**4. Role of HE4 in the pathogenesis of ovarian cancer**

HE4 is also involved in the pathogenesis of ovarian cancer. It aids in cellular proliferation, tumour growth, metastatic ability, chemoresistance and suppresses cytotoxic effect of mononuclear cells on ovarian carcinoma cells [18]. An inverse relationship between serum HE4 levels and CD8+ T cells in EOC has also been noted [19, 20].

Angiogenesis is one of the hallmarks of cancer and is necessary for bringing oxygen and nutrients to tumour cells and removal of waste products. It aids in tumour growth and invasion [21].

Hypoxia inducible factor 1 alpha (HIF1a) is a transcription factor that is involved in adaptation of cells to a hypoxic environment through its pro-angiogenic actions.

Interleukin 8 (IL-8) is also an important pro angiogenic factor produced by infiltrating macrophages in the tumour. Both of these factors are up-regulated by STAT3.

Recent studies have shown that HE4 promotes angiogenesis and is dependent on intact STAT3 signalling for its action. The addition of STAT3 inhibitors ablated elevated HIF1a levels in an in vitro experiment involving ovarian cancer cell lines and also blocked tube formation in human umbilical vein endothelial cell [19].

Several patients of ovarian cancer experience a chemo resistant recurrence within 2 years after first line therapy (cytoreduction surgery and platinum based chemotherapeutics) [18].

The diverse effects of HE4 that aid in tumour progression makes it an attractive therapeutic target for EOC and may serve as a effective treatment option for recurrent chemoresistant cases.

HE4 is produced as a, 13 kDa protein and converted to a, 25 kDa secreted glycosylated protein. HE4 is a highly over-expressed in epithelial ovarian cancer (EOC) [15, 22–24] compared to normal ovarian epithelium. US-FDA has approved HE4 as a biomarker for the diagnosis of ovarian cancer especially in the presence of an adnexal mass as part of the Risk of Ovarian Malignancy Algorithm (ROMA) [2].
