Giuli Maria V, Mancusi Angelica, Giuliani Eugenia, Screpanti Isabella, Checquolo Saula
Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome 00161, Italy.
Scientific Direction, San Gallicano Dermatological Institute IRCCS, Rome 00144, Italy.
Cancer Drug Resist. 2021 Aug 5;4(4):805-836. doi: 10.20517/cdr.2021.53. eCollection 2021.
Drug resistance is one of the main challenges in cancer therapy, including in the treatment of female-specific malignancies, which account for more than 60% of cancer cases among women. Therefore, elucidating the underlying molecular mechanisms is an urgent need in gynecological cancers to foster novel therapeutic approaches. Notably, Notch signaling, including either receptors or ligands, has emerged as a promising candidate given its multifaceted role in almost all of the hallmarks of cancer. Concerning the connection between Notch pathway and drug resistance in the afore-mentioned tumor contexts, several studies focused on the Notch-dependent regulation of the cancer stem cell (CSC) subpopulation or the induction of the epithelial-to-mesenchymal transition (EMT), both features implicated in either intrinsic or acquired resistance. Indeed, the present review provides an up-to-date overview of the published results on Notch signaling and EMT- or CSC-driven drug resistance. Moreover, other drug resistance-related mechanisms are examined such as the involvement of the Notch pathway in drug efflux and tumor microenvironment. Collectively, there is a long way to go before every facet will be fully understood; nevertheless, some small pieces are falling neatly into place. Overall, the main aim of this review is to provide strong evidence in support of Notch signaling inhibition as an effective strategy to evade or reverse resistance in female-specific cancers.
耐药性是癌症治疗中的主要挑战之一，包括在女性特有的恶性肿瘤治疗中，这类肿瘤占女性癌症病例的60%以上。因此，阐明潜在的分子机制是妇科癌症中迫切需要解决的问题，以促进新的治疗方法的发展。值得注意的是，Notch信号通路，包括受体或配体，因其在几乎所有癌症特征中的多方面作用，已成为一个有前景的候选对象。关于上述肿瘤背景下Notch通路与耐药性之间的联系，一些研究集中在Notch对癌症干细胞（CSC）亚群的依赖性调节或上皮-间质转化（EMT）的诱导，这两个特征都与内在或获得性耐药有关。事实上，本综述提供了关于Notch信号通路以及EMT或CSC驱动的耐药性已发表结果的最新概述。此外，还研究了其他与耐药性相关的机制，如Notch通路在药物外排和肿瘤微环境中的作用。总的来说，在全面理解每个方面之前还有很长的路要走；然而，一些小的方面正逐渐清晰起来。总体而言，本综述的主要目的是提供有力证据，支持抑制Notch信号通路作为逃避或逆转女性特异性癌症耐药性的有效策略。
