Hypoxia and angiogenesis in colorectal liver metastases

HYPOXIA AND ANGIOGENESIS IN COLORECTAL LIVER METASTASES Dr LJ Marshall MBChB Introduction Despite surgical resection being the only potential cure for colorectal liver metastases, not all patients are suitable for operative intervention. Most patients who undergo surgery die of recurrent disease. Understanding tumour behaviour may identify patients who might benefit from targeted adjuvant therapy. Tumour hypoxia and angiogenesis are a negative prognostic factor in various solid tumours. Carbonic anhydrase IX (CAIX), epidermal growth factor receptor (EGFR), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) have been associated with poor outcome. The aim of this study was to determine the prognostic significance of CAIX, EGFR, MMP-2 and MMP-9 in patients with colorectal liver metastases. Methods Patients having undergone a liver resection for colorectal liver metastases at our institutions between 1993 and 1999 were included. Standard immunohistochemical techniques were used to study the expression of CAIX, tumour necrosis, EGFR, MMP-2 and MMP-9 in 5pm tumour sections from paraffin-embedded tissue blocks. These factors were correlated with clinico-pathological data, microvessel density and vascular endothelial growth factor expression using the chi-squared test. The KaplanMeier method and log rank test were used for univariate survival analysis and the Cox proportional hazard model for multivariate survival analysis. Results 181 patients, male n=121, female n=60, aged between 25-81 years (mean 61 years) were included. Tumour necrosis, membranous CAIX and membranous EGFR were significantly correlated with poor survival on univariate (p=0.0002, p=0.002 and p=0.01 respectively) and multivariate analysis (p=0.019, p<0.0001 and p=0.027 respectively). MMP-9 significantly correlated with tumour edge contiguous vessels and central tumour vessels. MMP-2 correlated with membranous CAIX. Conclusion CAIX, EGFR and tumour necrosis are independent negative prognostic factor in patients with colorectal liver metastases. MMP-2 and MMP-9 may have an important role in tumour invasion. A C K N O W L E D G E M E N T S To Ken: thank you for your supervision and never-ending theories and ideas. To Dave: thank you for my full salary, much appreciated! By the way, have you any red ink left? To Louise Jones, Professor Louise Jones, for your immeasurable help and support in the interpretation of immunohistochemistry. I had been under the impression that different shades of brown and pink were only found on Changing Rooms. To Donna, Karen and everybody in the Cancer Translational Research Group and Breast Cancer Research Unit: thank you for your support, especially in the battle of the HIF. To everybody in the Specials Histopathology Laboratory at the Leicester Royal Infirmary, especially Tracy and Diana: thank you for your guidance. Xylene shouldn’t look cloudy, right? To Professor Furness. Thank you for letting me utilise the microscope. This button should save my photographs. oh dear. To Chris: thank you for your support and encouragement. C O N T E N T S Page Numbers Title i Abstract ii Acknowledgements iii List of