PDF(Pubmed)
Abstract：
Chemotherapy treatment against pancreatic ductal adenocarcinoma (PDAC) is thwarted by tumoral activation of multiple therapy resistance pathways. The growth hormone (GH)-GH receptor (GHR) pair is a covert driver of multimodal therapy resistance in cancer and is overexpressed in PDAC tumors, yet the therapeutic potential of targeting the same has not been explored. Here, we report that GHR expression is a negative prognostic factor in patients with PDAC. Combinations of gemcitabine with different GHR antagonists (GHRAs) markedly improve therapeutic outcomes in nude mice xenografts. Employing cultured cells, mouse xenografts, and analyses of the human PDAC transcriptome, we identified that attenuation of the multidrug transporter and epithelial-to-mesenchymal transition programs in the tumors underlie the observed augmentation of chemotherapy efficacy by GHRAs. Moreover, in human PDAC patients, GHR expression strongly correlates with a gene signature of tumor promotion and immune evasion, which corroborate with that in syngeneic tumors in wild-type vs. GH transgenic mice. Overall, we found that GH action in PDAC promoted a therapy-refractory gene signature in vivo, which can be effectively attenuated by GHR antagonism. Our results collectively present a proof of concept toward considering GHR antagonists to improve chemotherapeutic outcomes in the highly chemoresistant PDAC.
摘要：
针对胰腺导管腺癌（PDAC）的化疗治疗因多种治疗抵抗途径的肿瘤激活而受阻。生长激素（GH）-GH受体（GHR）对是癌症多模式治疗抵抗的隐性驱动因素，并且在PDAC肿瘤中过度表达。然而，靶向相同的治疗潜力尚未被探索。这里,我们报道GHR的表达是PDAC患者的不良预后因素.吉西他滨与不同GHR拮抗剂(GHRA)的组合显著改善裸鼠异种移植物的治疗结果。使用培养的细胞，小鼠异种移植物,以及人类PDAC转录组的分析，我们发现,肿瘤中多药转运体和上皮-间质转化程序的减弱是GHRAs观察到的化疗疗效增强的基础.此外，在人类PDAC患者中，GHR表达与肿瘤促进和免疫逃避的基因签名密切相关，这证实了野生型与同基因肿瘤的关系。GH转基因小鼠。总的来说,我们发现GH在PDAC中的作用促进了体内治疗难治性基因签名，可以通过GHR拮抗作用有效减弱。我们的结果共同证明了在高度化学抗性PDAC中考虑GHR拮抗剂以改善化疗结果的概念。
