Roles of Polo-like kinase 3 in suppressing tumor angiogenesis

When tumors grow to a certain size, a severe hypoxic microenvironment develops within the tumor mass [1]. Simple diffusion of oxygen and nutrients becomes insufficient to meet the demand of fast growing tumors [1]. It is believed that tumor size generally will not exceed 1 centimeter in diameter without the support of angiogenesis [2]. Tumor angiogenesis is a process leading to formation of vasculature that supplies the growth of solid tumors [1,2]. Logically, tumor angiogenesis tends to be more pronounced in aggressive and malignant tumors [3]. Since the initial discovery of tumor angiogenesis four decades ago [4], tumor angiogenesis has emerged as an important target for cancer therapy [1,2,5-7]. Many inhibitors of tumor angiogenesis have been developed and used in clinical application or is in the pipeline leading to clinics [1,2,6,7]. Since highly vascular tumors tend to have much higher potential for metastasis [8], these inhibitors of angiogenesis may have the added value of blocking tumor metastasis, thus making them more effective for cancer treatment.A primary consequence of increased tumor size is hypoxia, a result of oxygen restriction in the tumor mass. Hypoxia triggers tumor angiogenesis by activating the cellular hypoxia response pathways [1]. Located in the center of these pathways are the hypoxia inducible factors (HIFs) including the well characterized HIF-1 [1,9-11]. HIF-1 is a transcription factor that promotes transcription of a series of genes such as vascular endothelial growth factor (VEGF) that are critical for the cellular hypoxic response [1,5].HIF-1α is the inducible subunit of the HIF-1 transcription factor, whose protein level can be dramatically induced upon exposure to hypoxia [1,9-11]. The cellular level of HIF-1α protein is regulated primarily at the post-translational level [1,9-11]. The HIF-1α gene is constitutively transcribed and translated [1,9-11]. Under normoxic conditions, HIF-1α protein is hydroxylated by prolyl hydroxylases