**8. Hypoxia inducible factor (HIF): the forgotten pathway**

Hypoxia and induction of hypoxia-inducible factors (HIF) is a hallmark of many tumors [78, 79].

HIF-1 is a heterodimeric transcription factor discovered in 1991 [80], and is composed of two subunits, α and β. The HIF-1α subunit is oxygen sensitive and it is induced by hypoxic conditions, which are very common in cancer. Direct transcriptional targets of HIF-1 include genes regulating, among others, growth and apoptosis, cell migration, energy metabolism, angiogenesis, vasomotor regulation, matrix and barrier functions, and transport of metal ions and glucose [81].

In normoxic conditions, the HIF-1α unit is downregulated by Vitamin C dependent hydroxylases, while in hypoxic conditions (such as those existing in many different types of cancer), HIF-1α hydroxylation is repressed with consequent increase in HIF-dependent gene transcription, neo-angiogenesis, and tumor growth and progression [82].

More importantly, since Vitamin C stimulates HIF-1α prolyl hydroxylases, low levels of Vitamin C promote tumor growth and progression, by reducing HIF-1α hydroxylation [83], thereby stabilizing HIF1-α. On the contrary, high levels of HIF render cancer cells more sensitive to Vitamin C-induced toxicity. To confirm this view, Kuiper and Coll. [84] have recently found an inverse relationship between intra-tumor levels of Vitamin C and HIF activity in both endometrial cancer [85] and colorectal carcinoma (CRC) [86].

In 1925, Otto Warburg observed that cancer cells manifest increased rates of lactate production under aerobic conditions ("Warburg Effect") or, in other words, they preferentially utilize glycolysis, instead of oxidative phosphorylation, for metabolism even in the presence of oxygen [87, 88].

"Hypoxia" (low oxygen concentration) is a hallmark of solid tumors, usually occurring at the center of the tumor mass, where blood vessels are abnormal or insufficient to supply adequate amounts of oxygen [89].

In response to the reduced oxygen tension, the HIF is activated to mediate the primary transcriptional adaption to hypoxic stress in cancer cells [90, 91].

As previously mentioned, HIFs regulate angiogenesis, cell survival, proliferation, apoptosis, adhesion, and metabolism by transcriptionally activating downstream targets such as vascular endothelial growth factor and erythropoietin. Therefore, HIF (HIF1, in particular) plays a major role in tumor growth, and clinical data suggest that the upregulation of HIF, as determined by the low oxygen tension, is usually associated with increased mortality in a number of different cancers [92–94], and may represent a relevant target for new therapeutic approaches to the disease [95–97].
