，他们可能会指出增强癌症免疫治疗的一般策略。 公共卫生相关性：世纪以来，科学家和临床医生一直试图利用免疫系统的特异性和杀伤力来对抗癌症。这很困难，因为与细菌和病毒感染不同，癌症更难被免疫系统识别。这种普遍性的一个例外可能是由称为RP 3的致癌基因引起的甲状腺癌。在这种情况下，对癌症的免疫反应相对较强。我们的计划是探索这种高度认可的基础，希望将我们所学到的知识应用于免疫系统不太明显的癌症。

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. PUBLIC HEALTH RELEVANCE: For over a century scientists and clinicians have tried to harness the specificity and lethality of the immune system to battle cancer. This has been difficult because, unlike infections by bacteria and viruses, cancers are much harder for the immune system to recognize. An exception to this generality may be thyroid cancers that are caused by an oncogene termed RP3. In this case, immune responses to the cancer are relatively robust. Our plan is to explore the basis for this heightened recognition, with the hope of applying what we learn to cancers that are less visible to the immune system.