Role of chitinase-like proteins in cancer

Abstract Chitinase-like proteins (CLPs) are lectins combining properties of cytokines and growth factors. Human CLPs include YKL-40, YKL-39 and SI-CLP that are secreted by cancer cells, macrophages, neutrophils, synoviocytes, chondrocytes and other cells. The best investigated CLP in cancer is YKL-40. Serum and plasma levels of YKL-40 correlate with poor prognosis in breast, lung, prostate, liver, bladder, colon and other types of cancers. In combination with other circulating factors YKL-40 can be used as a predictive biomarker of cancer outcome. In experimental models YKL-40 supports tumor initiation through binding to RAGE, and is able to induce cancer cell proliferation via ERK1/2-MAPK pathway. YKL-40 supports tumor angiogenesis by interaction with syndecan-1 on endothelial cells and metastatic spread by stimulating production of pro-inflammatory and pro-invasive factors MMP9, CCL2 and CXCL2. CLPs induce production of pro- and anti-inflammatory cytokines and chemokines, and are potential modulators of inflammatory tumor microenvironment. Targeting YKL-40 using neutralizing antibodies exerts anti-cancer effect in preclinical animal models. Multifunctional role of CLPs in regulation of inflammation and intratumoral processes makes them attractive candidates for tumor therapy and immunomodulation. In this review we comprehensively analyze recent data about expression pattern, and involvement of human CLPs in cancer.

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Approaching 3R teaching in biomedical engineering

Biomedical Science and Engineering ◽

10.4081/bse.2019.84 ◽

2020 ◽

Author(s):

Valeria Chiono

Keyword(s):

Animal Models ◽

Biomedical Engineering ◽

Experimental Models ◽

Preclinical Testing ◽

Preclinical Trials ◽

European Standards ◽

Preclinical Animal Models ◽

In Silico Models

Since its adhesion to Centro3R, Politecnico di Torino has approached 3R teaching through a new Master course, entitled “New advances in alternative preclinical trials”. This is a multidisciplinary optional course for Master students in Biomedical Engineering, with the contribution of different teachers, who are experts on different aspects of preclinical testing of biomedical devices: European Standards for preclinical experimentation; preclinical animal models; protection of animal welfare in the European legislation; the role of statistics on the application of the 3R principle; preclinical experimental models in vitro; in silico models. This contribution describes the subjects faced by the course and their importance in the context of the 3R Principle.

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Breaching the Blood–Brain Tumor Barrier for Tumor Therapy

Cancers ◽

10.3390/cancers13102391 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2391

Author(s):

Fabrizio Marcucci ◽

Angelo Corti ◽

Andrés J. M. Ferreri

Keyword(s):

Drug Delivery ◽

Brain Tumors ◽

Tumor Therapy ◽

Clinical Testing ◽

Medical Need ◽

Tumor Tissues ◽

Anti Cancer ◽

The Central Nervous System ◽

Radio Sensitivity

Tumors affecting the central nervous system (CNS), either primary or secondary, are highly prevalent and represent an unmet medical need. Prognosis of these tumors remains poor, mostly due to the low intrinsic chemo/radio-sensitivity of tumor cells, a meagerly known role of the microenvironment and the poor CNS bioavailability of most used anti-cancer agents. The BBTB is the main obstacle for anticancer drugs to achieve therapeutic concentrations in the tumor tissues. During the last decades, many efforts have been devoted to the identification of modalities allowing to increase drug delivery into brain tumors. Until recently, success has been modest, as few of these approaches reached clinical testing and even less gained regulatory approval. In recent years, the scenario has changed, as various conjugates and drug delivery technologies have advanced into clinical testing, with encouraging results and without being burdened by a heavy adverse event profile. In this article, we review the different approaches aimed at increasing drug delivery to brain tumors, with particular attention to new, promising approaches that increase the permeability of the BBTB or exploit physiological transport mechanisms.

