From the Department of Medicine, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Ontario L8N 4A6, Canada.
the Department of Surgery, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Ontario L8N 4A6, Canada.
J Biol Chem. 2017 Dec 22;292(51):21180-21192. doi: 10.1074/jbc.M117.799908. Epub 2017 Oct 24.
Tumor cells display on their surface several molecular chaperones that normally reside in the endoplasmic reticulum. Because this display is unique to cancer cells, these chaperones are attractive targets for drug development. Previous epitope-mapping of autoantibodies (AutoAbs) from prostate cancer patients identified the 78-kDa glucose-regulated protein (GRP78) as one such target. Although we previously showed that anti-GRP78 AutoAbs increase tissue factor (TF) procoagulant activity on the surface of tumor cells, the direct effect of TF activation on tumor growth was not examined. In this study, we explore the interplay between the AutoAbs against cell surface-associated GRP78, TF expression/activity, and prostate cancer progression. First, we show that tumor GRP78 expression correlates with disease stage and that anti-GRP78 AutoAb levels parallel prostate-specific antigen concentrations in patient-derived serum samples. Second, we demonstrate that these anti-GRP78 AutoAbs target cell-surface GRP78, activating the unfolded protein response and inducing tumor cell proliferation through a TF-dependent mechanism, a specific effect reversed by neutralization or immunodepletion of the AutoAb pool. Finally, these AutoAbs enhance tumor growth in mice bearing human prostate cancer xenografts, and heparin derivatives specifically abrogate this effect by blocking AutoAb binding to cell-surface GRP78 and decreasing TF expression/activity. Together, these results establish a molecular mechanism in which AutoAbs against cell-surface GRP78 drive TF-mediated tumor progression in an experimental model of prostate cancer. Heparin derivatives counteract this mechanism and, as such, represent potentially appealing compounds to be evaluated in well-designed translational clinical trials.
肿瘤细胞表面显示出几种通常位于内质网中的分子伴侣。由于这种显示是癌细胞所特有的，这些伴侣是药物开发的有吸引力的靶点。以前从前列腺癌患者的自身抗体（AutoAbs）进行的表位作图确定了 78kDa 葡萄糖调节蛋白（GRP78）作为这样的靶标之一。尽管我们之前表明，抗-GRP78 AutoAbs 增加了肿瘤细胞表面组织因子（TF）促凝活性，但 TF 激活对肿瘤生长的直接影响尚未被检查。在这项研究中，我们探讨了针对细胞表面相关 GRP78 的 AutoAbs、TF 表达/活性和前列腺癌进展之间的相互作用。首先，我们表明肿瘤 GRP78 表达与疾病阶段相关，并且抗-GRP78 AutoAb 水平与患者来源的血清样本中前列腺特异性抗原浓度平行。其次，我们证明这些抗-GRP78 AutoAbs 靶向细胞表面 GRP78，通过 TF 依赖性机制激活未折叠蛋白反应并诱导肿瘤细胞增殖，这是通过中和或免疫耗竭 AutoAb 池来逆转的特定效应。最后，这些 AutoAbs 增强了携带人前列腺癌异种移植物的小鼠中的肿瘤生长，肝素衍生物通过阻止 AutoAb 与细胞表面 GRP78 结合并降低 TF 表达/活性特异性阻断这种作用。总之，这些结果确立了一种分子机制，其中针对细胞表面 GRP78 的 AutoAbs 通过 TF 介导的肿瘤进展驱动在前列腺癌的实验模型中。肝素衍生物拮抗这种机制，因此代表了在精心设计的转化临床试验中进行评估的潜在有吸引力的化合物。
