Original Scientific Paper 336 Regulation of tumor growth and angiogenesis in colorectal cancer 1 3 Summary Background Hypoxia in malignant tissues is associated with poor prognosis and treatment options. It is obvious that the grade of malignancy is associated with dediffer- entiation of a given tissue. Our aim was to assess the ex- pression of proteins that act as cellular oxygen sensors, which directly regulate the hypoxia-inducible factor 1 (HIF-1) pathway, i.e., prolyl hydroxylase domain pro- teins (PHD) PHD-1, PHD-2, PHD-3, and its target gene vascular endothelial growth factor (VEGF) in colorectal cancer (CRC). Methods In this study, we cultured a human colon cancer cell line (SW480) and its correspondent lymph- node metastasis cell line (SW620) under normoxic or hypoxic conditions for different time periods. We then measured the HIF-1α expression using Western-Blot, the messenger RNA (mRNA)-expression of the PHDs with real-time polymerase chain reaction (PCR) and the amount of one of the target-genes using an VEGF-ELISA. Results SW620 shows a clearly elevated HIF-1α ex- pression under normoxic and hypoxic states compared with SW480. Under hypoxic conditions, the amount of VEGF is elevated in both primary and secondary tumor- cell line, but the metastasis-cell line has a significant higher increase. PHD-1 shows no higher expression un- der hypoxic condition, PHD-2 expression is elevated but only in SW480. PHD-3 levels raised in both of the cell lines, with significant higher rates in SW480. Conclusions HIF-regulating proteins are highly ex- pressed in CRCs and their metastases. ese molecules play an important role in the control of hypoxia-induced genes and may also have a function in the regulation of cellular proliferation and differentiation during tumori- genesis and dedifferentiation of CRCs. Our results em- phasize the important role of PHDs not only as an oxy- gen-sensor, but also as a control-unit for tumor growth, apoptosis, and angiogenesis through HIF-1 pathway. Keywords: Hypoxia, Angiogenesis, Colorectal cancer, Metastasis Introduction e accessibility of oxygen is a pivotal part of every life form. Hypoxia-inducible factor 1 (HIF-1) is a dimer (α/β) transcriptional factor binding to hypoxia-responsive ele- ments, supporting the production of vascular endothelial growth factor (VEGF) [1, 2]. HIF-1-deficient cells show a decreased ability for tumor growth [3]. Tumor-cells often posses increased levels of HIF-1α and are relatively hypoxia resistant [4]. While growing, solid tumors show a decline of oxygen tension within its tissue. For colon- or rectal carcinoma and especially for its liver- and lymph- node metastases, it is accepted that tissue-immanent hypoxia induces a specific epigenetic expression profile [5]. For certain entities such as renal cell carcinoma, pancreatic endocrine tumors or nonsmall cell lung car- cinoma (NSCLC), it is known that hypoxia-related tran- scriptional factors advocate tumor growth and protect cells against apoptosis; for colorectal carcinoma and especially its metastases, the level of evidence is much lower [5–7]. Under normoxic conditions, HIF-1α is destabilized by three different oxygen-sensing enzymes called prolyl hydroxylase domain proteins (PHD) [8]. e relevance of the HIF-1 regulation system for tumor growth and progression is demonstrated by numerous mechanisms Eur Surg (2012) 44:336–340 DOI 10.1007/s10353-012-0160-1 Regulation of tumor growth and angiogenesis in colorectal cancer J. Nolde, C. deWit, E. Schloericke, H.-P. Bruch, T. Laubert Dr. J. Nolde () · Dr. E. Schloericke · Prof. Dr. H.-P.  Bruch · Dr. T. Laubert Department of Surgery, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany e-mail: jan.nolde@uni-luebeck.de Prof. Dr. C. deWit Institute of Physiology, University of Luebeck, Luebeck, Germany Received: 11 May 2012 / Accepted: 1 August 2012 / Published online: 8 November 2012 © Springer-Verlag Wien 2012