Expression, function and endogenous modulators of transient receptor potential channels TRPV1, TRPV6 and TRPM8 in gastroenteropancreatic neuroendocrine tumors

胃肠胰系统神经内分泌肿瘤（GEP-NETs）的肿瘤性质与许多其他癌症类似，由钙依赖的细胞机制决定。细胞内钙主要受瞬时受体电位通道（TRPs）调节。TRP通道亚型TRPM8、TRPV1和TRPV6在各种实体肿瘤中与癌变的功能相关性已被描述。这些TRPs在某些实体恶性肿瘤（如前列腺癌）中的不同表达水平与临床预后相关，因此TRPs被认为是一种新的预后标志物。在最近的一项研究中，申请人首次证明胰腺NETs表达TRPM8。目前的研究显示，胰腺和回肠NETs中TRPV1过表达，TRPV6表达降低。鉴于GEP-NETs的发病率增加和治疗选择有限，该项目的目的包括表征TRPM8、TRPV1和TRPV6在这种恶性肿瘤中调节肿瘤生物学过程的表达和特性。利用GEP-NET细胞模型和原代细胞培养，我们计划研究这些TRPs的分子、生化和药理学特征，并研究它们的关键信号通路。此外，我们旨在表征GEP-NETs中TRPM8、TRPV1和TRPV6与IGF-1、EGF和生长抑素膜受体配体之间的功能互扰。最后，利用内部建立的GEP-NETs动物模型，研究这三种不同TRPs的致癌活性。总的来说，这项研究的结果将有助于更好地理解GEP-NETs生物学，并有望通过利用TRPs来改善和扩展迄今为止可用于这种独特肿瘤疾病的诊断和治疗工具库。

Neoplastic properties of neuroendocrine tumors of the gastroenteropancreatic system (GEP-NETs) are, similar to numerous other cancers, determined by calcium-dependent cellular mechanisms. Intracellular calcium is substantially regulated by transient receptor potential channels (TRPs). The functional relevance of the TRP channel subtypes TRPM8, TRPV1, and TRPV6 for the carcinogenesis has been described in various solid tumors. The distinct expression levels of these TRPs in certain solid malignancies (e. g. prostate carcinoma) correlate with the clinical prognosis, and therefore TRPs are considered as novel prognostic markers. In a recent study the applicants demonstrated for the first time that pancreatic NETs express TRPM8. Current investigations revealed overexpression of TRPV1 and decreased expression of TRPV6 in NETs of pancreas and ileum. Given the increased incidence and limited therapeutic options of GEP-NETs, the aim of the project consist of the characterization of the expression and properties of TRPM8, TRPV1 and TRPV6 in regulating tumor biological processes in this malignancy. Using GEP-NET cell models and primary cell cultures, we plan to investigate the molecular, biochemical and pharmacological characteristics of these TRPs and to study their crucial signaling pathways. In addition, we aim to characterize the functional cross-talk between TRPM8, TRPV1 and TRPV6 and the oncogenically-relevant ligands of membrane receptors for IGF-1, EGF and somatostatin in GEP-NETs. Lastly, using in-house established animal models of GEP-NETs, the oncogenic activities of these three different TRPs will be studied. Overall, the results of this study will contribute to a better understanding of the GEP-NETs biology and hold promise to improve and extend of the arsenal of diagnostic and therapeutic tools available to date in this unique neoplastic disease by utilizing TRPs.