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Biological Rationale for Targeting MEK/ERK Pathways in Anti-Cancer Therapy and to Potentiate Tumour Responses to Radiation

International Journal of Molecular Sciences ◽

10.3390/ijms20102530 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2530 ◽

Cited By ~ 8

Author(s):

Francesco Marampon ◽

Carmela Ciccarelli ◽

Bianca Maria Zani

Keyword(s):

Mapk Pathway ◽

Cell Signalling ◽

Acquired Resistance ◽

Mitogen Activated Protein Kinases ◽

Anti Cancer ◽

Mitogen Activated Protein ◽

Splicing Isoforms ◽

Shed Light ◽

Pathological Tissues

ERK1 and ERK2 (ERKs), two extracellular regulated kinases (ERK1/2), are evolutionary-conserved and ubiquitous serine-threonine kinases involved in regulating cell signalling in normal and pathological tissues. The expression levels of these kinases are almost always different, with ERK2 being the more prominent. ERK1/2 activation is fundamental for the development and progression of cancer. Since their discovery, much research has been dedicated to their role in mitogen-activated protein kinases (MAPK) pathway signalling and in their activation by mitogens and mutated RAF or RAS in cancer cells. In order to gain a better understanding of the role of ERK1/2 in MAPK pathway signalling, many studies have been aimed at characterizing ERK1/2 splicing isoforms, mutants, substrates and partners. In this review, we highlight the differences between ERK1 and ERK2 without completely discarding the hypothesis that ERK1 and ERK2 exhibit functional redundancy. The main goal of this review is to shed light on the role of ERK1/2 in targeted therapy and radiotherapy and highlight the importance of identifying ERK inhibitors that may overcome acquired resistance. This is a highly relevant therapeutic issue that needs to be addressed to combat tumours that rely on constitutively active RAF and RAS mutants and the MAPK pathway.

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Understanding the Role of Chemokines and Cytokines in Experimental Models of Herpes Simplex Keratitis

Journal of Immunology Research ◽

10.1155/2017/7261980 ◽

2017 ◽

Vol 2017 ◽

pp. 1-5 ◽

Cited By ~ 13

Author(s):

Tayaba N. Azher ◽

Xiao-Tang Yin ◽

Patrick M. Stuart

Keyword(s):

Herpes Simplex ◽

Disease Process ◽

Neutrophil Infiltration ◽

Protective Role ◽

Experimental Models ◽

Cytokines And Chemokines ◽

Small Proteins ◽

Herpes Simplex Keratitis ◽

Proinflammatory Role

Herpes simplex keratitis is a disease of the cornea caused by HSV-1. It is a leading cause of corneal blindness in the world. Underlying molecular mechanism is still unknown, but experimental models have helped give a better understanding of the underlying molecular pathology. Cytokines and chemokines are small proteins released by cells that play an important proinflammatory or anti-inflammatory role in modulating the disease process. Cytokines such as IL-17, IL-6, IL-1α, and IFN-γand chemokines such as MIP-2, MCP-1, MIP-1α, and MIP-1βhave proinflammatory role in the destruction caused by HSV including neutrophil infiltration and corneal inflammation, and other chemokines and cytokines such as IL-10 and CCL3 can have a protective role. Most of the damage results from neutrophil infiltration and neovascularization. While many more studies are needed to better understand the role of these molecules in both experimental models and human corneas, current studies indicate that these molecules hold potential to be targets of future therapy.

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CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS-CoV-2 and its variants delta, alpha, beta, and gamma

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00760-8 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Jiejie Geng ◽

Liang Chen ◽

Yufeng Yuan ◽

Ke Wang ◽

Youchun Wang ◽

...

Keyword(s):

Viral Entry ◽

Neutralizing Antibodies ◽

Immune Escape ◽

Mapk Pathway ◽

Cytokine Storm ◽

Cytokines And Chemokines ◽

Signaling Axis ◽

Alpha Beta ◽

New Perspective ◽

Stat Pathway

AbstractSARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants—alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 μg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a “spike protein-CD147-CyPA signaling axis”: Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.

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