Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA, USA.
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
Gynecol Oncol. 2014 Feb;132(2):455-61. doi: 10.1016/j.ygyno.2013.12.031. Epub 2013 Dec 28.
The inability to successfully treat women with ovarian cancer is due to the presence of metastatic disease at diagnosis and the development of platinum resistance. Ovarian cancer metastasizes throughout the peritoneal cavity by attaching to and invading through the mesothelium lining the peritoneum using a mechanism that involves α4β1 integrin and its ligand (vascular cell adhesion molecule) VCAM-1. Integrin α4β1 expression on tumor cells is known to confer protection from therapy in other cancers, notably multiple myeloma. We evaluated the role of α4β1 integrin in response to platinum-based therapy in a mouse model of peritoneal ovarian cancer metastasis by treatment with a humanized anti-α4β1 integrin function-blocking antibody.
Integrin α4β1 expression on primary human ovarian cancer cells, fallopian tube and ovarian surface epithelia and fresh tumor was assessed by flow-cytometry. The therapeutic impact of anti-α4β1 treatment was assessed in murine models of platinum-resistant peritoneal disease and in vitro using the platinum resistant ovarian cancer cell lines.
Treatment of tumor-bearing mice with human-specific α4β1 integrin function-blocking antibodies, anti-VCAM-1 antibody or carboplatin alone had no effect on tumor burden compared to the IgG control group. However, the combined treatment of anti-α4β1 integrin or anti-VCAM-1 with carboplatin significantly reduced tumor burden. In vitro, the combination of carboplatin and anti-α4β1 integrin antibodies resulted in increased cell death and doubling time.
Our findings support a role for α4β1 integrin in regulating treatment response to carboplatin, implicating α4β1 integrin as a potential therapeutic target to influence platinum responsiveness in otherwise resistant disease.
女性卵巢癌治疗失败的原因是诊断时存在转移性疾病和铂类耐药的发生。卵巢癌细胞通过附着在腹膜衬里的间皮上并侵入其中，从而在整个腹膜腔中转移，其机制涉及α4β1 整合素及其配体（血管细胞黏附分子）VCAM-1。众所周知，肿瘤细胞上整合素α4β1 的表达可使其免受其他癌症（尤其是多发性骨髓瘤）治疗的影响。我们通过使用人源化抗α4β1 整合素功能阻断抗体对铂类耐药性腹膜卵巢癌转移的小鼠模型来评估α4β1 整合素在铂类治疗反应中的作用。
通过流式细胞术评估原发性人卵巢癌细胞、输卵管和卵巢表面上皮以及新鲜肿瘤中整合素α4β1 的表达。在铂耐药性腹膜疾病的小鼠模型中和体外使用铂耐药性卵巢癌细胞系评估抗α4β1 治疗的治疗效果。
与 IgG 对照组相比，用抗α4β1 整合素功能阻断抗体、抗 VCAM-1 抗体或卡铂单独治疗荷瘤小鼠对肿瘤负担没有影响。然而，抗α4β1 整合素或抗 VCAM-1 与卡铂联合治疗显著降低了肿瘤负担。在体外，卡铂和抗α4β1 整合素抗体的联合使用导致细胞死亡和倍增时间增加。
我们的研究结果支持α4β1 整合素在调节对卡铂治疗反应中的作用，表明α4β1 整合素可能是影响铂类耐药性疾病中铂类反应性的潜在治疗靶点。
