Masciullo Valeria, Valdivieso Paola, Amadio Giulia, Santoro Angela, Angelico Giuseppe, Sgambato Alessandro, Boffo Silvia, Giordano Antonio, Scambia Giovanni, Zannoni Gian Franco
Unità di Ginecologia Oncologica, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
Unità di Gineco-Patologia e Patologia Mammaria, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
Front Med (Lausanne). 2020 Nov 11;7:596226. doi: 10.3389/fmed.2020.596226. eCollection 2020.
Borderline ovarian tumors (BOT) are uncommon but not rare epithelial ovarian neoplasms, intermediate between benign and malignant categories. Emerging knowledge supports the notion that subtypes of borderline ovarian tumors comprise distinct biologic, pathogenetic, and molecular entities, precluding a single unifying concept for BOT. The identification of valuable markers for the diagnosis and classification of these tumors is in need. Among the molecular candidates, the Retinoblastoma (Rb) family members Rb/p105 and Rb2/p130 seem to play a pivotal role in ovarian cancer. In particular, Rb/p105, when in the unphosphorylated form, acts as a growth suppressor controlling cell cycle and tumor progression; whereas, the phosphorylated form activates gene transcription and cellular proliferation. While Rb/p105 is ubiquitously confined to the nuclei of cycling and quiescent cells, Rb2/p130 activity is also regulated by intracellular localization. According to this, Rb family members could represent a novel marker in diagnosis and classification risk for patients with BOT. In this study, we evaluated the expression and subcellular localization of proteins of the retinoblastoma (Rb) gene family in 65 ovarian borderline tumors. Statistically significant differences were found in nuclear and cytoplasmic expressions of Rb/p105 and Rb2/p130 according to different examined histotypes. In detail, the nuclear expression of Rb/p105 and Rb2/p130 was more frequently detected in serous (84.6%) than sero-mucinous (42.1%) and mucinous (50%) types. Conversely, the cytoplasmic expression of Rb2/p130 was not detected in serous tumors and frequently observed in mucinous subtypes (80%). Our findings suggest that Rb proteins do not play a key role in the tumor progression of serous borderline tumors since any cases showed cytoplasmic localization. By contrast, the observed higher cytoplasmic expression of Rb2/p130 in intestinal mucinous BOTs is indicative of Rb protein family involvement in the cancerogenesis pathway of mucinous ovarian tumors. Also, mucinous BOTs of intestinal-type, exhibiting low nuclear and high cytoplasmic levels of Rb2/p130 might potentially be considered a high-risk category of malignant evolution. Further studies on larger series are needed to clarify how BOTs could be stratified in different prognostic groups according to their Rb proteins immunohistochemical profile.
交界性卵巢肿瘤（BOT）是一种不常见但也并非罕见的上皮性卵巢肿瘤，介于良性和恶性之间。新出现的知识支持这样一种观点，即交界性卵巢肿瘤的亚型包含不同的生物学、发病机制和分子实体，因此不存在一个适用于BOT的统一概念。目前需要鉴定出用于这些肿瘤诊断和分类的有价值标志物。在众多分子候选物中，视网膜母细胞瘤（Rb）家族成员Rb/p105和Rb2/p130似乎在卵巢癌中起关键作用。特别是，Rb/p105在未磷酸化形式时，作为一种生长抑制因子控制细胞周期和肿瘤进展；而磷酸化形式则激活基因转录和细胞增殖。虽然Rb/p105普遍存在于增殖期和静止期细胞的细胞核中，但Rb2/p130的活性也受细胞内定位的调节。据此，Rb家族成员可能代表一种用于BOT患者诊断和分类风险评估的新型标志物。在本研究中，我们评估了视网膜母细胞瘤（Rb）基因家族蛋白在65例卵巢交界性肿瘤中的表达及亚细胞定位。根据不同的组织学类型，Rb/p105和Rb2/p130的核表达和胞质表达存在统计学显著差异。具体而言，Rb/p105和Rb2/p130的核表达在浆液性肿瘤（84.6%）中比浆液黏液性肿瘤（（42.1%）和黏液性肿瘤（50%）中更常见。相反，浆液性肿瘤中未检测到Rb2/p130的胞质表达，而在黏液性亚型中经常观察到（80%）。我们的研究结果表明，Rb蛋白在浆液性交界性肿瘤的肿瘤进展中不发挥关键作用，因为所有病例均显示为胞质定位。相比之下，在肠型黏液性BOT中观察到的Rb2/p130较高的胞质表达表明Rb蛋白家族参与了黏液性卵巢肿瘤的致癌途径。此外，肠型黏液性BOT中Rb2/p130核水平低而胞质水平高可能潜在地被认为是恶性进展的高危类别。需要对更大样本量进行进一步研究，以阐明如何根据BOT的Rb蛋白免疫组化特征将其分为不同的预后组。
