**4. Similarities between tumor growth and cyst growth in ADPKD**

The polycystin proteins PC1 and PC2 have been likened to tumor suppressors associated with many types of neoplasia (Grantham, 2001). Thus, when polycystin function is impaired as in ADPKD, cells revert to a more de-differentiated state marked by high proliferative capacity (Song et al., 2009). It has been recognized for many years that angiogenesis is necessary to support tumor growth (Folkman, 1971). Moreover, many non-neoplastic diseases including macular degeneration, arthritis and endometriosis are angiogenesis dependent (Folkman, 2006). Thus a facilitative role for angiogenesis in ADPKD cyst growth is suggested. Tumor cell expression of angiogenic growth factors including VEGF is mediated by hypoxia (Pugh and Ratcliffe, 2003). Central to the hypoxia response pathway are HIF-1 and 2. HIF-1 is targeted for destruction via the ubiquitin pathway regulated by Von Hippel Lindau (VHL) protein. Inactivation of VHL results in an increase of HIF-1 and VEGF level (Na et al., 2003). In progressive renal disease human proximal tubular epithelial cells demonstrate activation of intracellular hypoxia response pathways and VEGF signaling despite attenuated expression of VEGF-A (Rudnicki et al., 2009). Growth of renal cysts results in compression of the surrounding blood vessels. Significantly, an up-regulation of hypoxia-angiogenic pathways has been reported based on a systems biology approach in ADPKD (Song et al., 2009). A further key mediator of angiogenesis is the tumor suppressor gene phosphatase and tension homolog deleted on chromosome 10 (PTEN) which is frequently deficient or inactivated in human cancers (Mirohammadsadegh et al., 2006; Ohgaki & Kleihues, 2007; Tam et al., 2007). Activation of mammalian target of rapamycin (mTOR) is a feature of ADPKD and this pathway is regulated by PTEN (Boletta, 2009; Rosner et al., 2008; Shillingford et al., 2006). Thus the literature supports similarities between tumorigenesis and ADPKD and underscores a potential role for angiogenesis in ADPKD cyst growth.
