adrenomedullin and Colonic-Neoplasms

To investigate the contribution of adrenomedullin (AM) and its gene-related peptide, proadrenomedullin N-terminal 20 peptide (PAMP), to the progression and potential treatment of colon cancer we studied the effects of four small molecules (SM) related to AM and PAMP on a mouse model of colon cancer. For each SM, four experimental groups of male mice were used: (i) Control group; (ii) SM group; (iii) DSS group (injected with azoxymethane [AOM] and drank dextran sulfate sodium [DSS]); and (iv) DSS + SM group (treated with AOM, DSS, and the SM). None of the mice in groups i and ii developed tumors, whereas all mice in groups iii and iv developed colon neoplasias. No significant differences were found among mice treated with PAMP modulators (87877 and 106221). Mice that received the AM negative modulator, 16311, had worse colitis symptoms than their control counterparts, whereas mice injected with the AM positive modulator, 145425, had a lower number of tumors than their controls. SM 145425 regulated the expression of proliferation marker Lgr5 and had an impact on microbiota, preventing the DSS-elicited increase of the Bacteroides/Prevotella ratio. These results suggest that treatment with AM or with positive modulator SMs may represent a novel strategy for colon cancer.

Topics: Adrenomedullin; Animals; Antineoplastic Agents; Azoxymethane; Cluster Analysis; Colitis; Colon; Colonic Neoplasms; Disease Models, Animal; Disease Progression; Gastrointestinal Agents; Mice

Adrenomedullin (ADM), initially identified in human pheochromocytoma, participates in a wide range of physiological and pathological processes, including vasorelaxation, angiogenesis and apoptosis. Recent studies have reported that ADM protected tumor cells against apoptotic cell death via the upregulation of Bcl-2 or the activation of the phosphatidylinositol 3-kinase/Akt pathway. Several studies have also provided evidence that ADM is involved in tumor initiation and progression. However, this has not been shown in gastrointestinal tumors. To investigate the role of ADM in gastrointestinal tumor progression, we determined the expression levels of ADM in 72 cases of stomach cancer and 84 cases of colon cancer and determined whether there was an association between the ADM expression levels and pathological parameters or clinical survival rates. We found that the expression levels of ADM were significantly higher in colon cancers than in matching normal mucosal tissues. In addition, the expression levels of ADM in colon cancers were correlated with cancer stage and clinical survival rate. However, we did not find any significant correlations between ADM expression levels and clinical or pathological parameters in stomach cancers. Taken together, our data strongly suggest that ADM is involved in the progression of colon cancer.

Topics: Adenocarcinoma; Adrenomedullin; Colonic Neoplasms; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Neoplasm Staging; Stomach Neoplasms

Evidence has accumulated showing that vasoactive peptides, such as endothelin-1, adrenomedullin and urotensin-II, are expressed in various kinds of tumour cells. In the present study, the expression of endothelin-1 and endothelin receptors was studied in eight human tumour cell lines: T98G (glioblastoma), IMR-32 and NB69 (neuroblastoma), BeWo (choriocarcinoma), SW-13 (adrenocortical carcinoma), DLD-1 (colonic carcinoma), HeLa (cervical carcinoma) and VMRC-RCW (renal carcinoma). Reverse transcriptase-PCR showed expression of endothelin-1 mRNA in seven out of the eight cell lines, the exception being BeWo cells. ET(A) receptor mRNA was expressed in T98G, IMR-32 and NB69 cells, but weakly in the other cells. ET(B) receptor mRNA was expressed in IMR-32, NB69 and BeWo cells, but only weakly in T98G and HeLa cells. Immunoreactive endothelin was detected in the culture media of six out of the eight cell lines, but not in that of IMR-32 or BeWo cells. Treatment of T98G cells with an anti-endothelin-1 antibody or an anti-adrenomedullin antibody for 24 h decreased cell numbers to approx. 84% and 90% of control respectively. Treatment with the ET(A) receptor antagonist BQ-610 (1 microM) significantly decreased cell number to about 90% of control, whereas the ET(B) receptor antagonist BQ-788 had no significant effect. On the other hand, exogenously added endothelin-1, adrenomedullin or urotensin-II (0.1 microM) had no significant effects on cell number. These results suggest that endothelin-1 acts as a paracrine or autocrine growth stimulator in tumours. The effect of endothelin-1 on tumour growth appears to be mediated by the ET(A) receptor.

Topics: Adrenal Cortex Neoplasms; Adrenomedullin; Antibodies, Monoclonal; Cell Division; Choriocarcinoma; Colonic Neoplasms; Endothelin Receptor Antagonists; Endothelin-1; Glioblastoma; Growth Substances; HeLa Cells; Humans; Kidney Neoplasms; Neuroblastoma; Oligopeptides; Peptides; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger; Tumor Cells, Cultured; Urotensins; Vasodilator Agents