YKL-40/CHI3L1 drives inflammation on the road of tumor progression (original) (raw)
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Role of chitinase-like proteins in cancer
Biological Chemistry, 2016
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...
Immunologic Research, 2013
Elevated serum levels of a glycoprotein known as chitinase-3-like protein 1 (CHI3L1) have been correlated with poor prognosis and shorter survival of patients with cancer and inflammatory diseases. The biological and physiological functions of CHI3L1 in cancer have not yet been completely elucidated. In this review, we describe the role of CHI3L1 in inducing pro-inflammatory/pro-tumorigenic and angiogenic factors that could promote tumor growth and metastasis.
Serum YKL-40, A New Prognostic Biomarker in Cancer Patients?
Cancer Epidemiology Biomarkers & Prevention, 2006
YKL-40, a member of the ''mammalian chitinase-like proteins,'' is expressed and secreted by several types of solid tumors. The exact function of YKL-40 in cancer diseases is unknown and is an important objective of future studies. YKL-40 exhibits growth factor activity for cells involved in tissue remodeling processes. YKL-40 may have a role in cancer cell proliferation, survival, and invasiveness, in the inflammatory process around the tumor, angiogenesis, and remodeling of the extracellular matrix. YKL-40 is neither organ-nor tumor-specific. However, the present retrospective clinical studies of patients with eight different types of primary or advanced solid tumors suggest that serum concentration of YKL-40 may be a new biomarker in cancer patients used as a ''prognosticator.'' Elevated serum YKL-40 is found in a subgroup of patients with different types of solid tumors, including several types of adenocarcinomas, small cell lung carcinoma, glio-194
Overexpression of chitinase like protein YKL-40 in leukemia patients
YKL-40 is a member of mammalian chitanase (CHI3L1), expressed and secreted by several types of solid tumor cells, inflammatory cells and stem cells. The precise physiological role of YKL-40 in cancer is still not clear and it is suggested that it play a role in cancer cell proliferation, differentiation, metastatic potential, cell attachment and migration, reorganization and tissue remodeling. The aim of the study was to check the appearance of YKL-40 in leukemic cells and over-expression of YKL-40 in the plasma of leukemia patients in comparison to healthy controls, and find whether YKL-40 could serve as a peripheral biomarker for leukemia. The study was conducted between July 2012 and March 2013 and included 67 volunteers, 55 having leukemia at the stage of diagnosis of the disease and 12 normal healthy volunteers. YKL-40 levels were determined in all plasma samples using the YKL-40 enzyme-linked immunosorbent assay (ELISA) kit and expression of YKL-40 was observed by using immunocytochemical (ICC) analysis. YKL-40 plasma levels differed significantly between patients with leukemia and the normal healthy volunteers (P=<0.001) and YKL-40 was positively expressed in all four types of leukemia (AML, ALL, CLL and CML) specimens.
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2016
YKL-40, a chitinase-like glycoprotein, is expressed at a high level in cancer patients. Its exact function is unknown and is the subject of current investigation. Here, we report the correlation of plasma YKL-40 levels with clinicopathological features of cholangiocarcinoma (CCA), a lethal bile duct cancer, particularly prevalent in Northeastern Thailand. Statistical analysis of plasma YKL-40 concentrations in 57 CCA patients and 41 normal healthy subjects gave a median value of 169.5 ng/mL for CCA patients compared with 46.9 ng/mL for the control subjects (P < 0.0001). There was no significant association of plasma YKL-40 levels with patient age, tumor grade, or histology type. However, Kaplan-Meier analysis suggested that the elevated plasma YKL-40 level was particularly associated with short survival in CCA patients (P = 0.038). Immunohistochemical examination of 34 CCA tissues revealed low expression of YKL-40 in CCA cells, but high expression in adjacent intratumoral stroma,...
