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.

The Interaction of Adrenomedullin and Macrophages Induces Ovarian Cancer Cell Migration via Activation of RhoA Signaling Pathway

“…However, a recent study reported the opposite, namely that high expression level of ADM in primary tumors was related to a better outcome. They also observed that, for the vasoactive properties, actually the peptide could increase perfusion and chemotherapy sensitivity [22]. The inconsistency might be attributed to the differences within the study populations and/or designs, which makes the precise function of ADM in this disease more complicated.…”

“…Consistently, Baranello C. et al . noticed in vitro the capability of ADM to stimulate M2 differentiation [22]. We therefore considered that ADM, derived from ovarian cancer cells, might be a novel target to inhibit macrophages polarization.…”

Adrenomedullin and tumour microenvironment

“…Tumour cell lines evaluated included small cell lung carcinomas, non-small cell lung carcinomas, breast, nervous system (glioblastoma, neuroblastomas), ovarian, prostate, adrenal, chondrosarcoma, and chronic monocytic leukemia [ 166 ]. These data have been replicated on different tumour cell lines such as pancreatic cell lines (PANC1, L3.6, HPAFII, SU86.86) [ 110 , 116 , 169 ], gliomas [ 170 , 171 ], prostate cancer cell lines [ 162 , 172 – 175 ], ovarian cancer [ 149 , 176 , 177 ], osteosarcoma [ 109 ], renal carcinoma [ 121 , 178 ], multiple myeloma [ 179 ], bladder urothelial cell carcinoma [ 120 ], pituitary adenomas [ 145 ], colorectal cancer [ 119 , 147 , 148 ], breast cancer [ 144 ], endometrial cancer [ 38 ], hepatocellular carcinoma [ 132 ] and others.…”

“…AM gene expression levels may play a key role in the biology of epithelial ovarian cancer and may define a more aggressive tumour phenotype [ 124 ]. However, recent studies performed in ovarian cancer patients by Baranello et al found high expression levels of AM as a positive prognostic factor [ 149 ]. In hepatocellular carcinoma, AM expression was positively correlated with invasion and progression [ 132 , 133 ].…”

“…AM can stimulate cell growth and inhibit apoptosis in a variety of tumour cells, including prostate cancer [ 172 , 174 , 175 ], ovarian cancer [ 149 , 176 ], osteosarcoma [ 109 ], renal carcinoma [ 178 ], bladder carcinoma [ 120 ], breast cancer [ 186 ], colorectal cancer [ 119 , 148 ], gliomas [ 170 ], and hepatocellular carcinoma [ 132 ].…”