The role of HIF prolyl hydroxylases in tumor progression and metastasis
Final Report Abstract
Hypoxia is a major driving force for tumor vascularization and progression. The transcriptional regulator, hypoxia-inducible factor-1 (HIF-1), is a key regulator of the cellular response to hypoxia in physiological and pathological processes. HIF-1 activity and stability, in turn, are tightly controlled by prolyl and asparaginyl hydroxylases which serve as cellular oxygen sensors. Here, we have studied the function of the prolyl hydroxylase-2 (PHD2) in tumor progression, by modulating PHD2 both in the vascular and in the tumor cell compartment. In order to elucidate the function of the PHD2 in tumor cells, we manipulated its expression in mouse LM-8 osteosarcoma or Lewis Lung Carcinoma (LLC). Inhibition of PHD2 in LM-8 osteosarcoma cells stimulated vessel formation, but paradoxically resulted in a profound reduction of tumor growth. This effect relied on the anti-proliferative activity of the TGFbeta signaling pathway, in a largely HIF-independent manner. Because TGFbeta stimulates the growth of control LM-8 tumors in vivo, we conclude that its growth promoting activity can be reverted by PHD2 silencing. Our findings also reveal an intriguing role for MMP2 and MT1MMP in these settings, as these proteases display an anti-proliferative characteristic through the activation of downstream TGFbeta targets. The growth of transplanted LLC tumors was not affected by endothelial cell-specific ablation of the PHD2 gene in the host, yet vessel number and morphology were altered. Taken together, our data show that PHD2, acting at the tumorvessel interface, controls tumor cell proliferation and influences both tumor angiogenesis and vessel morphology. Modulation of its expression might be a promising strategy for the treatment of cancer.
