Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
Carcinogenesis. 2018 Dec 31;39(12):1431-1437. doi: 10.1093/carcin/bgy112.
Circulating insulin-like growth factor-1 (IGF-1) is consistently associated with prostate cancer risk. IGF-1 binds to IGF-1 receptor (IGF1R) and insulin receptor (IR), activating cancer hallmark pathways. Experimental evidence suggests that TMPRSS2:ERG may interact with IGF/insulin signaling to influence progression. We investigated IGF1R and IR expression and its association with lethal prostate cancer among 769 men. Protein expression of IGF1R, IR and ERG (i.e. a surrogate of ERG fusion genes) were assayed by immunohistochemistry. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for clinical characteristics. Among patients, 29% had strong tumor IGF1R expression and 10% had strong IR expression. During a mean follow-up of 13.2 years through 2012, 80 men (11%) developed lethal disease. Tumors with strong IGF1R or IR expression showed increased cell proliferation, decreased apoptosis and a higher prevalence of ERG. In multivariable models, strong IGF1R was associated with a borderline increased risk of lethal prostate cancer (HR 1.7; 95% CI 0.9-3.1). The association appeared greater in ERG-positive tumors (HR 2.8; 95% CI 0.9-8.4) than in ERG-negative tumors (HR 1.3; 95% CI 0.6-3.0, p-heterogeneity 0.08). There was no association between IR and lethal prostate cancer (HR 0.8; 95% CI 0.4-1.9). These results suggest that tumor IGF1R expression may play a role in prostate cancer progression to a lethal phenotype and that ERG-positive tumors may be more sensitive to IGF signaling. These data may improve our understanding of IGF signaling in prostate cancer and suggest therapeutic options for disease subtypes.
循环胰岛素样生长因子-1（IGF-1）与前列腺癌风险始终相关。IGF-1 与 IGF-1 受体（IGF1R）和胰岛素受体（IR）结合，激活癌症标志性通路。实验证据表明，TMPRSS2:ERG 可能与 IGF/胰岛素信号相互作用，影响进展。我们研究了 769 名男性中 IGF1R 和 IR 表达及其与致命性前列腺癌的关系。通过免疫组织化学检测 IGF1R、IR 和 ERG（即 ERG 融合基因的替代物）的蛋白表达。Cox 模型估计了调整临床特征后的危险比（HR）和 95%置信区间（CI）。在患者中，29%的肿瘤 IGF1R 表达强烈，10%的肿瘤 IR 表达强烈。在 2012 年通过平均 13.2 年的随访期间，80 名男性（11%）发展为致命性疾病。具有强烈 IGF1R 或 IR 表达的肿瘤显示出增加的细胞增殖、减少的凋亡和更高的 ERG 患病率。在多变量模型中，强烈的 IGF1R 与致命性前列腺癌的风险增加呈边缘相关（HR 1.7；95%CI 0.9-3.1）。在 ERG 阳性肿瘤中，这种相关性更强（HR 2.8；95%CI 0.9-8.4），而在 ERG 阴性肿瘤中则较弱（HR 1.3；95%CI 0.6-3.0，p-异质性 0.08）。IR 与致命性前列腺癌之间没有关联（HR 0.8；95%CI 0.4-1.9）。这些结果表明，肿瘤 IGF1R 表达可能在前列腺癌向致命表型的进展中发挥作用，并且 ERG 阳性肿瘤可能对 IGF 信号更敏感。这些数据可能有助于我们了解前列腺癌中的 IGF 信号，并为疾病亚型提供治疗选择。
