Prognostic assessment of hypoxia and metabolic markers in cervical cancer using automated digital image analysis of immunohistochemistry

Abstract

BackgroundHypoxia inducible factor-1 alpha (HIF-1α), induced by tumor hypoxia, regulates tumor cell metabolism and metastasis by up-regulation of c-Met, carbonic anhydrase 9 (CA9) and glucose transporter 1 (GLUT1). The prognostic significance of hypoxia and metabolic markers is not clearly defined in cervical cancer. Here, we have examined the primary players in the hypoxia signaling pathway, by immunohistochemistry, but confirming their interactions, as well as defining which proteins are associated with outcome.MethodsThe study subjects were comprised of cervical intraepithelial neoplasia (CIN, n = 209), carcinoma in situ (CIS, n = 74), cervical cancer (n = 179), and matched nonadjacent normal tissues (n = 357). Immunohistochemistry (IHC) was performed to identify HIF-1α, c-Met, CA9, and GLUT1. IHC scoring was performed using automated digital image analysis and the association of hypoxic markers with prognostic outcome was evaluated.ResultsHIF-1α, c-Met, CA9 and GLUT1 expression were higher in cervical cancer than in CIN and normal cervix (all P < 0.001). Among these markers, expression of HIF-1α and c-Met were significantly different in FIGO stage (P < 0.001 and P = 0.019, respectively) and patients with lymph node metastasis (P < 0.001 and P = 0.010, respectively). HIF-1α expression was correlated with c-Met expression in cervical cancer (P < 0.001). High expression of HIF-1α and c-Met showed worse 5-year overall survival rate (P = 0.047 and P = 0.005, respectively) than low expression group, but CA9 and GLUT1 did not show significant survival difference. After adjusting the prognostic covariates, c-Met was found to be an independent risk factor (HR=3.27; 95% CI, 1.05-10.23, P = 0.041) for overall survival in cervical cancer.ConclusionsWe demonstrate that c-Met correlates with HIF-1α and is a poor prognostic factor in survival in cervical cancer.

Glucose transporter GLUT1 expression and clinical outcome in solid tumors: a systematic review and meta-analysis

“…The main characteristics of included researches were presented in Table 1. Five researches appraised colorectal cancer [20–23, 33], five evaluated orals squamous cell carcinoma [24–28], three evaluated cervical cancer [35, 36, 38], two studies evaluated lung cancer [14, 15], two evaluated breast cancer [16, 17], two studies evaluated pancreatic cancer [19, 34] and one each evaluated esophageal cancer [18], hepatocellular carcinoma[10], gallbladder carcinoma [19], bladder cancer [29], ovarian cancer [30], head and neck squamous cell carcinoma [31], renal cancer [37], and salivary gland tumor [32]. All these 26 studies evaluated GLUT1.…”

Novel predictive biomarkers for cervical cancer prognosis

“…Direct measurement of oxygen levels in tumor tissues presents technical limitations, which has promoted the use of endogenous and exogenous markers associated with tumor hypoxia, endogenous markers including hypoxia-related proteins (HIF-1α, GLUT-1, CAIX) and exogenous markers including bio-reductive drugs (34)(35)(36). In the evaluation of GLUT 1 and CAIX in this study, tumor hypoxia was measured indirectly.…”

F-18 Fluoromisonidazole for Imaging Tumor Hypoxia: Imaging the Microenvironment for Personalized Cancer Therapy

“…Pre-therapy hypoxia and FMISO uptake in predicting prognosis has been confirmed in several human studies - glioblastoma multiforme (GBM), head and neck cancer 5853, 56, 101, 102 , lung cancer, 103, 104 , breast cancer 105 pancreatic cancer, 9 gynecologic cancers – cervical cancer 106 and sarcoma 107 as demonstrated in the following images. (Figures 4 – 7)…”