Epithelial insulin receptor expression – prognostic relevance in colorectal cancer

// Steffen M. Heckl 1 , Marie Pellinghaus 1 , Sandra Kruger 2 , Clara Bosselmann 1 , Franziska Wilhelm 2 , Hans-Michael Behrens 2 , Stefan Schreiber 1 and Christoph Rocken 2 1 Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany 2 Department of Pathology, Christian-Albrechts-University, Kiel, Germany Correspondence to: Steffen M. Heckl, email: Steffen.Heckl@uksh.de Keywords: colorectal cancer; insulin receptor; cancer risk factor; cancer prognosis; cancer therapeutic target Received: May 15, 2018      Accepted: December 10, 2018      Published: December 25, 2018 ABSTRACT Background: Metabolic reprogramming in cancer encompasses the insulin receptor (IR) as a player of energy homeostasis and proliferation. We aimed to characterize vascular (VIR) and epithelial (EIR) IR expression in CRC and correlate it with clinico-pathological parameters and survival. Methods: 1580 primary CRCs were explored by immunohistochemistry for evaluation of VIR and EIR. Subgroup analyses included in situ hybridization for IR isoform A (IR-A) and DNA mismatch repair protein immunohistochemistry. Clinico-pathological and survival parameters were studied. Results: High VIR was evident in 63.5% of all CRC samples and was associated with T-stage ( P = 0.005). EIR was present in 72.2% and was associated with lower T-stages ( P = 0.006) and UICC-stages ( P < 0.001). EIR negativity was associated with increased metastasis ( P = 0.028), nodal spread ( P < 0.001), lymphatic invasion ( P = 0.008) and a decreased tumor-specific ( P = 0.011) and overall survival ( P = 0.007; 95%–C.I.: 44.5–84.1). EIR negativity in UICC-stage II was associated with a significantly worse tumor-specific ( P = 0.045) and overall ( P = 0.043) survival. IR-A was expressed in CRC vessels and cells. Conclusions: We demonstrate VIR to be frequent in CRC and characterize EIR negativity as an important prognostic risk factor. The association between EIR negativity and worse survival in UICC-stage II should be prospectively evaluated for an application in therapeutic algorithms.