Laboratory of Tumor Microenvironment, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.
Department of Science and Drug Technology, University of Turin, Candiolo, Turin, Italy.
Mol Cancer Ther. 2020 Dec;19(12):2476-2489. doi: 10.1158/1535-7163.MCT-20-0055. Epub 2020 Oct 20.
Antiretrovirals belonging to the human immunodeficiency virus (HIV) protease inhibitor (HIV-PI) class exert inhibitory effects across several cancer types by targeting tumor cells and its microenvironment. Cervical carcinoma represents a leading cause of morbidity and mortality, particularly in women doubly infected with high-risk human papillomaviruses (HR-HPV) and HIV; of note, combined antiretroviral therapy has reduced cervical carcinoma onset and progression in HIV-infected women. We evaluated the effectiveness and mechanism(s) of action of HIV-PI against cervical carcinoma using a transgenic model of HR-HPV-induced estrogen-promoted cervical carcinoma (HPV16/E2) and found that treatment of mice with ritonavir-boosted HIV-PI, including indinavir, saquinavir, and lopinavir, blocked the growth and promoted the regression of murine cervical carcinoma. This was associated with inhibition of tumor angiogenesis, coupled to downregulation of matrix metalloproteinase (MMP)-9, reduction of VEGF/VEGFR2 complex, and concomitant upregulation of tissue inhibitor of metalloproteinase-3 (TIMP-3). HIV-PI also promoted deposition of collagen IV at the epithelial and vascular basement membrane and normalization of both vessel architecture and functionality. In agreement with this, HIV-PI reduced tumor hypoxia and enhanced the delivery and antitumor activity of conventional chemotherapy. Remarkably, TIMP-3 expression gradually decreased during progression of human dysplastic lesions into cervical carcinoma. This study identified the MMP-9/VEGF proangiogenic axis and its modulation by TIMP-3 as novel HIV-PI targets for the blockade of cervical intraepithelial neoplasia/cervical carcinoma development and invasiveness and the normalization of tumor vessel functions. These findings may lead to new therapeutic indications of HIV-PI to treat cervical carcinoma and other tumors in either HIV-infected or uninfected patients.
抗逆转录病毒属于人类免疫缺陷病毒（HIV）蛋白酶抑制剂（HIV-PI）类，通过靶向肿瘤细胞及其微环境，对多种癌症类型发挥抑制作用。宫颈癌是发病率和死亡率的主要原因，特别是在同时感染高危型人乳头瘤病毒（HR-HPV）和 HIV 的女性中；值得注意的是，联合抗逆转录病毒疗法降低了 HIV 感染女性宫颈癌的发病和进展。我们使用 HR-HPV 诱导的雌激素促进的宫颈癌（HPV16/E2）转基因模型评估了 HIV-PI 对宫颈癌的有效性和作用机制，发现用利托那韦增强的 HIV-PI 治疗包括茚地那韦、沙奎那韦和洛匹那韦在内的药物，可阻断小鼠宫颈癌的生长并促进其消退。这与肿瘤血管生成的抑制有关，同时伴随着基质金属蛋白酶（MMP）-9 的下调、VEGF/VEGFR2 复合物的减少以及组织金属蛋白酶抑制剂-3（TIMP-3）的上调。HIV-PI 还促进了胶原蛋白 IV 在上皮和血管基底膜的沉积，并使血管结构和功能正常化。与此一致的是，HIV-PI 降低了肿瘤缺氧，并增强了常规化疗的输送和抗肿瘤活性。值得注意的是，TIMP-3 的表达在人类发育不良病变进展为宫颈癌的过程中逐渐降低。本研究确定了 MMP-9/VEGF 促血管生成轴及其被 TIMP-3 调节，是阻断宫颈上皮内瘤变/宫颈癌发展和侵袭以及肿瘤血管功能正常化的新型 HIV-PI 靶点。这些发现可能为 HIV-PI 治疗宫颈癌和其他肿瘤提供新的治疗指征，无论是在 HIV 感染还是未感染的患者中。
