Aleksic Tamara, Verrill Clare, Bryant Richard J, Han Cheng, Worrall Andrew Ross, Brureau Laurent, Larré Stephane, Higgins Geoff S, Fazal Fahad, Sabbagh Ahmad, Haider Syed, Buffa Francesca M, Cole David, Macaulay Valentine M
Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU UK.
Br J Cancer. 2017 Nov 21;117(11):1600-1606. doi: 10.1038/bjc.2017.337. Epub 2017 Oct 3.
Activated type 1 insulin-like growth factor receptors (IGF-1Rs) undergo internalisation and nuclear translocation, promoting cell survival. We previously reported that IGF-1R inhibition delays DNA damage repair, sensitising prostate cancer cells to ionising radiation. Here we tested the clinical relevance of these findings.
We assessed associations between IGF-1R and clinical outcomes by immunohistochemistry in diagnostic biopsies of 136 men treated with 55-70 Gy external beam radiotherapy for prostate cancer, comparing results with publicly available transcriptional data in surgically treated patients.
Following radiotherapy, overall recurrence-free survival was shorter in patients whose tumours contained high total, cytoplasmic and internalised (nuclear/cytoplasmic) IGF-1R. High total IGF-1R associated with high primary Gleason grade and risk of metastasis, and cytoplasmic and internalised IGF-1R with biochemical recurrence, which includes patients experiencing local recurrence within the radiation field indicating radioresistance. In multivariate analysis, cytoplasmic, internalised and total IGF-1R were independently associated with risk of overall recurrence, and cytoplasmic IGF-1R was an independent predictor of biochemical recurrence post radiotherapy. Insulin-like growth factor receptors expression did not associate with biochemical recurrence after radical prostatectomy.
These data reveal increased risk of post-radiotherapy recurrence in men whose prostate cancers contain high levels of total or cytoplasmic IGF-1R.
活化的1型胰岛素样生长因子受体（IGF-1R）会发生内化和核转位，从而促进细胞存活。我们之前报道过，IGF-1R抑制会延迟DNA损伤修复，使前列腺癌细胞对电离辐射敏感。在此，我们测试了这些发现的临床相关性。
我们通过免疫组织化学评估了136名接受55-70Gy外照射放疗的前列腺癌男性患者诊断活检中IGF-1R与临床结果之间的关联，并将结果与手术治疗患者公开可用的转录数据进行比较。
放疗后，肿瘤中总IGF-1R、细胞质IGF-1R和内化（核/细胞质）IGF-1R含量高的患者无复发生存期较短。总IGF-1R含量高与高初始Gleason分级和转移风险相关，细胞质和内化IGF-1R与生化复发相关，生化复发包括在放射野内发生局部复发的患者，提示放射抵抗。在多变量分析中，细胞质、内化和总IGF-1R与总体复发风险独立相关，细胞质IGF-1R是放疗后生化复发的独立预测因子。胰岛素样生长因子受体表达与根治性前列腺切除术后的生化复发无关。
这些数据显示，前列腺癌中总IGF-1R或细胞质IGF-1R水平高的男性放疗后复发风险增加。
