Stromal fibroblasts present in breast carcinomas promote tumor growth and angiogenesis through adrenomedullin secretion.
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 (αAMR) treatment, suggesting that AM may function as a potent autocrine/paracrine growth factor. Systemic administration of αAMR 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. αAMR and AM22-52 therapies significantly suppressed the growth of CAFs/MCF-7 tumors. Histological examination of tumors treated with AM22-52 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.
Aix Marseille University, The Institut National pour la Recherche Médicale, Centre de Recherche en Oncologie et Oncopharmacologie, UMR 911, 13005, Marseille, France.
Zohra
Z
Benyahia
Aix Marseille University, The Institut National pour la Recherche Médicale, Centre de Recherche en Oncologie et Oncopharmacologie, UMR 911, 13005, Marseille, France.
Nadège
N
Dussault
Aix Marseille University, The Institut National pour la Recherche Médicale, Centre de Recherche en Oncologie et Oncopharmacologie, UMR 911, 13005, Marseille, France.
Mylène
M
Cayol
Aix Marseille University, The Institut National pour la Recherche Médicale, Centre de Recherche en Oncologie et Oncopharmacologie, UMR 911, 13005, Marseille, France.
Romain
R
Sigaud
Aix Marseille University, The Institut National pour la Recherche Médicale, Centre de Recherche en Oncologie et Oncopharmacologie, UMR 911, 13005, Marseille, France.
Caroline
C
Berenguer-Daizé
Aix Marseille University, The Institut National pour la Recherche Médicale, Centre de Recherche en Oncologie et Oncopharmacologie, UMR 911, 13005, Marseille, France.
Christine
C
Delfino
Aix Marseille University, The Institut National pour la Recherche Médicale, Centre de Recherche en Oncologie et Oncopharmacologie, UMR 911, 13005, Marseille, France.
Asma
A
Tounsi
Assistance Publique Hôpitaux de Marseille, Laboratoire d'Anatomie Pathologique, 13015, Marseille, France.
Stéphane
S
Garcia
Aix Marseille University, The Institut National pour la Recherche Médicale, Centre de Recherche en Oncologie et Oncopharmacologie, UMR 911, 13005, Marseille, France.
Pierre-Marie
PM
Martin
Aix Marseille University, CNRS, ICR, UMR 7273 CROPS, 13397, Marseille, France.
Kamel
K
Mabrouk
Aix Marseille University, The Institut National pour la Recherche Médicale, Centre de Recherche en Oncologie et Oncopharmacologie, UMR 911, 13005, Marseille, France.|Assistance Publique Hôpitaux de Marseille, Service de Transfert d'Oncologie Biologique, 13015, Marseille, France.
L'Houcine
L
Ouafik
D053607:Adrenomedullin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D058265:Receptors, Adrenomedullin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics
D057134:Antibodies, Neutralizing; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D058265:Receptors, Adrenomedullin; D053607:Adrenomedullin
adrenomedullin; breast cancer; invasion; myofibroblasts; tumor growth