Identification of Novel Endogenous Anti(lymph)angiogenic Factors in the Aqueous Humor

Bock, Felix; Onderka, Jasmine; Braun, Gabriele; Schneider, Ann-Charlott; Hos, Deniz; Yang, Bi; Bachmann, Björn; Cursiefen, Claus

doi:10.1167/iovs.15-18526

Cited by 29 publications

(16 citation statements)

References 27 publications

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“…They may also extend into the cornea when neovascularization of the cornea develops (223). No lymphatics are located within the globe of the eye, which may be due to the presence of anti-angiogenic factors present in the aqueous humor like vasoactive intestinal peptide and α-melanocyte stimulating hormone (103). Lymphatics only contact the globe at the limbus, following the pattern of the limbal loop blood vessels.…”

Section: Organization and Anatomy Of The Lymphatic Systemmentioning

confidence: 99%

Lymphatic Vessel Network Structure and Physiology

Breslin

Yang

Scallan

et al. 2018

Comprehensive Physiology

264

258

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The lymphatic system is comprised of a network of vessels interrelated with lymphoid tissue, which has the holistic function to maintain the local physiologic environment for every cell in all tissues of the body. The lymphatic system maintains extracellular fluid homeostasis favorable for optimal tissue function, removing substances that arise due to metabolism or cell death, and optimizing immunity against bacteria, viruses, parasites, and other antigens. This article provides a comprehensive review of important findings over the past century along with recent advances in the understanding of the anatomy and physiology of lymphatic vessels, including tissue/organ specificity, development, mechanisms of lymph formation and transport, lymphangiogenesis, and the roles of lymphatics in disease.

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Section: Organization and Anatomy Of The Lymphatic Systemmentioning

confidence: 99%

Lymphatic Vessel Network Structure and Physiology

Breslin

Yang

Scallan

et al. 2018

Comprehensive Physiology

264

258

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“…The first series of experiments evidenced that while in primary cultures of human melanocytes the αMSH acted as a mitogenic agent [ 1 , 3 ], in Mel 13 human melanoma cell line and in the B16-F10 murine melanoma cell line, this hormone did not exert the same effect. In the case of melanocyte cultures, the hyper-proliferation in response to αMSH stimulus can be found in literature [ 1 , 3 , 15 – 17 ]. This kind of response contravenes one of the axioms of cell biology, which associates the differentiation process with a decrease in proliferation rates.…”

Section: Discussionmentioning

confidence: 99%

“…Only sporadic and very old studies have dealt with the capacity of activated MC1R to modulate proliferation in melanoma cells and melanocytes: transformed cells respond to αMSH by proliferating or down-regulating proliferation, according to the degree of pigmentation and the progression of the pathology [ 13 , 14 ]; primary cultures of human melanocytes respond to αMSH with a hyper-proliferative behaviour [ 1 , 3 , 15 – 17 ] and some authors have defined αMSH as a mitogenic agent for melanocytes [ 1 , 3 ]. The mechanism promoting hyper-proliferation in melanocytes could be recognized in the cAMP/PKA pathway itself (the canonical pathway triggered by the activation of MC1R).…”

Section: Introductionmentioning

confidence: 99%

The α-melanocyte stimulating hormone/peroxisome proliferator activated receptor-γ pathway down-regulates proliferation in melanoma cell lines

