1 Det Sundhedsvidenskabelige Fakultet, SDU2 Department of Biochemistry, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU3 Clinical Pathology, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU4 Department of Oncology, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU5 Department of Oncology, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU6 Clinical Pathology, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU7 Department of Biochemistry, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU
Clinical Aspects of Hypoxia-inducible Factors in Colorectal Cancer Birgitte Mayland Havelund1,4 MD, Karen-Lise Garm Spindler1,4 MD, PhD, Flemming Brandt Sørensen2,4 MD, DMSc, Ivan Brandslund3 MD, DMSc, Anders Jakobsen1,4 MD, DMSc. 1Department of Oncology, 2Pathology and 3Biochemistry, Vejle Hospital, Vejle, Denmark 4Institute of Regional Health Services Research, University of Southern Denmark, Odense Denmark Background Prognostic and predictive markers are needed for individualizing the treatment of colorectal cancer. Hypoxia-inducible factor 1α (HIF-1α) is a transcription-inducing factor which activates transcription of numerous genes associated with angiogenesis, ATP-metabolism, cell-proliferation, glycolysis and apoptosis. HIF-1α is over expressed in many malignant tumors and is reported to play an important role in tumor invasion and progression. The aim of this Ph.D. project is to investigate the predictive and prognostic value of HIF-1α in colorectal cancer. Materials and Methods The project is divided into 3 substudies: 1. Biological and methodological aspects. The expression of HIF-1α measured by immunohistochemistry in paraffin embedded tissue is related to single nucleotide polymorphism (SNP), neoangiogenesis and other markers. The role of preanalytic treatment of the tissue including peroperative ischemia is investigated in biopsies taken preoperatively with momentarily fixation compared to the resected rectal tumor. Tumor heterogeneity is explored in biopsies taken according to a standardized scheme. 2. The prognostic value of HIF-1α is investigated by SNP analysis and HIF-1α expression in tissue from 300 patients operated for colorectal cancer and the results is validated in a prospectively population of 200 patients. 3. The predictive value of HIF-1α will be investigated in patients with locally advanced rectal cancer, treated with preoperative chemoradiation (CRT). Preliminary Results Expression of HIF-1α has been investigated in diagnostic biopsies from 58 rectal tumors who received preoperative long-course CRT. An association was found between major response to CRT as measured by tumor regression grade (TRG) and strong intensity of the nuclear HIF-1α staining of tumor cells (p=0,04), the same applied to staining of >10% of the cancer stromal cells (p=0,03). Conclusion: Results are hypothesis generating and need to be validated.