Molecular Mechanisms and Translational studies in Colon Cancer

结肠癌的分子机制和转化研究

• 批准号: 9240497
• 负责人: Lopa Mishra
• 金额: --
• 依托单位: U.S. DEPT/VETS AFFAIRS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240497
• 关键词: Address; Age; Animal Model; Anti-CEA Antibody; Antibodies; Beckwith-Wiedemann Syndrome; Benign; Biological Markers; Biological Models; Cancer Etiology; Carcinoma; Caring; Case Study; Cell physiology; Colon; Colon Carcinoma; Colonic Adenoma; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Comorbidity; DNA; Data Set; Development; Diagnosis; Disease; Evaluation; Exposure to; Family; Future; Genes; Genome; Genomics; Goals; Healthcare Systems; Homeostasis; Human; Human Cell Line; Incidence; Inherited; Interleukin-6; Label; Lead; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Measures; Mediating; Military Personnel; Mismatch Repair; Molecular; Mucous Membrane; Mutant Strains Mice; Mutation; Oncogenic; PIK3CG gene; Pathway interactions; Phenocopy; Polyps; Population; Prevention program; Prevention strategy; Preventive screening; Process; Prognostic Factor; Property; Quality of life; Radiation; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; STAT3 gene; Sampling; Screening for cancer; Sequence Analysis; Side; Signal Transduction; Small Interfering RNA; Stem cells; Subgroup; Survival Rate; Syndrome; TGFBR1 gene; TP53 gene; Testing; The Cancer Genome Atlas; Tissue Sample; Toxin; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Translational Research; Treatment-related toxicity; Tumor Suppressor Proteins; Tumorigenicity; United States; Vaccines; Veterans; actionable mutation; adenoma; base; cancer invasiveness; cancer stem cell; colorectal cancer prevention; exome; genome sequencing; genomic profiles; high risk; improved; in vivo; inhibitor/antagonist; insight; member; mortality; mouse model; neoplastic; novel; programs; therapeutic development; transcriptome; transcriptome sequencing; transcriptomics; translational study; tumor; tumorigenesis; tumorigenic; whole genome

Colorectal cancer (CRC) remains the second most common cause of cancer mortality worldwide, and among Veterans in the United States, the third despite the successful implementation of successful preventive screening measures. One contributing factor that has newly emerged is the rapid development of cancers in small, sessile adenomas (polyps), with mutational processes and signatures that drive early CRC tumorigenesis. Yet, to date, biomarkers and risk factors for polyps (adenomas) that inordinately and rapidly develop into colon cancer remain poorly defined. We recently observed surprisingly high mutational profiles through whole-genome sequence (WGS) analysis in 2 of 4 pairs of benign colorectal adenoma tissue samples. Extending this to unsupervised hierarchical clustered transcriptomic analysis of a further 7 pairs of adenomas reveals distinct mutational signatures regardless of adenoma size. Strikingly, we observe mutations in the TGF-β pathway and CEA-associated genes in 4 out of 11 adenomas, overlapping with the Wnt pathway. Immunohistochemical labeling reveals a nearly 5-fold increase in CEA levels in 23% of adenoma samples tested, with a concomitant loss of TGF-β signaling. We have defined a functional role by which the CEA B3 domain interacts with TGFBR1, potentially inactivating the tumor suppressor function of TGF-β signaling. Raised CEA levels occur with concomitant loss of TGF-β signaling and activation of oncogenic molecules that include STAT3. Furthermore, deletion of Smad3/4 adaptor β2SP results in loss of TGF-β signaling, with a spontaneous formation of adenomas as well as overt CRC, and presents a strong mouse model of CRC. The overall hypothesis of this application is that disruption of the TGF-β tumor suppressor pathway, and concomitantly raised levels of oncogenic molecules such as CEA, STAT3, disrupt normal colonic mucosa and promote oncogenesis in CRC. Our aims are to: AIM 1a) Expand and validate the significance of loss of the TGF-β pathway associated with high CEA and/or CEACAM6 levels as prognostic factors in advanced adenomas that rapidly progress to CRC through i) First, whole transcriptomic sequence, immunohistochemical and RT-PCR analyses of 40 additional adenomas ii) Secondly, by examining The Cancer Genome Atlas (TCGA) Pan gastrointestinal cancer (GI) datasets to obtain a complete evaluation of our findings. 1b) Determine whether CEA/CEACAM6 and STAT3 with loss of TGF-β signaling are drivers of early CRC in vivo. 2 a) Determine the molecular mechanisms by which CEA inhibits the TGF-β tumor suppressor pathway in early and advanced CRC. We plan to accomplish this through i) Analyzing the role of CEA and CEACAM6 in the disruption of the TGF-β pathway and concomitant IL-6/STAT3 activation in CRC. ii) Determine antitumor activity of CEA inhibition, with and without STAT3 inhibitors and characterize their mechanisms of action. Through translational studies- interrogating human cell lines/genomics, and animal model systems of colon cancer, this application proposes an integrated approach for human CRC, providing novel insights into early and advanced CRC. With vaccines available, as well as new low toxicity therapeutics, identifying specific populations particularly among Veterans with multiple co-morbidities, that could respond to treatment, these goals are centrally important for improving the quality of life under treatment, as well as the mortality from this common cancer.

