Impact of nerves on cancer initiating cells and tumor progression

描述(申请人提供)：头颈部癌(SCCHN)患者经常对治疗产生抵抗力，从而导致肿瘤复发。因此，几乎一半的SCCHN患者在确诊后五年内死亡。启动癌症的细胞(CIC)在成功的治疗后存活下来，重新生成肿瘤(复发)，并扩散到远处。SCCHN是一种嗜神经的癌症，它侵犯神经，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至关重要的作用。令人惊讶的是，神经通过对CIC的影响而对肿瘤复发和肿瘤扩散的影响尚未被研究。在初步研究中，我们表明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在SCCHN中诱导多种亲侵袭细胞因子的转录。这项建议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。假说是，周围神经通过细胞因子促进肿瘤复发和扩散，从而促进CIC的存活、侵袭和增殖。其基本原理是，对CIC的神经生态位的研究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。我们将通过以下目的来验证这一假说：1)研究神经在CIC介导的肿瘤复发和转移中的作用；2)研究神经诱导肿瘤进展的机制。因此，拟议的研究将探讨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.