Carmi Yifat Koren, Agbarya Abed, Khamaisi Hazem, Farah Raymond, Shechtman Yelena, Korobochka Roman, Gopas Jacob, Mahajna Jamal
Department of Nutrition and Natural Products, Migal - Galilee Research Institute, Kiryat Shmona, Israel; Shraga Segal Department of Microbiology, Immunology and Genetics, and Department of Oncology, Soroka University Medical Center, Ben Gurion University of the Negev, Beer Sheva, Israel.
Oncology Department, Bnai Zion MC, Haifa, Israel.
Transl Oncol. 2024 Jun;44:101939. doi: 10.1016/j.tranon.2024.101939. Epub 2024 Mar 14.
Ovarian cancer (OC), the second most common form of gynecologic malignancy, has a poor prognosis and is often discovered in the late stages. Platinum-based chemotherapy is the first line of therapy. Nevertheless, treatment OC has proven challenging due to toxicity and the development of acquired resistance to therapy. Tumor microenvironment (TME) has been associated with platinum chemoresistance. Malignant ascites has been used as OC tumor microenvironment and its ability to induce platinum chemoresistance has been investigated. Our results suggest that exposure to OC ascites induces platinum chemoresistance in 11 of 13 cases (85 %) on OC cells. In contrast, 75 % of cirrhotic ascites (3 of 4) failed to confer platinum chemoresistance to OC cells. Cytokine array analysis revealed that IL -6 and to a lesser extent HGF were enriched in OC ascites, whereas IL -22 was enriched in cirrhotic ascites. Pharmaceutical inhibitors targeting the IL -6/ JAK pathway were mildly effective in overcoming platinum chemoresistance induced by malignant ascites. In contrast, crizotinib, an HGF/c- MET inhibitor, and 2-hydroxyestradiol (2HE2) were effective in restoring platinum chemosensitivity to OC. Our results demonstrate the importance of OC ascites in supporting platinum chemoresistance and the potential of combination therapy to restore chemosensitivity of OC cells.
卵巢癌（OC）是妇科恶性肿瘤的第二常见形式，预后较差，且常于晚期被发现。铂类化疗是一线治疗方法。然而，由于毒性以及对治疗产生获得性耐药，治疗OC已被证明具有挑战性。肿瘤微环境（TME）与铂类化疗耐药有关。恶性腹水已被用作OC肿瘤微环境，并且其诱导铂类化疗耐药的能力已得到研究。我们的结果表明，在13例OC细胞中有11例（85%）暴露于OC腹水后会诱导铂类化疗耐药。相比之下，75%的肝硬化腹水（4例中的3例）未能赋予OC细胞铂类化疗耐药性。细胞因子阵列分析显示，IL -6以及程度较轻的HGF在OC腹水中富集，而IL -22在肝硬化腹水中富集。靶向IL -6/JAK途径的药物抑制剂在克服恶性腹水诱导的铂类化疗耐药方面效果欠佳。相比之下，克唑替尼（一种HGF/c-MET抑制剂）和2-羟基雌二醇（2HE2）在恢复OC对铂类的化疗敏感性方面有效。我们的结果证明了OC腹水在支持铂类化疗耐药中的重要性以及联合治疗恢复OC细胞化疗敏感性的潜力。
