糖原合成酶激酶 3β:胰腺癌化疗抗药性、侵袭能力和癌症干细胞的纽带。

IF 4.6 Q1 ONCOLOGY 癌症耐药(英文) Pub Date : 2024-01-31 eCollection Date: 2024-01-01 DOI:10.20517/cdr.2023.84
Masahiro Uehara, Takahiro Domoto, Satoshi Takenaka, Osamu Takeuchi, Takeo Shimasaki, Tomoharu Miyashita, Toshinari Minamoto
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引用次数: 0

摘要

由于符合治愈性(R0)手术条件的患者人数有限、靶向疗法和免疫疗法的临床开发失败以及化疗耐药性的普遍存在,胰腺癌的治疗仍然是一项重大的临床挑战。难治性胰腺癌具有高侵袭性和耐药性,这两种特性都与肿瘤细胞的干性有关。这些恶性特征相互促进,导致癌症迅速发展。在过去二十年中,大量研究证明糖原合酶激酶(GSK)3β在包括胰腺癌在内的超过 25 种不同癌症类型的进展过程中起着关键作用。在这篇综述中,我们总结了目前关于异常 GSK3β 在支持肿瘤细胞增殖和侵袭中的病理作用及其对胰腺癌吉西他滨耐药性的贡献的知识。重要的是,我们讨论了 GSK3β 作为分子枢纽的核心作用,它从机理上将胰腺癌的化疗耐药性、肿瘤细胞侵袭和干性联系在一起。我们还讨论了 GSK3β 参与脱鳞肿瘤基质的形成和促进抗癌免疫逃避的情况,这两者都是成功治疗癌症的主要障碍。总之,GSK3β具有克服胰腺癌化疗耐药性的治疗靶点的特征。
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Glycogen synthase kinase 3β: the nexus of chemoresistance, invasive capacity, and cancer stemness in pancreatic cancer.

The treatment of pancreatic cancer remains a significant clinical challenge due to the limited number of patients eligible for curative (R0) surgery, failures in the clinical development of targeted and immune therapies, and the pervasive acquisition of chemotherapeutic resistance. Refractory pancreatic cancer is typified by high invasiveness and resistance to therapy, with both attributes related to tumor cell stemness. These malignant characteristics mutually enhance each other, leading to rapid cancer progression. Over the past two decades, numerous studies have produced evidence of the pivotal role of glycogen synthase kinase (GSK)3β in the progression of over 25 different cancer types, including pancreatic cancer. In this review, we synthesize the current knowledge on the pathological roles of aberrant GSK3β in supporting tumor cell proliferation and invasion, as well as its contribution to gemcitabine resistance in pancreatic cancer. Importantly, we discuss the central role of GSK3β as a molecular hub that mechanistically connects chemoresistance, tumor cell invasion, and stemness in pancreatic cancer. We also discuss the involvement of GSK3β in the formation of desmoplastic tumor stroma and in promoting anti-cancer immune evasion, both of which constitute major obstacles to successful cancer treatment. Overall, GSK3β has characteristics of a promising therapeutic target to overcome chemoresistance in pancreatic cancer.

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