title: Adrenomedullin in ovarian cancer: foe in vitro and friend in vivo?
abstract: Stromal elements within a tumor interact with cancer cells to create a microenvironment that supports tumor growth and survival. Adrenomedullin (ADM) is an autocrine/paracrine factor produced by both stromal cells and cancer cells to create such a microenvironment. During differentiation of macrophages, ADM is produced in response to pro-inflammatory stimuli and hypoxia. In this study we investigated the role of ADM as a growth factor for ovarian cancer cells and as a modulator of macrophages. We also analyzed ADM expression levels in a retrospective clinical study using nanofluidic technology and assessment of ADM at the gene level in 220 ovarian cancer patients. To study the effects of ADM, ovarian cancer cell lines A2780, OVCAR-3, and HEY and their drug-resistant counterparts were used for proliferation assays, while monocytes from healthy donors were differentiated in vitro. ADM was a weak growth factor, as revealed by proliferation assays and cell cycle analysis. After culturing cancer cells under stressing conditions, such as serum starvation and/or hypoxia, ADM was found to be a survival factor in HEY but not in other cell lines. In macrophages, ADM showed activity on proliferation/differentiation, primarily in type 2 macrophages (M2). Unexpectedly, the clinical study revealed that high expression of ADM was linked to positive outcome and to cancer with low Ca125. In conclusion, although in vitro ADM was a potential factor in biological aggressiveness, this possibility was not confirmed in patients. Therefore, use of an ADM antagonist would be inappropriate in managing ovarian cancer patients.
authors.affiliation: Department of Oncology, Catholic University of the Sacred Heart, Campobasso, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Baranello
authors.forename: Marisa
authors.initials: M
authors.lastname: Mariani
authors.forename: Mirko
authors.initials: M
authors.lastname: Andreoli
authors.forename: Mara
authors.initials: M
authors.lastname: Fanelli
authors.forename: Enrica
authors.initials: E
authors.lastname: Martinelli
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ferrandina
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.forename: Shohreh
authors.initials: S
authors.lastname: Shahabi
authors.forename: Cristiano
authors.initials: C
authors.lastname: Ferlini
mesh_terms: D000231:Adenocarcinoma, Papillary / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018394:CA-125 Antigen / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016895:Culture Media, Serum-Free; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008264:Macrophages / Q000378:metabolism / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies
chemical_list: D018394:CA-125 Antigen; D016895:Culture Media, Serum-Free; D016207:Cytokines; C451759:MUC16 protein, human; D008565:Membrane Proteins; D053607:Adrenomedullin