Endocrine Related Cancer, 2014
Chitinase 3-like 1 (CHI3L1 or YKL40) is a secreted glycoprotein highly expressed in tumours from patients with advanced stage cancers, including prostate cancer (PCa). The exact function of YKL40 is poorly understood, but it has been shown to play an important role in promoting tumour angiogenesis and metastasis. The therapeutic value and biological function of YKL40 are unknown in PCa. The objective of this study was to examine the expression and function of YKL40 in PCa. Gene expression analysis demonstrated that YKL40 was highly expressed in metastatic PCa cells when compared with less invasive and normal prostate epithelial cell lines. In addition, the expression was primarily limited to androgen receptor-positive cell lines. Evaluation of YKL40 tissue expression in PCa patients showed a progressive increase in patients with aggressive disease when compared with those with less aggressive cancers and normal controls. Treatment of LNCaP and C4-2B cells with androgens increased YKL40 expression, whereas treatment with an anti-androgen agent decreased the gene expression of YKL40 in androgen-sensitive LNCaP cells. Furthermore, knockdown of YKL40 significantly decreased invasion and migration of PCa cells, whereas overexpression rendered them more invasive and migratory, which was commensurate with an enhancement in the anchorage-independent growth of cells. To our knowledge, this study characterises the role of YKL40 for the first time in PCa. Together, these results suggest that YKL40 plays an important role in PCa progression and thus inhibition of YKL40 may be a potential therapeutic strategy for the treatment of PCa.
RIG-like Helicase Regulation of Chitinase 3-like 1 Axis and Pulmonary Metastasis
Scientific Reports, 2016
Chi3l1 is induced by a variety of cancers where it portends a poor prognosis and plays a key role in the generation of metastasis. However, the mechanisms that Chi3l1 uses to mediate these responses and the pathways that control Chi3l1-induced tumor responses are poorly understood. We characterized the mechanisms that Chi3l1 uses to foster tumor progression and the ability of the RIG-like helicase (RLH) innate immune response to control Chi3l1 elaboration and pulmonary metastasis. Here we demonstrate that RLH activation inhibits tumor induction of Chi3l1 and the expression of receptor IL-13Rα2 and pulmonary metastasis while restoring NK cell accumulation and activation, augmenting the expression of IFN-α/β, chemerin and its receptor ChemR23, p-cofilin, LIMK2 and PTEN and inhibiting BRAF and NLRX1 in a MAVS-dependent manner. These studies demonstrate that Chi3l1 is a multifaceted immune stimulator of tumor progression and metastasis whose elaboration and tissue effects are abrogated by RLH innate immune responses. The prototypic chitinase-like protein (CLP), Chitinase 3-like-1 (Chi3l1) (also called as YKL-40 in humans and BRP-39 in rodents) is a member of the 18 glycosyl hydrolase (GH 18) gene family, which binds to but does not degrade chitin 1. The retention of GH 18 moieties over species and evolutionary time has led to the belief that these moieties play essential roles in biology 2,3. In support of this speculation, recent studies from our laboratory and others demonstrated that Chi3l1 plays a major role in anti-pathogen, antigen and oxidant-induced inflammatory, repair and remodeling responses by regulating a variety of essential biologic processes including oxidant injury, apoptosis, pyroptosis, inflammasome activation, Th1/Th2 cytokine balance, M2 macrophage differentiation, TGF-β 1 elaboration, dendritic cell accumulation and activation, fat accumulation and the activation of MAPK, Akt and Wnt/β-catenin signaling 4-11. Studies from our laboratory and others have demonstrated that Chi3l1 is expressed by a variety of cells including macrophages, and epithelial cells and is stimulated by a number of mediators including IL-13, IL-6, IL-1β , and IFN-γ 7,8. These studies also identified significant correlations between dysregulated Chi3l1 and the development, severity and/or progression of a number of diseases including asthma, pulmonary fibrosis and obesity (as reviewed in references 1,12). Chi3l1 dysregulation is particularly striking in solid tumors with the levels of circulating Chi3l1/YKL-40 being increased in patients with cancers of the lung, prostate, colon, rectum, ovary, kidney, breast, glioblastomas and malignant melanoma where they correlate directly with disease progression and inversely with disease free interval and patient survival 12-21. These studies strongly suggest that Chi3l1 