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

Abstract

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.

Cancer‑associated fibroblast regulation of tumor neo‑angiogenesis as a therapeutic target in cancer (Review)

“…In order to positively participate in neo-angiogenesis, human breast CAFs deposit and secrete more adrenomedullin (AM) compared with normal fibroblasts. AM blockade is able to impair tumor vascular formation and induce apoptosis (115). Notch signaling is an evolutionarily conserved pathway that regulates cell biological characteristics, whose accommodative dysfunction has been implicated in various tumors.…”

Tumor Microenvironment Heterogeneity: Challenges and Opportunities

“…Accumulating evidence suggests that both stromal fibroblasts and CSCs mediate tumor growth and metastasis (Benyahia et al, 2017; Elkabets et al, 2011; Ghesquiere et al, 2014; Mao et al, 2013; Tripathi et al, 2012). Since these components have a direct influence in the TME of these reproductive cancers, they represent attractive targets for therapeutic development.…”

Involvement of Adrenomedullin Expression in Tumor Cells and Stroma in the Development of Diabetes in Pancreatic Cancer Patients

“…Although the differences were not signi cant, we did nd a stronger in ammatory response in the DM than in the non-DM group, suggesting that AM expression in response to in ammation may be more closely related to the development of diabetes in PC patients, as reported previously 6 7 17 . Regarding broblasts, Bhowmick et al 18 showed that stromal broblasts in tumors are biologically distinct from normal broblasts, and Benyahia et al 19 reported that stromal broblasts in breast cancer promote tumor growth and angiogenesis through AM secretion. We expect that the AM expression of stromal broblasts in PC will be found to have multiple functions and to be associated with the onset of diabetes.…”

“…In the DM and non-DM groups, respectively, median serum CA19-9 was 724 and 1,144 U/ml, median amylase was 58 and 72 IU/l, and median CRP levels were 0.14 and 0.12 mg/dl. The number of signi cant dilatations ≥ 5 mm in diameter of the main pancreatic duct was 11 52 and 9 33 in the DM and non-DM groups, respectively, whereas the number of patients in the DM and non-DM groups with invasion to the portal vein was 4 19 and 9 33 , respectively, and 5 24 and 15 56 patients, respectively, had liver metastases. The number of clinical Stage cases in the DM and non-DM groups was 14 67…”