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

胃肠胰腺系统神经内分泌肿瘤（GEP-NET）的肿瘤特性与许多其他癌症相似，由钙依赖性细胞机制决定。细胞内钙离子主要受瞬时受体电位通道（TRP）调节。TRP通道亚型TRPM 8、TRPV 1和TRPV 6与致癌作用的功能相关性已在各种实体瘤中描述。这些TRP在某些实体恶性肿瘤中的不同表达水平（例如，G.前列腺癌）与临床预后相关，因此TRP被认为是新的预后标志物。在最近的研究中，申请人首次证明胰腺NET表达TRPM 8。目前的研究表明，TRPV 1在胰腺和回肠的NET中过表达，而TRPV 6的表达降低。鉴于GEP-NET的发病率增加和治疗选择有限，该项目的目的包括TRPM 8，TRPV 1和TRPV 6在调节这种恶性肿瘤的肿瘤生物学过程中的表达和特性的表征。利用GEP-NET细胞模型和原代细胞培养，我们计划研究这些TRP的分子，生化和药理学特征，并研究其关键的信号通路。此外，我们的目标是表征TRPM 8，TRPV 1和TRPV 6与GEP-NET中IGF-1，EGF和生长抑素的膜受体的致癌相关配体之间的功能性串扰。最后，使用内部建立的GEP-NET动物模型，将研究这三种不同TRP的致癌活性。总的来说，这项研究的结果将有助于更好地了解GEP-NETs生物学，并有望通过利用TRP来改善和扩展迄今为止在这种独特的肿瘤疾病中可用的诊断和治疗工具。

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.