Stromal fibroblasts present in breast carcinomas promote tumor growth and angiogenesis through adrenomedullin secretion

Zohra Benyahia (1) , Nadège Dussault (1) , Mylène Cayol (1) , Romain Sigaud (1) , Caroline Berenguer-Daizé (1) , Christine Delfino (1) , Asma Tounsi (1) , Stéphane Garcia (2) , Pierre-Marie Martin (1) , Kamel Mabrouk (3) , L’houcine Ouafik (1, 4)

1 CRO2 - Centre de Recherches en Oncologie biologique et Oncopharmacologie
2 Laboratoire d'anatomie pathologique - [Hôpital Nord - APHM]
3 ICR - Institut de Chimie Radicalaire
4 Laboratoire de Transfert d'Oncologie Biologique [Hôpital Nord - APHM]

Tumor-or cancer-associated fibroblasts (TAFs or CAFs) are active players in tumorigenesis and exhibit distinct angiogenic and tumorigenic properties. Adrenomedullin (AM), a multifunctional peptide plays an important role in angiogenesis and tumor growth through its receptors calcitonin receptor-like receptor/receptor activity modifying protein-2 and-3 (CLR/RAMP2 and CLR/RAMP3). We show that AM and AM receptors mRNAs are highly expressed in CAFs prepared from invasive breast carcinoma when compared to normal fibroblasts. Immunostaining demonstrates the presence of immunoreactive AM and AM receptors in the CAFs (n = 9). The proliferation of CAFs is decreased by anti-AM antibody (αAM) and anti-AM receptors antibody (aAMR) treatment, suggesting that AM may function as a potent autocrine/paracrine growth factor. Systemic administration of aAMR reduced neovascularization of in vivo Matrigel plugs containing CAFs as demonstrated by reduced numbers of the vessel structures, suggesting that AM is one of the CAFs-derived factors responsible for endothelial cell-like and pericytes recruitment to built a neovascularization. We show that MCF-7 admixed with CAFs generated tumors of greater volume significantly different from the MCF-7 xenografts in nude mice due in part to the induced angiogenesis. aAMR and AM 22-52 therapies significantly suppressed the growth of CAFs/MCF-7 tumors. Histological examination of tumors treated with AM 22-52 and aAMR showed evidence of disruption of tumor vasculature with depletion of vascular endothelial cells, induced apoptosis and decrease of tumor cell proliferation. Our findings highlight the importance of CAFs-derived AM pathway in growth of breast carcinoma and in neovascularization by supplying and amplifying signals that are essential for pathologic angiogenesis.

Keywords: adrenomedullin; breast cancer; myofibroblasts; invasion; tumor growth

Domains: Life Sciences [q-bio]; Cancer

Zohra Benyahia, Nadège Dussault, Mylène Cayol, Romain Sigaud, Caroline Berenguer-Daizé, et al.. Stromal fibroblasts present in breast carcinomas promote tumor growth and angiogenesis through adrenomedullin secretion. Oncotarget, 2017, 8 (9), ⟨10.18632/oncotarget.14999⟩. ⟨hal-01699152⟩