and cancer Sample Clauses

and cancer. Overexpression of HIF-1α and subsequently of HIF-1 dependent genes contributes to the phenotype of many solid tumors. Greater than 70% of human cancers across more than 13 tumor types have to found to have overexpressed HIF-1 (166, 167). Moreover, there is a negative correlation between HIF-1α overexpression and patient survival especially in the case of breast, endometrial, and esophageal cancers (168-172). This overexpression is typically due to genetic alterations. Loss of function of the tumor suppressor PTEN can augment the expression of HIF-1α and therefore can increase HIF- 1-mediated gene expression (173, 174). Gene deletion or inactivating deletion of p53 also further enhances HIF-1α accumulation. Additionally, gain-of-function mutations in the P13K and MAPK pathways upregulate HIF-1. In most of these cases, upregulation of HIF-1 activity seem to occur in the earliest detectable stages of neoplastic lesions (175). The greatest effects of HIF-1 regulation are observed in most renal cell carcinomas (RCCa), which have lost functional VHL and therefore have constitutively expressed HIF-1α. Lost of VHL is caused by inactivating mutations and is common in hereditary cancer syndromes, particularly in central nervous system hemangioblastomas and solid tumors including renal carcinomas (176). VHL-disease is commonly associated with the sporadic formation of tumors. Reintroduction of VHL into renal carcinoma cell lines reverses tumorigenicity. Therapeutic anti-HIF strategies The high extent of HIF-1 regulation highlights its importance in cellular responses and cancer biology. Due to the many mechanisms of HIF-1 upregulation in response to hypoxia and cellular stress, several strategies have been postulated to inhibit the HIF-1 pathway. These strategies include inhibiting HIF-1 mRNA or protein expression by decreasing the rate of protein synthesis and/or increasing the rate of degradation, inhibiting the binding of HIF-1 to DNA, or inhibiting the transcriptional activity of the HIF-1 complex. A majority of the focus in preventing the induction of the HIF-1 pathway is on small molecule development (177, 178). This has taken the form of agents like the natural product echinomycin which specifically targets HIF-1 DNA binding or chetomin, which disrupts the interaction between HIF-1 and its coactivator p300. Additional efforts have been ongoing to develop small molecule inhibitors that hinder the dimerization of the alpha and beta HIF-1 subunits. Currently, the...