Correlation of Volumetric Perfusion CT Parameters with HIF-1 alpha Expression in Rabbit VX2 Tumor Model

Abstract

Introduction: Angiogenesis is essential for tumor growth and adaptation to hypoxia of the tumor. Hypoxia inducible factor-1alpha (HIF-1α), a major regulator of adaptation to hypoxic stress, facilitates tumoral angiogenesis, growth and aggressive tumoral behavior such as invasion or metastasis. HIF-1α overexpression relates with increase of disease mortality and resistance to chemo- or radiation therapy. Perfusion CT is one of feasible techniques to evaluate tumor vascularity and it provides regional maps and quantitative measurements of various hemodynamic parameters of tumors. Therefore, the purpose of this study was to investigate the relationship between perfusion CT parameters and HIF-1α expression in a VX2 tumor rabbit model. Methods: VX2 carcinoma tumors implanted in bilateral back muscle of 10 rabbits were evaluated with perfusion CT. Serial perfusion CT was performed on 7days, 10days and 14 days after tumor implantation. CT Perfusion data were analyzed to calculate blood flow (BF), blood volume (BV), and permeability of the whole tumor and the nonnecrotic peripheral area. These parameters were correlated with intratumoral HIF-1α expression. For statistical analysis, Spearman rank correlation analysis and Mann-Whitney test were used. Results: A total of 20 tumors were analyzed for HIF-1α expression. HIF-1α was expressed in twelve tumors

2, 3 and 7 tumors were classified as score 1, 2 and 3. Five (5/6, 83.3%), 4 (4/6, 66.7%) and 3 (3/8, 37.5%) tumors were obtained on days 7, 10, and 14 after tumor implantation. Permeability of the whole tumor showed significant positive correlation with HIF-1α score (r = 0.45, p < 0.05). Permeability of the periphery showed more significant positive correlation with HIF-1α score (r = 0.89, p < 0.001). Permeability of HIF-1α positive group was significantly higher than HIF-1α negative group (p < 0.05

the whole tumor, p < 0.001

the periphery). Conclusions: In VX2 tumor, HIF-1α expression positively correlated with permeability from perfusion CT imaging and the correlation of the periphery was stronger than the whole tumor. Perfusion CT can be used as surrogate marker in the surveillance of HIF-1α activity.