结直肠癌（CRC）仍然是全世界癌症死亡的第二大常见原因， 在美国退伍军人中，尽管第三次成功地实施了成功的预防性措施， 筛选措施。新出现的一个促成因素是癌症的迅速发展， 小的无蒂腺瘤（息肉），具有驱动早期CRC的突变过程和特征 肿瘤发生然而，到目前为止，息肉（腺瘤）的生物标志物和风险因素， 发展成结肠癌仍然不明确。我们最近观察到了惊人的高突变率 通过全基因组序列（WGS）分析，在4对良性结直肠腺瘤组织样本中的2对中。 将其扩展到另外7对腺瘤的无监督分层聚类转录组学分析 显示出不同的突变特征，而与腺瘤大小无关。引人注目的是，我们观察到 TGF-β通路和CEA相关基因在11个腺瘤中的4个中，与Wnt通路重叠。 免疫组织化学标记显示23%的腺瘤样本中CEA水平增加近5倍 测试，伴随着TGF-β信号传导的损失。我们已经定义了一个功能角色，通过该功能角色，CEA B3 结构域与TGFBR 1相互作用，可能使TGF-β信号传导的肿瘤抑制功能失活。 CEA水平升高伴随着TGF-β信号传导的丧失和致癌分子的激活， 包括STAT 3。此外，Smad 3/4接头β2SP的缺失导致TGF-β信号转导的丧失， 自发形成的腺瘤以及明显的CRC，并提出了一个强大的CRC小鼠模型。的 本申请的总体假设是TGF-β肿瘤抑制途径的破坏， 同时升高的致癌分子如CEA、STAT 3的水平，破坏正常的结肠 并促进CRC中的肿瘤发生。我们的目标是： 目的1a）扩展并验证与高CEA和/或CEA相关的TGF-β途径的缺失的意义。 CEACAM 6水平作为通过i）首先， 另外40例腺瘤的全转录组序列、免疫组化和RT-PCR分析ii） 其次，通过检查癌症基因组图谱（TCGA）泛胃肠道癌症（GI）数据集， 对我们的发现进行全面评估1b）确定CEA/CEACAM 6和STAT 3是否具有TGF-β的损失 信号传导是体内早期CRC的驱动因素。 2a）确定CEA抑制TGF-β肿瘤抑制途径的分子机制， 早期和晚期CRC。我们计划通过以下方式实现这一目标：i）分析CEA和CEACAM 6在以下方面的作用： CRC中TGF-β通路的破坏和伴随的IL-6/STAT 3活化。ii）确定抗肿瘤 在有和没有STAT 3抑制剂的情况下测定CEA抑制活性，并表征其作用机制。 通过转化研究-询问人类细胞系/基因组学和结肠的动物模型系统 癌症，该申请提出了一种用于人类CRC的综合方法，提供了对早期CRC的新见解。 和高级CRC。随着疫苗的可用，以及新的低毒性疗法，确定特定的 人群，特别是退伍军人与多种共病，可以响应治疗，这些 目标对于改善治疗中的生活质量以及由此引起的死亡率至关重要。 常见的癌症