**6. Role of HE4 in tumorigenesis**

HE4 promotes tumorigenesis through its pro-angiogenic effects. Various studies have shown the role of HE4 in tumour angiogenesis. HE4 modulates angiogenesis by regulating the expression of different genes in multiple cell types of the tumour environment [19]. HE4 activates protein kinase B (AKT) which plays a role in tumour angiogenesis [41, 42]. James et al. have shown that HE4 activates signal transducer and activator of transcription 3 (STAT3) signalling pathway which up-regulates the

*Role of Human Epididymis Protein 4 in Tumour Angiogenesis DOI: http://dx.doi.org/10.5772/intechopen.105678*

pro-angiogenic genes interleukin 8 (IL8), hypoxia inducible factor 1A (HIF1A) in ovarian cancer cells, endothelial cells, and immune cells [19, 42, 43]. Levels of both HE4 and the pro-angiogenic factors were found elevated in ovarian cancer tissue in comparison to adjacent normal ovarian tissue [19, 42]. IL8 and HIF1A are potent angiogenic factors that promote tumour vessel formation and tumour growth [42]. IL8 also leads to persistent neutrophil recruitment in the tumour tissue which stimulates neoangiogenesis [44, 45]. HIF1A plays a role in hypoxic adaptation of cancer cells [46, 47]. STAT3 inhibitors block the effect of HE4- mediated tube formation of endothelium by suppressing STAT3 activation and down-regulating IL8 and HIF1A [19]. HE4 has been shown to be associated with increased levels of matrix metalloproteinases which are responsible for angiogenesis [48, 49]. Levels of HE4 and interleukin-1 alpha (IL1A) are directly proportional [50, 51]. IL1A promotes VEGF formation [52]. Annexin II (ANXA2) too is involved in angiogenesis and its gene expression has been increased by HE4 [53]. HE4 has also been found to promote tube formation in in-vitro model of angiogenesis [19]. Serum levels of HE4 positively correlated with the microvascular density in ovarian cancer tissue as reflected by the increased CD34+ areas in the tumour tissue. However, the new vessel formation is dysregulated [19]. These dysfunctional tumoral vasculature impair the movement of cytotoxic T cells along with other immune cells involved in host's anti-tumour immune responses [54].
