Adrenomedullin interacts with VEGF in endometrial cancer and has varied modulation in tumours of different grades

ObjectiveEndometrial cancer, in developed countries, is the most common malignancy of the female genital tract. Surgery and radiotherapy are successful in many patients but systemic and recurrent diseases have no consistently effective treatments, and for high grade advanced disease the prognosis is poor. The study investigated characteristics of adrenomedullin in endometrial cancer to assist in identifying targets for developing treatments.MethodsEndometrial samples of women with and without cancer, and the Ishikawa cell line were used to investigate adrenomedullin mRNA regulation, peptide expression, adrenomedullin secretion and effects of adrenomedullin on VEGF secretion.ResultsExpression of adrenomedullin mRNA was upregulated compared to that in healthy post-menopausal endometria. Adrenomedullin secretion was increased by cobalt chloride in this study. Secretion was reduced by the naturally-occurring compounds, (−)-epigallocatechin gallate (EGCG) and 3,4′,5-trihydroxystilbene (resveratrol), which we have previously demonstrated to also suppress VEGF secretion in endometrial tumour tissue. We noted, for the first time, that adrenomedullin enhanced VEGF secretion from tumour cells.ConclusionsIncreased adrenomedullin expression may result in amplifying both tumorigenic and angiogenic activities. A substantial impact on growth of tumours may result in vivo as a consequence of the synergism between adrenomedullin and VEGF. Adrenomedullin, which has altered cellular characteristics in tumour compared to healthy tissue, offers an understudied target with potential to modify endometrial cancer behaviour, complementing other treatments.

► Adrenomedullin mRNA was upregulated in endometrial cancer, and peptide expression was reduced in high grade tumours.
► Adrenomedullin augmented VEGF release, and itself was modified by exogenous factors.
► Adrenomedullin or its receptors may, therefore, be effective non-classical targets to modify endometrial cancer in combinatorial treatments.