Jamroze Anmbreen, Liu Xiaozhuo, Tang Dean G
Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
Experimental Therapeutics (ET) Graduate Program, University at Buffalo & Roswell Park Comprehensive Cancer Center, NY 14263, USA.
Cancer Heterog Plast. 2024;1(1). doi: 10.47248/chp2401010005. Epub 2024 Aug 25.
Most human cancers are heterogeneous consisting of cancer cells at different epigenetic and transcriptional states and with distinct phenotypes, functions, and drug sensitivities. This inherent cancer cell heterogeneity contributes to tumor resistance to clinical treatment, especially the molecularly targeted therapies such as tyrosine kinase inhibitors (TKIs) and androgen receptor signaling inhibitors (ARSIs). Therapeutic interventions, in turn, induce lineage plasticity (also called lineage infidelity) in cancer cells that also drives therapy resistance. In this Perspective, we focus our discussions on cancer cell lineage plasticity manifested as treatment-induced switching of epithelial cancer cells to basal/stem-like, mesenchymal, and neural lineages. We employ prostate cancer (PCa) as the prime example to highlight ARSI-induced lineage plasticity during and towards development of castration-resistant PCa (CRPC). We further discuss how the tumor microenvironment (TME) influences therapy-induced lineage plasticity. Finally, we offer an updated summary on the regulators and mechanisms driving cancer cell lineage infidelity, which should be therapeutically targeted to extend the therapeutic window and improve patients' survival.
大多数人类癌症是异质性的，由处于不同表观遗传和转录状态、具有不同表型、功能和药物敏感性的癌细胞组成。这种固有的癌细胞异质性导致肿瘤对临床治疗产生抗性，尤其是对酪氨酸激酶抑制剂（TKIs）和雄激素受体信号抑制剂（ARSIs）等分子靶向疗法。反过来，治疗干预会诱导癌细胞的谱系可塑性（也称为谱系不忠实），这也会导致治疗抗性。在这篇观点文章中，我们将讨论重点放在癌细胞谱系可塑性上，这种可塑性表现为治疗诱导的上皮癌细胞向基底/干细胞样、间充质和神经谱系的转变。我们以前列腺癌（PCa）为例，强调在去势抵抗性前列腺癌（CRPC）的发展过程中以及发展为CRPC时，ARSIs诱导的谱系可塑性。我们进一步讨论肿瘤微环境（TME）如何影响治疗诱导的谱系可塑性。最后，我们提供了关于驱动癌细胞谱系不忠实的调节因子和机制的最新总结，这些应该成为治疗靶点以延长治疗窗口并提高患者生存率。
