Turdo Alice, Veschi Veronica, Gaggianesi Miriam, Chinnici Aurora, Bianca Paola, Todaro Matilde, Stassi Giorgio
Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy.
Department of PROMISE, University of Palermo, Palermo, Italy.
Front Cell Dev Biol. 2019 Feb 18;7:16. doi: 10.3389/fcell.2019.00016. eCollection 2019.
Notwithstanding cancer patients benefit from a plethora of therapeutic alternatives, drug resistance remains a critical hurdle. Indeed, the high mortality rate is associated with metastatic disease, which is mostly incurable due to the refractoriness of metastatic cells to current treatments. Increasing data demonstrate that tumors contain a small subpopulation of cancer stem cells (CSCs) able to establish primary tumor and metastasis. CSCs are endowed with multiple treatment resistance capabilities comprising a highly efficient DNA damage repair machinery, the activation of survival pathways, enhanced cellular plasticity, immune evasion and the adaptation to a hostile microenvironment. Due to the presence of distinct cell populations within a tumor, cancer research has to face the major challenge of targeting the intra-tumoral as well as inter-tumoral heterogeneity. Thus, targeting molecular drivers operating in CSCs, in combination with standard treatments, may improve cancer patients' outcomes, yielding long-lasting responses. Here, we report a comprehensive overview on the most significant therapeutic advances that have changed the known paradigms of cancer treatment with a particular emphasis on newly developed compounds that selectively affect the CSC population. Specifically, we are focusing on innovative therapeutic approaches including differentiation therapy, anti-angiogenic compounds, immunotherapy and inhibition of epigenetic enzymes and microenvironmental cues.
尽管癌症患者受益于大量的治疗选择，但耐药性仍然是一个关键障碍。事实上，高死亡率与转移性疾病相关，由于转移细胞对当前治疗的难治性，转移性疾病大多无法治愈。越来越多的数据表明，肿瘤包含一小部分能够形成原发性肿瘤和转移的癌症干细胞（CSC）。CSC具有多种耐药能力，包括高效的DNA损伤修复机制、生存途径的激活、增强的细胞可塑性、免疫逃避以及对恶劣微环境的适应。由于肿瘤内存在不同的细胞群体，癌症研究必须面对靶向肿瘤内以及肿瘤间异质性的重大挑战。因此，靶向CSC中起作用的分子驱动因素，并结合标准治疗，可能会改善癌症患者的治疗结果，产生持久的反应。在这里，我们全面概述了改变癌症治疗已知范式的最重要治疗进展，特别强调了选择性影响CSC群体的新开发化合物。具体来说，我们专注于创新的治疗方法，包括分化疗法、抗血管生成化合物、免疫疗法以及对表观遗传酶和微环境信号的抑制。
