Adrenomedullin in Ovarian Cancer: Foe In Vitro and Friend In Vivo?

Cinzia Baranello,Mirko Andreoli,Marisa Mariani,Giovanni Scambia,Shohreh Shahabi,Mara Fanelli,Gabriella Ferrandina,Cristiano Ferlini,Enrica Martinelli,Konradin Metze

doi:10.1371/journal.pone.0040678

Cinzia Baranello, Mirko Andreoli + Show 8 more

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https://doi.org/10.1371/journal.pone.0040678

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Journal: PloS one	Publication Date: Jul 30, 2012
Citations: 31	License type: CC BY 4.0

Affiliation: Università Cattolica del Sacro Cuore, Danbury Hospital

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.

Highlights

Cancer microenvironment is a topic that has recently begun to interest investigators
In order to evaluate the effects of ADM on the growth of ovarian cancer cell lines, OVCAR-3, OVCAR-EPO10, and A2780 and its paclitaxel-resistant counterparts TC1 and TC3 cells were treated with recombinant human ADM at 1, 10, and 100 nM concentration for 72 hours
This mechanism seems relevant in clear-cell renal carcinoma, a disease characterized by intensified vascularization inside the tumor [16]

Summary

Introduction

Cancer microenvironment is a topic that has recently begun to interest investigators. For years research focused on the cancer cell itself, but a solid tumor contains nonmalignant stromal elements, including macrophages, lymphocytes, mast cells, endothelial cells, fibroblasts, myofibroblasts, pericytes, and mesenchymal stem cells, all of which interact with cancer cells to create a microenvironment that supports tumor growth and survival [1,2]. Receptors for chemokines are expressed in a variety of infiltrating cells, including macrophages, which are recruited by chemokines [4]. This interaction is a 2-way process: ovarian cancer cells are capable of modulating the macrophage phenotype, since the cytokines and cell surface receptors which are induced in co-cultured macrophages in vitro are detected in human ovarian cancer [5]. ADM is capable of promoting angiogenesis and melanoma growth [6] both via the paracrine effect, mediated by the endothelial nitric oxide synthase signaling pathway, and by the autocrine effect, which stimulates the polarization of macrophages toward an alternatively activated phenotype (M2)

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