Molecular mechanisms of perineural invasion in pancreatic cancer

胰腺癌神经周围浸润的分子机制

• 批准号: 7707218
• 负责人: Haiyong Han
• 金额: $ 22.04万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707218
• 关键词: Abdomen; Accounting; Affinity; Back Pain; Biological Models; Cancer Etiology; Cancer Patient; Candidate Disease Gene; Cells; Cessation of life; Coculture Techniques; Communication; Curative Surgery; DNA; DNA Microarray Chip; Diagnosis; Disease; Distal; Excision; Formalin; Freezing; Gene Proteins; Genes; Goals; Human; Immunohistochemistry; In Vitro; Infiltration; Invaded; Literature; Malignant Neoplasms; Malignant neoplasm of pancreas; Membrane; MicroRNAs; Molecular; Molecular Profiling; Molecular Target; NGFR Protein; NGFR gene; Nature; Nerve; Nerve Growth Factors; Nervous system structure; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 1; Oligonucleotide Microarrays; Oncogenic; Operative Surgical Procedures; Outcome; Pain; Pancreas; Paraffin; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Population; Protein Tyrosine Kinase; Quality of life; RNA; Radiation therapy; Recurrence; Reporting; Research; Resectable; Retroperitoneal Space; Reverse Transcriptase Polymerase Chain Reaction; Role; Route; Schwann Cells; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Stromal Cells; Surgical margins; Survival Rate; System; Time; Tissue Microarray; Tissue Sample; Tissues; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumor Tissue; United States; Work; base; cancer cell; cell stroma; chemotherapy; improved; inhibitor/antagonist; laser capture microdissection; member; neoplastic cell; neuromechanism; neurotrophic factor; neutralizing antibody; outcome forecast; pancreatic neoplasm; perineural; prevent; public health relevance; receptor; receptor expression; relating to nervous system; research study; sobriety; therapeutic development; tumor

DESCRIPTION (provided by applicant): With a 5-year survival rate of less than 4% pancreatic cancer is the fourth leading cause of cancer death in the United States. Current chemotherapy and radiation therapy are largely ineffective in the treatment of this disease. Surgical treatment offers the only hope for long term survival. Unfortunately, only ~15% of patients have resectable disease at the time of diagnosis. The 5-year survival rate for patients who have undergone a successful resection (negative surgical margin) is still sobering, varying from 5-30% in the literature. Among the reasons for this poor prognosis is perineural invasion of cancer cells into noncancerous pancreas or the retroperitoneum plexus. Perineural invasion is a feature of pancreatic cancer; up to 100% of patients show involvement of intrapancreatic nerves and >70% invade extrapancreatic nerves. This infiltration accounts for local recurrence after tumor resection. Severe abdominal and back pain is very common in patients with pancreatic cancer and correlates strongly with perineural invasion. Recent reports indicate that expression of nerve growth factor (NGF) and its receptors correlate with perineural invasion and pain in human pancreatic cancer. However, the molecular mechanisms of perineural invasion in pancreatic cancer and the role of the NGF signaling pathway are still not clear. In this project experiments will elucidate the role of NGF and its receptors in perineural invasion of pancreatic cancer and to identify additional genes/proteins that regulate perineural invasion. The central hypothesis of this project is that there exist direct communications through signaling molecules such as NGF and its receptors between pancreatic cancer cells and the nerve cells which stimulate the infiltration of cancer cells into the perineurium space. The specific aims of this project are: 1) to determine the specific role of NGF and its receptors (TrkA and p75NTR) in the invasion of pancreatic cancer cells into peripheral nerves using in vitro and ex vivo perineural invasion model systems; and 2) to discover and validate additional genes and pathways that drive perineural invasion. This will be done using DNA microarray based gene and microRNA (miRNA) expression profiling of microdissected nerve cells, stroma cells and pancreatic cancer cells within nerve bundles. The goal of this research is to understand the molecular mechanisms of neural invasion by pancreatic cancer and identify molecular targets for the development of therapeutics that may prevent neural invasion. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth leading course of cancer death in the United States. Even with treatment, the medium survival for pancreatic cancer patients is 6 months and the 5-year survival rate is less than 4%. One of the main reasons for this dismal prognosis of the disease is its highly invasive and metastatic nature. Perineural invasion is one of the most common features of pancreatic cancer and it causes pain. This pain has a tremendous impact on the patient quality of life ad it is very difficult to manage. Reasons for the high affinity of pancreatic cancer cells for neural tissues are not clear. The current proposal seeks to investigate the molecular mechanisms of neural invasion in pancreatic cancer and identify new molecular targets for the development of therapeutics that may prevent neural invasion. The results generated in this proposal therefore have the potential to directly benefit pancreatic cancer patients with improved treatment.

描述（由申请人提供）：胰腺癌的 5 年生存率低于 4%，是美国第四大癌症死亡原因。目前的化疗和放疗对这种疾病的治疗基本上无效。手术治疗是长期生存的唯一希望。不幸的是，只有约 15% 的患者在诊断时患有可切除的疾病。成功切除（手术切缘阴性）的患者的 5 年生存率仍然令人震惊，文献报道的生存率为 5-30%。预后不良的原因之一是癌细胞神经周围侵入非癌性胰腺或腹膜后神经丛。神经周围侵犯是胰腺癌的一个特征；高达 100% 的患者表现出胰内神经受累，>70% 的患者表现出胰外神经受累。这种浸润是肿瘤切除后局部复发的原因。严重的腹部和背部疼痛在胰腺癌患者中很常见，并且与神经周围侵犯密切相关。最近的报告表明，神经生长因子（NGF）及其受体的表达与人类胰腺癌的神经周围浸润和疼痛相关。然而，胰腺癌神经周围浸润的分子机制以及NGF信号通路的作用仍不清楚。在该项目中，实验将阐明 NGF 及其受体在胰腺癌神经周围侵袭中的作用，并鉴定调节神经周围侵袭的其他基因/蛋白质。该项目的中心假设是，胰腺癌细胞和神经细胞之间存在通过信号分子（例如 NGF 及其受体）的直接通讯，从而刺激癌细胞浸润到神经束膜间隙。该项目的具体目标是：1）利用体外和离体神经周围侵袭模型系统确定NGF及其受体（TrkA和p75NTR）在胰腺癌细胞侵袭周围神经中的具体作用； 2）发现并验证驱动神经周围侵袭的其他基因和途径。这将使用基于 DNA 微阵列的基因和 microRNA (miRNA) 表达谱对神经束内的显微解剖神经细胞、基质细胞和胰腺癌细胞进行分析来完成。这项研究的目的是了解胰腺癌神经侵袭的分子机制，并确定开发可能预防神经侵袭的疗法的分子靶点。公共健康相关性：胰腺癌是美国第四大癌症死亡原因。即使经过治疗，胰腺癌患者的中位生存期为6个月，5年生存率不到4%。该疾病预后不佳的主要原因之一是其高度侵袭性和转移性。神经周围侵犯是胰腺癌最常见的特征之一，它会引起疼痛。这种疼痛对患者的生活质量有巨大影响，而且很难控制。胰腺癌细胞对神经组织具有高亲和力的原因尚不清楚。目前的提案旨在研究胰腺癌神经侵袭的分子机制，并确定新的分子靶点，以开发可能预防神经侵袭的疗法。因此，该提案中产生的结果有可能通过改善治疗直接使胰腺癌患者受益。