Role of Id1 in NSCLC Progression and Metastasis

描述(申请人提供)：非小细胞肺癌(NSCLC)与吸烟高度相关，吸烟者约占NSCLC患者的75%。香烟烟雾中存在的许多烟草特有的致癌物质会造成DNA损伤，导致Ras、P53和Rb等重要基因的突变。此外，许多烟草致癌物质以及尼古丁本身都可以通过激活烟碱型乙酰胆碱受体(NAChRs)促进细胞增殖和血管生成。吸烟者和非吸烟者的NSCLC在性质上是不同的，具有不同的分子特征；例如，非吸烟者的癌症主要在EGFR的激活域发生突变。吸烟者和非吸烟者的NSCLC在组织学上也有区别，前者主要是鳞状细胞癌，后者主要是腺癌。然而，这两组患者的NSCLC都是高度转移性的，导致死亡。鉴于引起这些肿瘤的肺原代细胞可以在通过烟碱型乙酰胆碱受体和EGFR信号转导的反应中增殖，并且由于来自这些组织的肿瘤细胞在nAChR和EGFR信号转导的反应中积极分裂和侵袭，我们假设在吸烟者和非吸烟者中可能存在这些信号的共同媒介。具体地说，我们提出，在吸烟者和非吸烟者中，螺旋-环-螺旋蛋白Id1是NSCLC增殖、侵袭和血管生成的常见介质。目前已知ID1在多种肿瘤的进展和转移中起重要作用，包括乳腺癌、前列腺癌和胰腺癌；同时，人们对其在非小细胞肺癌生物学中的潜在作用知之甚少。我们的初步数据显示，Id1在NSCLC细胞中被诱导，以响应nAChR和EGFR信号，并且Id1的缺失阻止了尼古丁和EGF诱导的增殖和侵袭。Id1的缺失也极大地减少了尼古丁和血管内皮生长因子诱导的基质细胞血管新生小管的形成。此外，ID1在人类非小细胞肺癌样本中升高，在转移性肿瘤中含量最高。我们假设nAChRs和EGFR都以一种依赖于Src和STAT3的方式诱导ID1，并有助于这些癌症的侵袭和转移特性。基于这些观察，我们提出了三个特定的目标：(1)评估Id1是否是烟碱受体和EGFR信号反应中NSCLC生长的常见介质(2)评估Id1在nAChR诱导的血管生成和转移中的作用(3)评估Id1在吸烟者和非吸烟者NSCLC生长和转移中的作用，并评估Id1升高是否与预后不良相关。我们相信，这些研究将确定与非小细胞肺癌的发生和发展有关的新途径，并将导致开发新的治疗药物来对抗这种疾病。公共卫生相关性：非小细胞肺癌主要由吸烟引起，75%的患者是吸烟者。与此同时，只有大约10%-20%的吸烟者患有非小细胞肺癌。另一方面，25%的非小细胞肺癌患者不吸烟。吸烟者和非吸烟者的疾病既有共同点，也有许多不同之处。我们推测，尽管吸烟者和非吸烟者的NSCLC是由不同基因的突变引起的，但可能有共同的信号分子促进这些肿瘤的生长和转移扩散。我们建议研究一个这样的分子，Id1，它与其他类型癌症的转移扩散密切相关。我们相信，本申请中提出的深入机制分析将导致以Id1蛋白为靶点的新型非小细胞肺癌治疗剂的开发。

DESCRIPTION (provided by applicant): Non-small cell lung carcinoma (NSCLC) is highly correlated with smoking and smokers constitute about 75% of NSCLC patients. Many tobacco-specific carcinogens present in cigarette smoke cause DNA damage, leading to the mutation of vital genes like Ras, p53 and Rb. In addition, many of these tobacco carcinogens as well as nicotine itself can promote cell proliferation and angiogenesis through the activation of nicotinic acetylcholine receptors (nAChRs). NSCLC in smokers and non-smokers are qualitatively different and have different molecular signatures; for example, cancers in non-smokers predominantly have mutations in the kinase domain of EGFR. There are also histological distinctions between NSCLC in smokers and non-smokers, the former being predominantly squamous cell carcinomas and the latter mainly adenocarcinomas. Nevertheless, NSCLC in both the groups of patients are highly metastatic, leading to mortality. Given the fact that the primary cells of the lung that give rise to these tumors can proliferate in response to signals transduced through nicotinic acetylcholine receptors as well as EGFR, and since tumor cells derived from these tissues actively divide and invade in response to nAChR and EGFR signaling, we hypothesize that there might be common mediators of these signals in smokers and non-smokers. Specifically, we propose that the helix-loop- helix protein Id1 is a common mediator of proliferation, invasion and angiogenesis in NSCLC in smokers and non-smokers. Id1 is known to play a significant role in the progression and metastasis of a variety of tumors, including those of breast, prostate and pancreas; at the same time, little is known about its potential role in the biology of NSCLC. Our preliminary data shows that Id1 is induced in NSCLC cells in response to nAChR as well as EGFR signaling and that depletion of Id1 prevents nicotine and EGF-induced proliferation and invasion. Depletion of Id1 also greatly reduced nicotine and VEGF-induced angiogenic tubule formation in matrigel. Further, Id1 was elevated in human NSCLC samples, with maximal amount present in metastatic tumors. We hypothesize that both nAChRs and EGFR induce Id1 in a Src and STAT3-dependent fashion and contributes to the invasive and metastatic properties of these cancers. Based on these observations, we propose three specific aims: (1) To assess whether Id1 is a common mediator of NSCLC growth in response to nicotinic receptor and EGFR signaling (2) To evaluate the role of Id1 in nAChR-induced angiogenesis and metastasis (3) To evaluate the contribution of Id1 to the growth and metastasis of NSCLC in smokers and non-smokers and to assess whether elevated Id1 correlates with poor prognosis. We believe that these studies will identify novel pathways that are involved in the genesis and progression of non-small cell lung cancers and will lead to the development of novel therapeutic agents to combat this disease. PUBLIC HEALTH RELEVANCE: Non-small cell lung cancer is mainly caused by cigarette smoking and 75% of patients are smokers. At the same time, only about 10-20% of smokers are afflicted with NSCLC. On the other hand, 25% of NSCLC patients are non-smokers. The disease in smokers and non-smokers show many differences as well as commonalities. We hypothesize that even though NSCLC in smokers and non-smokers are caused by mutation of different genes, there may be common signaling molecules that facilitate the growth and metastatic spread of these tumors. We propose to study one such molecule, Id1, which is strongly correlated with the metastatic spread of other types of cancers. We believe that an in-depth mechanistic analysis as proposed in this application will lead to the development of novel therapeutic agents for non-small cell lungs cancer based on targeting the Id1 protein.