Adrenomedullin and tumour microenvironment

Abstract

Adrenomedullin (AM) is a regulatory peptide whose involvement in tumour progression is becoming more relevant with recent studies. AM is produced and secreted by the tumour cells but also by numerous stromal cells including macrophages, mast cells, endothelial cells, and vascular smooth muscle cells. Most cancer patients present high levels of circulating AM and in some cases these higher levels correlate with a worst prognosis. In some cases it has been shown that the high AM levels return to normal following surgical removal of the tumour, thus indicating the tumour as the source of this excessive production of AM. Expression of this peptide is a good investment for the tumour cell since AM acts as an autocrine/paracrine growth factor, prevents apoptosis-mediated cell death, increases tumour cell motility and metastasis, induces angiogenesis, and blocks immunosurveillance by inhibiting the immune system. In addition, AM expression gets rapidly activated by hypoxia through a HIF-1α mediated mechanism, thus characterizing AM as a major survival factor for tumour cells. Accordingly, a number of studies have shown that inhibition of this peptide or its receptors results in a significant reduction in tumour progression. In conclusion, AM is a great target for drug development and new drugs interfering with this system are being developed.

MYB Promotes Desmoplasia in Pancreatic Cancer through Direct Transcriptional Up-regulation and Cooperative Action of Sonic Hedgehog and Adrenomedullin

“…In fact, not only the tumor cells, but also the hypoxic and inflammatory tumor microenvironment could also influence stromal composition of pancreatic tumors (23,24,26). Studies on bi-directional tumor-stromal cross-talk in PC have reported signaling pathways that could influence the production of SHH and ADM (27,33). Moreover, hypoxic tumor microenvironment has also been shown to promote synthesis and secretion of SHH by pancreatic tumor cells to promote desmoplasia and thus engage in vicious hypoxia-desmoplasia loop (34).…”

Adrenomedullin in the growth modulation and differentiation of acute myeloid leukemia cells

“…The development of hematopoietic malignancies causes a remodeling of BM microenvironment followed by the alteration of HSC function, leukemia survival, protection of cancer cells from apoptotic stimuli and development of drug-resistant phenotype (67,71). Hypoxic conditions in leukemia niche are demonstrated to support the progression of cancer and to upregulate ADM (72), thus, suggesting a correlation between the survival of leukemia cells and the increased release of ADM in tumor microenviroment (10). Consistent with the above evidence, and studies in several human tumor cell lines, including HL60 and chronic monocytic leukemia (U937) (73), our results suggest for ADM a regulatory role in the proliferation of APL by paracrine effects, as already demonstrated for ADM in modulating the activity of the hypothalamo-pituitaryadrenal axis (74), the growth of cardiac and vascular smooth muscle cells (75), the hemodynamics of brain, lungs, and kidneys (76), physiological and pathological angiogenesis (12).…”

“…ADM is produced and secreted by several cell types, such as neurons, epithelial and endothelial cells supporting their survival and/or proliferation (9). Compelling evidence has shown that adrenomedullin can contribute to the pathogenesis of solid tumors in several ways (10). Firstly, the hypoxic conditions induce an upregulation of the peptide in the tumor cells leading to stimulation of cell growth and inhibition of apoptosis (11).…”

Bench-to-bedside pharmacology of adrenomedullin

“…Comparable to this, a number of studies showed the expression of AM and its receptors in cultured tumor cells and tissues, raising the possibility that AM acts in an autocrine or paracrine manner (Larráyoz et al, 2014;Miller et al, 1996;Nikitenko et al, 2013Nikitenko et al, , 2006. AM inhibits the proliferation of vascular smooth muscle cells or cardiac fibroblasts, but in contrast, either AM or AM signaling pathways were reported to stimulate the proliferation or to inhibit the apoptosis of endothelial and tumor cells (Kato et al, , 2003aLarráyoz et al, 2014;Nikitenko et al, 2006).…”