Impact of nerves on cancer initiating cells and tumor progression

神经对癌症起始细胞和肿瘤进展的影响

基本信息

批准号：
8871714
负责人：
Nisha J D'Silva
金额：
$ 19.38万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8871714
关键词：
Address Area Biological Assay Cell Communication Cell Survival Cells Data Set Diagnosis Distant Epithelial Figs - dietary G-Protein-Coupled Receptors GALR2 gene Galanin Genes Genetic Transcription Grant Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Health In Vitro Invaded Investigation Knowledge Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Manuscripts Mediating Meta-Analysis Modeling Natural regeneration Neoplasm Metastasis Nerve Nerve Growth Factors Neuropeptides Normal tissue morphology Oncogenic Patients Peripheral Nerves Phenotype Pilot Projects Platelet Factor 4 Property Proteins Publishing Recurrence Relapse Resistance development Role Route Site Skin Testing autocrine base cancer site cancer stem cell cytokine in vivo in vivo Model malignant mouth neoplasm nerve stem cell neurotrophic factor neurotropic perineural preclinical study prognostic relating to nervous system stem cell differentiation targeted treatment tissue regeneration transcription factor tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Patients with head and neck cancer (SCCHN) often develop resistance to treatment, which leads to tumor recurrence. Consequently, almost half of SCCHN patients die within five years of diagnosis. Cancer-initiating cells (CIC) survive "successful" treatment to regenerate a tumor (recurrence) and spread to distant sites. SCCHN is a neurotropic cancer i.e. it invades nerves, which is an important route of tumor spread. In normal tissues, the nerves have an essential role in tissue regeneration. Surprisingly, the impact of nerves on tumor recurrence and tumor spread via effects on CIC has not been investigated. In pilot studies, we show that nerves have an important role in tumor progression. Furthermore, a neuropeptide released by nerves induces transcription of multiple pro-invasive cytokines in SCCHN by activating a transcription factor. The strategic objective of this proposal is to investigate the impact of nerves on tumor progression via survival and spread of CIC. The hypothesis is that peripheral nerves promote tumor recurrence and spread via cytokines that promote survival, invasion, and proliferation of CIC. The rationale is that investigation of the neural niche for CIC will elucidate an overlooked mechanism of CIC survival and tumor recurrence thereby revealing an important treatment target. We will test the hypothesis by pursuing the following aims: 1) To investigate the impact of nerves on CIC-mediated tumor recurrence and metastasis; and 2) To investigate the mechanism of nerve- induced tumor progression. Thus, the proposed studies will investigate an important but understudied area of CIC-mediated tumor regeneration and metastasis.

描述（由申请人提供）：头颈癌（SCCHN）患者经常对治疗产生耐药性，从而导致肿瘤复发。因此，几乎一半的 SCCHN 患者在诊断后五年内死亡。癌症起始细胞（CIC）在“成功”治疗后存活下来，再生肿瘤（复发）并扩散到远处。 SCCHN是一种嗜神经性癌症，即侵犯神经，这是肿瘤扩散的重要途径。在正常组织中，神经在组织再生中起着重要作用。令人惊讶的是，神经通过对 CIC 的影响对肿瘤复发和肿瘤扩散的影响尚未得到研究。在初步研究中，我们表明神经在肿瘤进展中发挥着重要作用。此外，神经释放的神经肽通过激活转录因子诱导 SCCHN 中多种促侵袭细胞因子的转录。该提案的战略目标是研究神经通过 CIC 的存活和扩散对肿瘤进展的影响。该假说认为，周围神经通过促进 CIC 存活、侵袭和增殖的细胞因子促进肿瘤复发和扩散。其基本原理是，对 CIC 神经生态位的研究将阐明被忽视的 CIC 存活和肿瘤复发机制，从而揭示重要的治疗靶点。我们将通过以下目标来检验这一假设：1）研究神经对CIC介导的肿瘤复发和转移的影响； 2) 研究神经诱导肿瘤进展的机制。因此，拟议的研究将调查 CIC 介导的肿瘤再生和转移的一个重要但尚未充分研究的领域。