Impact of nerves on cancer initiating cells and tumor progression

描述（由申请人提供）：头颈癌（SCCHN）患者通常对治疗产生耐药性，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，以再生肿瘤（复发）并扩散到远处。SCCHN是一种嗜神经性癌症，即它侵入神经，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重要作用。令人惊讶的是，尚未研究神经通过对CIC的影响对肿瘤复发和肿瘤扩散的影响。在初步研究中，我们发现神经在肿瘤进展中起着重要作用。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通过CIC的生存和扩散来研究神经对肿瘤进展的影响。假设外周神经通过促进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，研究CIC的神经生态位将阐明一个被忽视的CIC生存和肿瘤复发的机制，从而揭示一个重要的治疗靶点。我们将通过追求以下目标来检验该假设：1）研究神经对CIC介导的肿瘤复发和转移的影响;以及2）研究神经诱导的肿瘤进展的机制。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研究不足的领域。

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.