Unit of Gynecological Oncology Research, European Institute of Oncology, Via G. Ripamonti 435, 20141 Milano, Italy.
Molecular Medicine Program, European Institute of Oncology, Milan, Italy.
Stem Cell Reports. 2018 Apr 10;10(4):1412-1425. doi: 10.1016/j.stemcr.2018.02.009. Epub 2018 Mar 15.
Cancer-initiating cells (CICs) have been implicated in tumor development and aggressiveness. In ovarian carcinoma (OC), CICs drive tumor formation, dissemination, and recurrence, as well as drug resistance, thus accounting for the high death-to-incidence ratio of this neoplasm. However, the molecular mechanisms that underlie such a pathogenic role of ovarian CICs (OCICs) remain elusive. Here, we have capitalized on primary cells either from OC or from its tissues of origin to obtain the transcriptomic profile associated with OCICs. Among the genes differentially expressed in OCICs, we focused on CD73, which encodes the membrane-associated 5'-ectonucleotidase. The genetic inactivation of CD73 in OC cells revealed that this molecule is causally involved in sphere formation and tumor initiation, thus emerging as a driver of OCIC function. Furthermore, functional inhibition of CD73 via either a chemical compound or a neutralizing antibody reduced sphere formation and tumorigenesis, highlighting the druggability of CD73 in the context of OCIC-directed therapies. The biological function of CD73 in OCICs required its enzymatic activity and involved adenosine signaling. Mechanistically, CD73 promotes the expression of stemness and epithelial-mesenchymal transition-associated genes, implying a regulation of OCIC function at the transcriptional level. CD73, therefore, is involved in OCIC biology and may represent a therapeutic target for innovative treatments aimed at OC eradication.
癌症起始细胞(CICs)被认为与肿瘤的发生和侵袭有关。在卵巢癌(OC)中,CICs 驱动肿瘤的形成、扩散和复发,以及耐药性,从而导致这种肿瘤的高死亡率与发病率之比。然而,卵巢 CICs(OCICs)发挥这种致病作用的分子机制仍不清楚。在这里,我们利用源自 OC 或其组织的原代细胞,获得了与 OCICs 相关的转录组谱。在 OCICs 中差异表达的基因中,我们重点关注编码膜相关 5'-核苷酸酶的 CD73。OC 细胞中 CD73 的基因失活表明,该分子在球体形成和肿瘤起始中起因果作用,因此成为 OCIC 功能的驱动因素。此外,通过化学化合物或中和抗体抑制 CD73 的功能可减少球体形成和肿瘤发生,突出了在 OCIC 定向治疗中 CD73 的可用药性。CD73 在 OCICs 中的生物学功能需要其酶活性,并涉及腺苷信号。在机制上,CD73 促进了干性和上皮-间充质转化相关基因的表达,暗示了 OCIC 功能在转录水平上的调控。因此,CD73 参与了 OCIC 的生物学特性,可能代表了旨在消除 OC 的创新治疗的治疗靶点。