Targeting Adrenomedullin in Oncology: A Feasible Strategy With Potential as Much More Than an Alternative Anti-Angiogenic Therapy

Abstract

The development, maintenance and metastasis of solid tumors are highly dependent on the formation of blood and lymphatic vessels from pre-existing ones through a series of processes that are respectively known as angiogenesis and lymphangiogenesis. Both are mediated by specific growth-stimulating molecules, such as the vascular endothelial growth factor (VEGF) and adrenomedullin (AM), secreted by diverse cell types which involve not only the cancerogenic ones, but also those constituting the tumor stroma (i.e., macrophages, pericytes, fibroblasts, and endothelial cells). In this sense, anti-angiogenic therapy represents a clinically-validated strategy in oncology. Current therapeutic approaches are mainly based on VEGF-targeting agents, which, unfortunately, are usually limited by toxicity and/or tumor-acquired resistance. AM is a ubiquitous peptide hormone mainly secreted in the endothelium with an important involvement in blood vessel development and cardiovascular homeostasis. In this review, we will introduce the state-of-the-art in terms of AM physiology, while putting a special focus on its pro-tumorigenic role, and discuss its potential as a therapeutic target in oncology. A large amount of research has evidenced AM overexpression in a vast majority of solid tumors and a correlation between AM levels and disease stage, progression and/or vascular density has been observed. The analysis presented here indicates that the involvement of AM in the pathogenesis of cancer arises from: 1) direct promotion of cell proliferation and survival; 2) increased vascularization and the subsequent supply of nutrients and oxygen to the tumor; 3) and/or alteration of the cell phenotype into a more aggressive one. Furthermore, we have performed a deep scrutiny of the pathophysiological prominence of each of the AM receptors (AM1 and AM2) in different cancers, highlighting their differential locations and functions, as well as regulatory mechanisms. From the therapeutic point of view, we summarize here an exhaustive series of preclinical studies showing a reduction of tumor angiogenesis, metastasis and growth following treatment with AM-neutralizing antibodies, AM receptor antagonists, or AM receptor interference. Anti-AM therapy is a promising strategy to be explored in oncology, not only as an anti-angiogenic alternative in the context of acquired resistance to VEGF treatment, but also as a potential anti-metastatic approach.

Role of the Tyrosine Phosphatase SHP-2 in Mediating Adrenomedullin Proangiogenic Activity in Solid Tumors

“…Thus, new therapeutic alternatives are needed, and improvements are likely to come from a more thorough understanding of the molecular and cellular mechanisms governing tumor angiogenesis and the response to antiangiogenic agents. Some of these mechanisms may be triggered by molecules produced in response to increased hypoxia (e.g., HGF, SDF1a, Ang2, CXCl8, CXCl12, AM, PDGF, bFGF) which, result from excessive pruning by longer treatment duration and/ or higher doses of angiogenesis inhibitors (4,37).…”

“…AM is a multifunctional peptide hormone (1) that exerts its activity through two different complex receptors formed by a G protein-coupled receptor, the calcitonin receptor-like receptor (CLR), and receptor activity modifying protein (RAMP) -2 or -3 (2,3), which confers CLR specificity for the hormone giving place to the receptors AM 1 and AM 2 , respectively. AM is widely expressed in a variety of tumor types (4,5) and was shown to be mitogenic for many human cancer cell lines in vitro (4,6) whereas several in vivo studies have also highlighted its strong contribution to neoplastic angiogenesis. Regression of tumor neo-vessels and tumor-growth inhibition were both observed upon treatment with AM-neutralizing antibodies (7)(8)(9), AM receptor (AMR) antagonist (10,11), or AMR interference (12).…”

Gene expression changes contribute to stemness and therapy resistance of relapsed acute myeloid leukemia: roles of SOCS2, CALCRL, MTSS1, and KDM6A

“…The ligand for the CALCRL/RAMP1 complex is calcitonin generelated peptide (CGRP), whereas adrenomedullin (ADM) binds to CALCRL/RAMP2 and CALCRL/ RAMP3 complexes [ 51 − 53 ]. CGRP and ADM have multiple physiological roles, including the regulation of blood pressure [ 52 − 56 ]. They also contribute to various pathologic processes [ 53 , 56 ], and the key role of CGRP in migraines has led to the development and regulatory approval of inhibitory antibodies and small molecule antagonists [ 55 ].…”

“…CGRP and ADM have multiple physiological roles, including the regulation of blood pressure [ 52 − 56 ]. They also contribute to various pathologic processes [ 53 , 56 ], and the key role of CGRP in migraines has led to the development and regulatory approval of inhibitory antibodies and small molecule antagonists [ 55 ]. On the basis of gene expression data [ 52 , 56 − 60 ] and their abilities to stimulate proliferation, migration, invasiveness, and angiogenesis and to inhibit apoptosis and antitumor immune responses [ 52 , 56 , 57 , 59 − 65 ], CALCRL and its ligands have also been implicated in the pathogenesis of various malignant diseases.…”

“…They also contribute to various pathologic processes [ 53 , 56 ], and the key role of CGRP in migraines has led to the development and regulatory approval of inhibitory antibodies and small molecule antagonists [ 55 ]. On the basis of gene expression data [ 52 , 56 − 60 ] and their abilities to stimulate proliferation, migration, invasiveness, and angiogenesis and to inhibit apoptosis and antitumor immune responses [ 52 , 56 , 57 , 59 − 65 ], CALCRL and its ligands have also been implicated in the pathogenesis of various malignant diseases. Accordingly, genetic or pharmacologic inhibition of CGRP or ADM signaling reduced tumor-related properties in vitro and in animal models [ 52 , 56 , 57 , 59 , 65 ].…”