plays an important role(s) in the biology that underlies these malignancies. However, the mechanisms that Chi3l1 uses to contribute to tumor progression have not been adequately defined. Metastatic spread is an ominous prognostic event in cancer biology. This can be readily appreciated in malignant melanoma where there is a good chance of recovery if the primary lesion is detected early and the 5 year survival is less than 10% in patients with distant melanoma metastases (stages III and IV) 22. Malignant melanoma is one of the most aggressive forms of cancer, accounts for 80% of skin cancer deaths and is increasing faster than any other malignancy 22,23. Patients with malignant melanoma have increased levels of circulating Chi3l1/ YKL-40 which have been shown to be a risk factor for disease progression 17,20. Recent studies from our laboratory also demonstrated that the induction of Chi3l1 is a critical event in the generation of a metastasis permissive
Diverse pathological implications of YKL-40: Answers may lie in ‘outside-in’ signaling
Cellular Signalling, 2013
The developing paradigms about YKL-40, a member of the "mammalian chitinase-like proteins", from across the 23 globe, project it as a vital parameter for the detection of disease onset and progression. It is expressed and secret-24 ed by cancer cells of different origins along with a variety of non-malignant cells including inflammatory and 25 structural cells. Numerous studies demonstrate that YKL-40 over-expression is associated with increased patient 26 mortality though the cellular receptors responsible for mediating these effects have not yet been identified. The 27 putative YKL-40 ligands are thought to be carbohydrate structures, since it is capable of binding chitin, 28 chito-oligosaccharides and heparin. Binding of collagen to YKL-40, identified it as the only non-carbohydrate ex-29 tracellular matrix (ECM) ligand for YKL-40. Our broad understanding of YKL-40 as a versatile biomarker and its 30 involvement in activating several signaling pathways make us anticipate that its specific receptors/binding part-31 ners may exist on the cell surface also. The cell surface heparan sulfate (HS) moieties seem to be the potential 32 candidates for this role, suggesting that it could interact with HS-proteoglycans. It is recommended to clearly de-33 lineate YKL-40-mediated signaling mechanisms before promoting the YKL-40 know-how for translational re-34 search, in both diagnostic and therapeutic applications. The present review provides an overview of YKL-40 as 35 a versatile biomarker, discussing the related pathological mechanisms and aims to reassess and unify the already 36 proposed diverse hypotheses in YKL-40-regulated signaling mechanisms.
Biomarker insights
Human Glyco_18 domain-containing proteins constitute a family of chitinases and chitinase-like proteins. Chitotriosidase and AMCase are true enzymes which hydrolyse chitin and have a C-terminal chitin-binding domain. YKL-40, YKL-39, SI-CLP and murine YM1/2 proteins possess solely Glyco_18 domain and do not have the hydrolytic activity. The major sources of Glyco_18 containing proteins are macrophages, neutrophils, epithelial cells, chondrocytes, synovial cells, and cancer cells. Both macrophages and neutrophils use the regulated secretory mechanism for the release of Glyco_18 containing proteins. Glyco_18 containing proteins are established biomarkers for human diseases. Chitotriosidase is overproduced by lipid-laden macrophages and is a major marker for the inherited lysosomal storage Gaucher disease. AMCase and murine lectin YM1 are upregulated in Th2-environment, and enzymatic activity of AMCase contributes to asthma pathogenesis. YKL proteins act as soluble mediators for the cell proliferation and migration, and are also involved in rheumatoid arthritis, infl ammatory bowel disease, hepatic fi brosis and cirrhosis. Chitotriosidase and YKL-40 refl ect the macrophage activation in atherosclerotic plaques. Serum level of YKL-40 is a diagnostic and prognostic marker for numerous types of solid tumors. YKL-39 is a marker for the activation of chondrocytes and the progression of the osteoarthritis in human. Recently identifi ed SI-CLP is upregulated by Th2 cytokine IL-4 as well as by glucocorticoids. This unique feature of SI-CLP makes it an attractive candidate for the examination of individual sensitivity of patients to glucocorticoid treatment and prediction of side effects of glucocorticoid therapy. Human chitinases and chitinase-like proteins are found in tissues and circulation, and can be detected by non-invasive technologies.