κ Opioid receptor ligands regulate angiogenesis in development and in tumours

Abstract

Opioid systems mainly regulate physiological functions such as pain, emotional tone and reward circuitry in neural tissues (brain and spinal cord). These systems are also found in extraneural tissues (ganglia, gut, spleen, stomach, lung, pancreas, liver, heart, blood and blood vessels), and recent studies have elucidated their roles in various organs. The current review focuses on the roles of opioid systems in blood vessels, especially angiogenesis, during development and tumour malignancy. The balance between endogenous activators and inhibitors of angiogenesis delicately maintains a normally quiescent vasculature to sustain homeostasis. Disturbance of this balance causes pathogenic angiogenesis and, especially in tumours, several activators such as VEGF are highly expressed in the tumour microenvironment and strongly induce tumour angiogenesis, the so-called angiogenic switch. Recently, we demonstrated that κ opioid receptor agonists function as anti-angiogenic factors, which impede the angiogenic switch, in vascular development and tumour angiogenesis by inhibiting the expression of receptors for VEGF. In clinical medicine, angiogenesis inhibitors that target VEGF signalling such as bevacizumab are used as anti-cancer drugs. Although therapies that inhibit tumour angiogenesis have been highly successful for tumour therapy, most patients eventually develop resistance to this anti-angiogenic therapy. Thus, we must identify novel targets for anti-angiogenic agents to sustain inhibition of angiogenesis for tumour therapy. The regulation of responses to κ opioid receptor ligands could be useful for controlling vascular formation under physiological conditions and in cancers, and thus could offer therapeutic benefits beyond the relief of pain. LINKED ARTICLESThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 AbbreviationsBBB, blood-brain barrier; E, embryonic day; ECs, endothelial cells; ES, embryonic stem; FGF, fibroblast growth factor; Gi, inhibitory G protein; HIF, hypoxia inducible factor; iPS, induced pluripotent stem; LLC, Lewis lung carcinoma; NRP, neuropilin; TKIs, tyrosine kinase inhibitors; TSP1, thrombospondin1 IntroductionOne of the earliest events in organogenesis is the development of the vascular system, which contributes to the formation of most organs in our bodies. The vascular system is first formed as a primitive vascular network by the differentiation and assembly of vascular progenitor cells derived from mesodermal cells. These progenitor cells undergo a complex remodelling process, in which growth, migration, sprouting and pruning lead to the development of a functional circulatory system. Earlier studies have suggested that many of the events in normal vascular formation during embryogenesis are recapitulated during de novo angiogenesis in adults such as tumour angiogenesis and neovascularization induced after tissue damage (Carmeliet, 2003). Furthermore,...

The dual effect of morphine on tumor development

“…They also confirmed that this inhibitory effect was mediated by hypoxia-induced mitochondrial p38 MAPK pathway inhibition [25]. Others [26] have argued that morphine also inhibits angiogenesis by suppressing VEGF signaling via the KOR, as KOR knockout mice grafted with Lewis lung carcinoma or B16 melanoma had more proliferation and enhanced angiogenesis compared to wild type mice [26]. In addition to its direct effect, morphine can also suppress the migration of leukocytes and reduce angiogenesis [27].…”

Generation of a KOR‐Cre knockin mouse strain to study cells involved in kappa opioid signaling

“…Kappa agonists act on the pituitary to trigger the release of prolactin. KOR signaling is also important in the periphery, and KOR is expressed in the heart, vasculature, and gut (Pugsley, 2002;Yamamizu et al, 2015;Zhu et al, 1998). KOR and dynorphin null mice have an increase in vascular formation during embryogenesis (Yamamizu et al, 2015).…”

Promoting effect of Se-allylselenocysteine on 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumorigenesis

“…Several studies have indicated that angiogenic activators play an important part in the growth and spread of tumors. Disturbance of the balance between endogenous activators such as vascular endothelial growth factor (VEGF) and inhibitors of angiogenesis in the tumor microenvironment strongly induce tumor angiogenesis (Yamamizu et al, 2015). Angiogenesis is a normal and vital process in growth and development as well as in wound healing.…”