Insulin-like growth factor 1 receptor affects the survival of primary prostate cancer patients depending on TMPRSS2-ERG status

Abstract

BackgroundProstate cancer (PCa) is characterized by clinical and biological heterogeneity and has differential outcomes and mortality rates. Therefore, it is necessary to identify molecular alterations to define new therapeutic strategies based on the risk of progression. In this study, the prognostic relevance of the insulin-like growth factor (IGF) system was examined in molecular subtypes defined by TMPRSS2-ERG (T2E) gene fusion within a series of patients with primary localized PCa.MethodsA cohort of 270 formalin-fixed and paraffin-embedded (FFPE) primary PCa samples from patients with more than 5 years’ follow-up was collected. IGF-1R, IGF-1, IGFBP-3 and INSR expression was analyzed using quantitative RT-PCR. The T2E status and immunohistochemical ERG findings were considered in the analyses. The association with both biochemical and clinical progression-free survival (BPFS and PFS, respectively) was evaluated for the different molecular subtypes using the Kaplan-Meier proportional risk log-rank test and the Cox proportional hazards model.ResultsAn association between IGF-1R overexpression and better BPFS was found in T2E-negative patients (35.3% BPFS, p-value = 0.016). Multivariate analysis demonstrated that IGF-1R expression constitutes an independent variable in T2E-negative patients [HR: 0.41. CI 95% (0.2–0.82), p = 0.013]. These data were confirmed using immunohistochemistry of ERG as subrogate of T2E. High IGF-1 expression correlated with prolonged BPFS and PFS independent of the T2E status.Conclusions IGF-1R, a reported target of T2E, constitutes an independent factor for good prognosis in T2E-negative PCa. Quantitative evaluation of IGF-1/IGF-1R expression combined with molecular assessment of T2E status or ERG protein expression represents a useful marker for tumor progression in localized PCa.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3356-8) contains supplementary material, which is available to authorized users.

Expression of IGF/insulin receptor in prostate cancer tissue and progression to lethal disease

“…The only other cohort study that has investigated cancer outcomes examined mRNA expression of IGF1R and IR in among 270 patients and used biochemical recurrence rather than lethal prostate cancer as the end point (14). Although they found a positive correlation between IGF1R, IR and ERG, they found that IR and IGF1R expression were downregulated in tumor versus benign tissue, which contrasts with our study findings.…”

“…There is limited evidence to date on IGF1R and IR expression in tumor tissue and prostate cancer progression in patient cohorts, and none have used lethal disease as an end point (14). We hypothesized that higher tumor expression of IGF1R and IR would be associated with an increased risk of lethal prostate cancer, with a stronger effect in men whose tumors were positive for ERG.…”

The role of insulin-like growth factors in the development of prostate cancer

“…In a follow-up, IGF-IR expression showed a borderline association with increased risk of lethal disease [136]. In contrast a study of samples from 270 men with more than 5 years follow-up reported that in men who were negative for the TMPRSS2-ERG gene fusion, high IGF-IR was associated with prolonged biochemical progression free survival [137].…”

Updates on Molecular and Biochemical Development and Progression of Prostate Cancer

“…For instance, a recent comprehensive systematic review and meta-analysis suggested a link between milk ingestion and PCa through the modulation of IGFs [ 20 ]. Another clinical study linked the prognosis of PCa to the overexpression of IGFR-1 receptor in transmembrane serine protease 2-erythroblast transformation-specific-related gene (TMPRSS2-ERG) (T2E) gene-negative subgroup of patients [ 21 ].…”