br The role of apelin in cancer

The role of apelin in cancer Studies on cancers are intensively conducted worldwide. It is thought that this large family of diseases is among the most studied. The researchers test newly-discovered substances hoping to find remedies and diagnostic indices for this illness. One of such substances is apelin. In tumour tissues, the overexpression of endogenous apelin and its receptor APJ is observed [74]. Moreover, recent studies have indicated that apelin overexpression in cancerous tissues induces intratumoral lymphangiogenesis and promotes lymphatic metastasis [75]. There was an interesting finding in a comparative experiment on patients with gastric cancer and chronic gastritis. It was noticed that in patients suffering from cancer (in vivo study), apelin Phosphatase Inhibitor Cocktail 2 (100X in ddH2O) receptor was higher than in the other group; nevertheless, no differences in serum apelin levels were found. High expression of apelin in gastric cancer samples was associated with poor differentiation, lymph node and distant metastases. In the in vitro study on the gastric cancer cell lines SGC-7901, MKN-45 and AGS, higher expression of apelin and APJ receptor was observed than in the normal cell line GES-1. Furthermore, in gastric cancer cell lines treated with apelin, overexpression of IL-1, IL6, MMP1, MMP9 and BMP-2 was visible. This may suggest that apelin promotes tumour invasiveness through up-regulation of factors that correlate with its metastasis and growth [76]. Recently, it has been reported that apelin promotes proliferation of colon carcinoma and that the JAG1/Notch3 signalling pathways play a critical role in this process [77]. Several researchers have suggested that apelin may be treated as a marker in evaluating tumour cancer development. One of the antitumor therapies is normalization of the tumour vasculature. During anti-angiogenic therapy using Bevacizumab (an anti-angiogenic monoclonal antibody that binds VEGF and inhibits the activation of the VEGF signalling pathway) in patients with colorectal cancer, higher endogenous apelin expression in non-responding patients in comparison with responders has been found. These data suggest that apelin may take part in the compensation of VEGF signalling loss. According to the authors, apelin can serve as a potential Bevacizumab response-predictive biomarker in patients suffering from colorectal cancer [78]. Kidoya et al. [79] also noticed that the apelin/APJ system can induce the morphological and functional maturation of blood vessels in tumours and, at the same time, improve immunotherapy of maturated vessels. However, the induction of tumour vascular normalization by recombinant apelin administration is difficult since apelin peptide is unstable. Also, Maden et al. [80] suggested that high apelin levels could be used as a diagnostic and prognostic marker in multiple myeloma. Overexpression of apelin and its receptor has been also detected in clinical glioblastoma samples. Apelin-13, (Pyr1)-apelin-13 and apelin-36 increase the number of tumour spheres, and apelin-13 likewise increases the frequency of colony-forming cells in patients with glioblastoma [81]. Also, it was noticed that in stage 4 non-small cell lung cancer patients undergoing chemotherapy and having apelin overexpression, the overall survival was shortened in comparison to patients without such overexpression [82]. Similarly, Hall et al. [83] showed that apelin promotes cholangiocarcinoma angiogenesis and proliferation in mouse and that intravenous administration of APJ antagonist (ML221) causes tumour growth inhibition.
Conclusions
Funding This work was supported by the statutory funding of The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences.
Disclosure
Introduction Apelin is an endogenous peptide capable of binding the apelin receptor, which was originally described as an orphan G-protein-coupled receptor [1]. Upon proteolysis through a not fully elucidated mechanism, pre-pro-apelin is converted into specific fragments ranging from 36 to 13 amino acids, with the 12 C-terminal amino acids conserved among all apelin isoforms [2]. Both apelin and apelin receptor are expressed across a wide range of eukaryotes including humans, in a variety of tissues including the central nervous and cardiovascular systems [3]. Apelin and its cognate receptor are essential for diverse biological processes and play important roles in the regulation of cardiovascular function [4], [5]. The beneficial effects of the apelin/apelin receptor system are well established by treating with apelin in conditions as diverse as hypertension, atherosclerosis, myocardial infarction, heart failure (HF) and pulmonary arterial hypertension (PAH) [6], [7], [8]. Recently, the apelin receptor has been shown to be activated by a novel endogenous peptide ligand known as apela/Elabela/Toddler, with an important role in cardiovascular development and function [9], [10]. This further enriched the understanding of the multiple physiological mechanisms of the apelin/apelin receptor system. The abilities of exogenous apelin to rescue heart and vascular diseases support the therapeutic potential of apelin in preventing and treating cardiovascular diseases. Nonetheless, therapeutic application of apelin is limited by its short half-life and parenteral administration. Thus great effort has been directed to the development of novel agonists or analogues, efficient delivery methods and improved efficacy of agonists at the apelin receptor [11]. This review summarizes the development and the latest advances concerning the apelin/apelin receptor signaling pathway and its role in cardiovascular physiology.