Robert Sacha, Roman Ortiz Natasha Ivelisse, LaRocca Christopher J, Ostrander Julie Hanson, Davydova Julia
Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
Viruses. 2024 Apr 5;16(4):567. doi: 10.3390/v16040567.
Adjuvant systemic therapies effectively reduce the risk of breast cancer recurrence and metastasis, but therapy resistance can develop in some patients due to breast cancer stem cells (BCSCs). Oncolytic adenovirus (OAd) represents a promising therapeutic approach as it can specifically target cancer cells. However, its potential to target BCSCs remains unclear. Here, we evaluated a Cox-2 promoter-controlled, Ad5/3 fiber-modified OAd designed to encode the human sodium iodide symporter (hNIS) in breast cancer models. To confirm the potential of OAds to target BCSCs, we employed BCSC-enriched estrogen receptor-positive (ER+) paclitaxel-resistant (TaxR) cells and tumorsphere assays. OAd-hNIS demonstrated significantly enhanced binding and superior oncolysis in breast cancer cells, including ER+ cells, while exhibiting no activity in normal mammary epithelial cells. We observed improved NIS expression as the result of adenovirus death protein deletion. OAd-hNIS demonstrated efficacy in targeting TaxR BCSCs, exhibiting superior killing and hNIS expression compared to the parental cells. Our vector was capable of inhibiting tumorsphere formation upon early infection and reversing paclitaxel resistance in TaxR cells. Importantly, OAd-hNIS also destroyed already formed tumorspheres seven days after their initiation. Overall, our findings highlight the promise of OAd-hNIS as a potential tool for studying and targeting ER+ breast cancer recurrence and metastasis.
辅助性全身治疗可有效降低乳腺癌复发和转移的风险，但由于乳腺癌干细胞（BCSCs）的存在，一些患者可能会产生治疗抗性。溶瘤腺病毒（OAd）是一种很有前景的治疗方法，因为它可以特异性地靶向癌细胞。然而，其靶向BCSCs的潜力仍不明确。在此，我们在乳腺癌模型中评估了一种由Cox-2启动子控制、Ad5/3纤维修饰的OAd，该OAd设计用于编码人钠碘同向转运体（hNIS）。为了证实OAds靶向BCSCs的潜力，我们使用了富含BCSCs的雌激素受体阳性（ER+）耐紫杉醇（TaxR）细胞和肿瘤球测定法。OAd-hNIS在包括ER+细胞在内的乳腺癌细胞中表现出显著增强的结合能力和卓越的溶瘤作用，而在正常乳腺上皮细胞中无活性。我们观察到由于腺病毒死亡蛋白缺失，NIS表达有所改善。OAd-hNIS在靶向TaxR BCSCs方面显示出疗效，与亲代细胞相比，具有更强的杀伤作用和hNIS表达。我们的载体能够在早期感染时抑制肿瘤球形成，并逆转TaxR细胞中的紫杉醇抗性。重要的是，OAd-hNIS在肿瘤球形成七天后也能将其破坏。总体而言，我们的研究结果突出了OAd-hNIS作为研究和靶向ER+乳腺癌复发和转移的潜在工具的前景。