Flori

Rosati

Cardinali

et al. 2017

J Exp Clin Cancer Res

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BackgroundThe α-Melanocyte Stimulating Hormone (αMSH)/Melanocortin-1 receptor (MC1R) interaction promotes melanogenesis through the cAMP/PKA pathway. The direct induction of this pathway by Forskolin (FSK) is also known to enhance melanocyte proliferation. αMSH acts as a mitogenic agent in melanocytes and its effect on proliferation of melanoma cells is less known. We previously identified the αMSH/Peroxisome Proliferator Activated Receptor (PPARγ) pathway as a new pathway on the B16-F10 mouse melanoma cell line. αMSH induced the translocation of PPARγ into the nucleus as an active transcription factor. This effect was independent of the cAMP/PKA pathway and was mediated by the activation of the PI(4,5)P2/PLC pathway, a pathway which we have described to be triggered by the αMSH-dependent MC1R stimulation. Moreover, in the same study, preliminary experiments showed that mouse melanoma cells responded to αMSH by reducing proliferation and that PPARγ was involved in this effect. Due to its key role in the control of cell proliferation, PPARγ agonists are used in therapeutic models for different forms of cancer, including melanoma. The purpose of this study was: (a) to confirm the different proliferative behavior in response to αMSH in healthy and in melanoma condition; (b) to verify whether the cAMP/PKA pathway and the PLC/PPARγ pathway could exert an antagonistic function in the control of proliferation; (c) to deepen the knowledge of the molecular basis responsible for the down-proliferative response of melanoma cells after exposure to αMSH.MethodsWe employed B16-F10 cell line, a human melanoma cell line (Mel 13) and two primary cultures of human melanocytes (NHM 1 and NHM 2, respectively), all expressing a wild type MC1R and responding to the αMSH in terms of pigmentation. We evaluated cell proliferation through: a) cell counting, b) cell cycle analysis c) protein expression of proliferation modulators (p27, p21, cyclin D1 and cyclin E).ResultsThe αMSH acted as a mitogenic agent in primary cultures of human melanocytes, whereas it determined a slow down of proliferation in melanoma cell lines. FSK, as an inducer of the cAMP/PKA pathway, reproduced the αMSH mediated effect on proliferation in NHMs but it did not mimic the αMSH effect on proliferation in B16-F10 and Mel 13 melanoma cell lines. Meanwhile, 3 M3-FBS (3 M3), as an inducer of PI(4,5)P2/PLC pathway, reproduced the αMSH proliferative effect. Further experiments, treating melanoma cell lines with αMSH in the presence/absence of GW9662, as an inhibitor of PPARγ, confirmed the key role of this transcription factor in decreasing cell proliferation in response to the hormone exposure.ConclusionsIn both melanoma cell lines, αMSH determined the reduction of proliferation through the PI(4,5)P2/PLC pathway, employing PPARγ as an effector element. These evidence could offer perspectives for new therapeutic approaches for melanoma.Electronic supplementary materialThe online version of this article (10.1186/s13046-017-0611-4) contains supplementary material, which i...

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“…Moreover, it also contains several immunomodulatory factors. Just recently, we have shown that the aqueous humor exerts anti-hem-and anti-lymphangiogenic effects in vivo and in vitro [96]. Thereby, we have demonstrated that the immunomodulatory factors α-melanocyte-stimulating hormone (α-MSH) and vasoactive intestinal peptide (VIP) contained in the aqueous humor partially mediate the anti-lymphangiogenic effect [96].…”

Section: Proteins and Peptides In Lymphangiogenesismentioning

confidence: 99%

Role of Endogenous Regulators of Hem- And Lymphangiogenesis in Corneal Transplantation

Clahsen

Büttner

Hatami

et al. 2020

JCM

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Under normal conditions, the cornea, being the transparent "windscreen" of the eye, is free of both blood and lymphatic vessels. However, various diseases of the eye, like infections, can interfere with the balance between promoting and inhibiting factors, which leads to ingrowth of blood and lymphatic vessels. The newly formed lymphatic vessels increase the risk of graft rejection after subsequent corneal transplantation. Corneal transplantation is one of the most commonly performed transplantations worldwide, with more than 40,000 surgeries per year in Europe. To date, various anti-hem-and anti-lymphangiogenic treatment strategies have been developed specifically for the corneal vascular endothelial growth factor (VEGF) pathway. Currently, however, no treatment strategies are clinically available to specifically modulate lymphangiogenesis. In this review, we will give an overview about endogenous regulators of hem-and lymphangiogenesis and discuss potential new strategies for targeting pathological lymphangiogenesis. Furthermore, we will review recently identified modulators and demonstrate that the cornea is a suitable model for the identification of novel endogenous modulators of lymphangiogenesis. The identification of novel modulators of lymphangiogenesis and a better understanding of the signaling pathways involved will contribute to the development of new therapeutic targets for the treatment of pathological lymphangiogenesis. This, in turn, will improve graft rejection, not only for the cornea.

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Identification of Novel Endogenous Anti(lymph)angiogenic Factors in the Aqueous Humor

Cited by 29 publications

References 27 publications

Lymphatic Vessel Network Structure and Physiology

Lymphatic Vessel Network Structure and Physiology

The α-melanocyte stimulating hormone/peroxisome proliferator activated receptor-γ pathway down-regulates proliferation in melanoma cell lines

Role of Endogenous Regulators of Hem- And Lymphangiogenesis in Corneal Transplantation

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