RETRACTED: Expression of adrenomedullin in human colorectal tumors and its role in cell growth and invasion in vitro and in xenograft growth in vivo

Abstract

Adrenomedullin (AM) is a multifunctional peptide vasodilator that transduces its effects through calcitonin receptor-like receptor/receptor activity-modifying protein-2 and -3 (CLR/RAMP2 and CLR/RAMP3). In this study, real-time quantitative reverse transcription demonstrated a significant expression of AM mRNA in tumor samples from colorectal cancer (CRC) patients in clinical stage II, III, and IV when compared with normal colorectal tissue. AM, CLR, RAMP2, and RAMP3 proteins were immunohistochemically localized in the carcinomatous epithelial compartment of CRC tissue. Tissue microarray analysis revealed a clear increase of AM, CLR, RAMP2, and RAMP3 staining in lymph node and distant metastasis when compared with primary tumors. The human colon carcinoma cells HT-29 expressed and secreted AM into the culture medium with a significant increase under hypoxia. Treatment of HT-29 cells with synthetic AM stimulated cell proliferation and invasion in vitro. Incubation with anti-AM antibody (αAM), anti-AM receptors antibodies (αAMR), or AM antagonist AM22–52 inhibited significantly basal levels of proliferation of HT-29 cells, suggesting that AM may function as an autocrine growth factor for CRC cells. Treatment with αAM significantly suppressed the growth of HT-29 tumor xenografts in vivo. Histological examination of αAM-treated tumors showed evidence of disruption of tumor vascularity with decreased microvessel density, depletion of endothelial cells and pericytes, and increased tumor cell apoptosis. These findings highlight the potential importance of AM and its receptors in the progression of CRC and support the conclusion that αAM treatment inhibits tumor growth by suppression of angiogenesis and tumor growth, suggesting that AM may be a useful therapeutic target.

LY75 Ablation Mediates Mesenchymal-Epithelial Transition (MET) in Epithelial Ovarian Cancer (EOC) Cells Associated with DNA Methylation Alterations and Suppression of the Wnt/β-Catenin Pathway

“…A specific combination of RAMP members and calcitonin-receptor-like receptor defines Ramp2 ligand affinity for either calcitonin or adrenomedullin [29]. A dual role of Ramp2 has been described in different cancer types; thus Ramp2 and its ligand adrenomedullin were shown to be overexpressed and to promote vascularization and metastasis in human colon cancer [30], while RAMP2 expression has been suppressed by promoter hypermethylation in lung cancer, and ectopic expression of RAMP2 directed apoptosis and inhibited lung cancer cell growth [31]. Similarly, the literature data for Jmjd8 implication in carcinogenesis are rather controversial.…”

Metformin limits the adipocyte tumor-promoting effect on ovarian cancer

“…It has been shown to induce proliferation of breast and endometrial cells and promote vasculogenesis [73, 74]. PfKl is a key enzyme in the glycolysis pathway and has been associated with increased glycolytic capacity of the cell [75].…”

Lack of Adrenomedullin Results in Microbiota Changes and Aggravates Azoxymethane and Dextran Sulfate Sodium-Induced Colitis in Mice

“…However, these results should be considered with care since IBD patients have an elevated risk of developing colitis-associated CRC, and the involvement of AM in tumor progression has become evident in the last years (Larráyoz et al, 2014). In the particular case of CRC, several studies postulate that blocking AM might prevent tumor growth (Nougueréde et al, 2013). …”