Role and Mechanisms of RAGE-Ligand Complexes and RAGE-Inhibitors in Cancer Progression

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Abstract

Interactions of the receptor for advanced glycation end product (RAGE) and its ligands in the context of their role in diabetes mellitus, inflammation, and carcinogenesis have been extensively investigated. This review focuses on the role of RAGE-ligands and anti-RAGE drugs capable of controlling cancer progression. Different studies have demonstrated interaction of RAGE with a diverse range of acidic (negatively charged) ligands such as advanced glycation end products (AGEs), high-mobility group box1 (HMGB1), and S100s, and their importance to cancer progression. Some RAGE-ligands displayed effects on anti- and pro-apoptotic proteins through upregulation of the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs), matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), and nuclear factor kappa B (NF- κ B) pathways, while downregulating p53 in cancer progression. In addition, RAGE may undergo ligand-driven multimodal dimerization or oligomerization mediated through self-association of some of its subunits. We conclude our review by proposing possible future lines of study that could result in control of cancer progression through RAGE inhibition.

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VEGF as a Key Mediator of Angiogenesis in Cancer

Peter Carmeliet (2005)

Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein with a molecular weight of approximately 45 kDa. It is the key mediator of angiogenesis (the formation of new blood vessels), and binds two VEGF receptors (VEGF receptor-1 and VEGF receptor-2), which are expressed on vascular endothelial cells. In healthy humans, VEGF promotes angiogenesis in embryonic development and is important in wound healing in adults. VEGF is the key mediator of angiogenesis in cancer, in which it is up-regulated by oncogene expression, a variety of growth factors and also hypoxia. Angiogenesis is essential for cancer development and growth: before a tumor can grow beyond 1–2 mm, it requires blood vessels for nutrients and oxygen. The production of VEGF and other growth factors by the tumor results in the ‘angiogenic switch’, where new vasculature is formed in and around the tumor, allowing it to grow exponentially. Tumor vasculature formed under the influence of VEGF is structurally and functionally abnormal. Blood vessels are irregularly shaped, tortuous, have dead ends and are not organized into venules, arterioles and capillaries. They are also leaky and hemorrhagic, which leads to high interstitial pressure. These characteristics mean that tumor blood flow is suboptimal, resulting in hypoxia and further VEGF production. This central role of VEGF in the production of tumor vasculature makes it a rational target for anticancer therapy.

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S100 proteins in cancer.

Anne Bresnick, David Weber, Danna B Zimmer (2015)

In humans, the S100 protein family is composed of 21 members that exhibit a high degree of structural similarity, but are not functionally interchangeable. This family of proteins modulates cellular responses by functioning both as intracellular Ca(2+) sensors and as extracellular factors. Dysregulated expression of multiple members of the S100 family is a common feature of human cancers, with each type of cancer showing a unique S100 protein profile or signature. Emerging in vivo evidence indicates that the biology of most S100 proteins is complex and multifactorial, and that these proteins actively contribute to tumorigenic processes such as cell proliferation, metastasis, angiogenesis and immune evasion. Drug discovery efforts have identified leads for inhibiting several S100 family members, and two of the identified inhibitors have progressed to clinical trials in patients with cancer. This Review highlights new findings regarding the role of S100 family members in cancer diagnosis and treatment, the contribution of S100 signalling to tumour biology, and the discovery and development of S100 inhibitors for treating cancer.

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Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?

Rakesh R Ramjiawan, Arjan Griffioen, Dan G Duda (2017)

Angiogenesis is defined as the formation of new blood vessels from preexisting vessels and has been characterized as an essential process for tumor cell proliferation and viability. This has led to the development of pharmacological agents for anti-angiogenesis to disrupt the vascular supply and starve tumor of nutrients and oxygen, primarily through blockade of VEGF/VEGFR signaling. This effort has resulted in 11 anti-VEGF drugs approved for certain advanced cancers, alone or in combination with chemotherapy or other targeted therapies. But this success had only limited impact on overall survival of cancer patients and rarely resulted in durable responses. Given the recent success of immunotherapies, combinations of anti-angiogenics with immune checkpoint blockers have become an attractive strategy. However, implementing such combinations will require a better mechanistic understanding of their interaction. Due to overexpression of pro-angiogenic factors in tumors, their vasculature is often tortuous and disorganized, with excessively branched leaky vessels. This enhances vascular permeability, which in turn is associated with high interstitial fluid pressure, and a reduction in blood perfusion and oxygenation. Judicious dosing of anti-angiogenic treatment can transiently normalize the tumor vasculature by decreasing vascular permeability and improving tumor perfusion and blood flow, and synergize with immunotherapy in this time window. However, anti-angiogenics may also excessively prune tumor vessels in a dose and time-dependent manner, which induces hypoxia and immunosuppression, including increased expression of the immune checkpoint programmed death receptor ligand (PD-L1). This review focuses on revisiting the concept of anti-angiogenesis in combination with immunotherapy as a strategy for cancer treatment.

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Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 20 May 2020

Publication date Collection: May 2020

Volume: 21

Issue: 10

Electronic Location Identifier: 3613

Affiliations

[1 ]Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Damanhour 22511, Egypt; ali.elfar@ 123456damanhour.edu.eg

[2 ]Rensselaer Polytechnic Institute, NY (RPI), Troy, NY 12180, USA; srogag@ 123456rpi.edu

[3 ]Department of Hematology/Pediatric Oncology, King Abdulaziz University, Yousef Abdulatif Jameel Scientific Chair of Prophetic Medicine Application, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; saljaouni@ 123456kau.edu.sa

[4 ]The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA

Author notes

[* ]Correspondence: shaker.mousa@ 123456acphs.edu

Author information

Ali H. El-Far https://orcid.org/0000-0001-9721-4360

Shaker A. Mousa https://orcid.org/0000-0002-9294-015X

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Publisher ID: ijms-21-03613

DOI: 10.3390/ijms21103613

PMC ID: 7279268

PubMed ID: 32443845

SO-VID: 8d73039b-14ec-4e91-ba07-677968ad0f85

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Role and Mechanisms of RAGE-Ligand Complexes and RAGE-Inhibitors in Cancer Progression

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Most cited references 131

VEGF as a Key Mediator of Angiogenesis in Cancer

S100 proteins in cancer.

Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?

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