YKL-40 Protein Research Articles

YKL-40 Protein is a Marker of Asthma

Background. Gaining asthma control is still a challenge in a large number of patients. It could be facilitated by using biomarkers indicating the grade of inflammation and correlating with clinical picture. Chitinases and chitinase-like proteins play a role in Th2-type inflammation. Thus, they may be useful in diagnosing and monitoring of asthma. Objectives. The aim of the study was to investigate the relevance of YKL-40 as a good biomarker of asthma, its control, and severity. Methods. Level of YKL-40 was determined by means of immunoassay in sera of 59 asthmatics (39 women, 20 men, aged 23–76 years) and 29 healthy controls (18 women, 11 men, aged 20–80 years). Asthma severity and control were assessed according to GINA guidelines. Differences between groups were compared with the use of Mann–Whitney’s U-test. Correlations between variables were assessed with Pearson’s test. Results. Symptoms of asthma were found to be controlled in 12 (20%), partly controlled in 17 (29%), and uncontrolled in 30 (51%) patients. YKL-40 levels were significantly higher, on average, in asthmatics compared to control group (median levels: 125.3 U and 84.1 U, respectively, p < .001). YKL-40 correlated with the number of blood eosinophils (r = 0.376, p = 0.05). However, no relations have been found between YKL-40 level and asthma severity, control, or total serum IgE (r = −0.05, p = .05). Conclusion. YKL-40 seems to be a good marker of asthma. However, its level may not correlate with clinical outcome.

Study of biomaterial-induced macrophage activation, cell-mediated immune response and molecular oxidative damage in patients with dermal bioimplants

Several soft-tissue dermal fillers have been reported to provoke immunogenicity and may cause adverse reactions despite claims regarding their safety. This study aimed to assess biomaterial-induced macrophage activation, cell-mediated immune response and oxidative stress in 169 patients with dermal bioimplants. To this end, we analysed plasma concentrations of myeloperoxidase (MPO), the chitinase-like proteins chitotriosidase and YKL-40 and molecular oxidative damage. The present study shows, for the first time, that the components of innate immunity: chitotriosidase and YKL-40, are significantly higher in patients with certain bioimplants and these markers of monocyte/macrophage activation rose progressively as adverse reactions (AR) evolved. Plasma MPO levels increased 4-fold in filler users with AR and 3-fold in those without. Analysis by filler type showed subjects injected with calcium hydroxylapatite, methacrylate, acrylamides and silicone to have values significantly above those of non-filler subjects for at least two plasma biomarkers, probably because the afore-mentioned biomaterials are permanent and prone to trigger AR in the long term. By contrast, hyaluronic acid alone elicited little immune response. Plasma concentrations of markers of oxidative damage to lipids and proteins were found to be significantly higher in users of four of the nine dermal fillers studied. These diffusible products of molecular peroxidation would stem from the reaction catalysed by MPO that generates potent oxidants, leading to cell oxidative damage which, in turn, may exert deleterious effects on the organism. Overall, the results of this study on the effects of a range of dermal fillers point to chronic activation of the immune response mediated by macrophages and PMNs. The increases in plasma of MPO, chitotriosidase and YKL-40 proteins and products of macromolecular peroxidation suggests that these molecules could serve as blood-based biochemical markers and alert to the risk of chronic immune system activation and development of adverse events that may arise from the use of certain bioimplants.

Increased tissue immunoexpression of YKL-40 protein in high grade serous ovarian cancers

YKL-40 is a glycoprotein secreted by numerous human cells, such as cartilage, synovial, and endothelial cells. The biological role of YKL-40 has not yet been fully unveiled, however, its participation is perceived in angiogenesis, growth, proliferation, differentiation, and remodeling processes. The primary goal of our study was to evaluate possible differences in tissue immunoexpression of YKL-40, assumed between high grade and low-grade ovarian cancers and between the above-mentioned cancer types and benign lesions. Another purpose was to find out whether immunoexpression of the studied protein could correlate with the tumor proliferation process, evaluated by Ki-67 immunoexpression. The analysis comprised 45 women, diagnosed and treated for epithelial ovarian tumors at the Medical University of Lodz between 1997 and 2002. YKL-40 protein immunoexpression was semiquantitatively assessed, whereas immunoexpression of Ki-67 was evaluated using a computer image analysis system. Significantly higher immunoexpression values of both examined proteins were observed in high-grade serous ovarian cancers vs. low-grade and benign tumors. Moreover, a significant positive correlation was identified between the immunoexpressions of YKL-40 and Ki-67 proteins in the studied groups of tumors. In conclusion, the obtained data suggest an overt prominence of TKL-40 tissue immunoexpression of YKL-40 in high-grade serous ovarian tumors, which could then be approached as a helpful, additional marker to identify more aggressive ovarian cancers.

YKL‐40 and MMP‐9 as serum markers for patients with primary central nervous system lymphoma

To evaluate YKL-40 and MMP-9 proteins as tumor biomarkers in serum samples from patients with primary central nervous system lymphoma (PCNSL). In this prospective longitudinal study, serum samples from consecutive patients with histologically confirmed PCNSL were collected concurrently with magnetic resonance imaging (MRI) scans at multiple time points and were analyzed for levels of YKL-40 and MMP-9 by enzyme-linked immunosorbent assay. Marker levels were correlated to disease status and survival. Forty-five patients with PCNSL were accrued. Median follow-up for survivors was 25 months, and 21 (47%) died during the study. A total of 230 serum samples were collected, and 93% had corresponding MRI scans. PCNSL patients without evidence of radiographic disease (29 patients, 131 samples) had significantly lower levels of serum YKL-40 and MMP-9 than patients with active tumor (n = 34 patients, 84 samples; p = 0.03 and 0.01, respectively). There was a significant inverse correlation between survival and doubling of the YKL-40 level (hazard ratio, 1.7; p = 0.01). In patients with PCNSL, serum levels of YKL-40 and MMP-9 are associated with radiographic disease status. Longitudinal increase in serum levels of YKL-40, but not MMP-9, predicts survival in patients with PCNSL.

The effect of mud pack therapy on serum YKL-40 and hsCRP levels in patients with knee osteoarthritis

The aim of this study was to evaluate the efficacy of treatment with mud pack in knee osteoarthritis (OA) and to determine whether mud pack effects serum levels of YKL-40 and high-sensitivity C-reactive protein (hsCRP) which are reported to be biological markers for articular damage or inflammation in patients with OA. Forty-four patients with the diagnosis of knee OA assigned into two groups were treated with local natural mineral-rich mud pack or hot pack. Treatments were applied for 6 days a week for 2 weeks as a total of 12 sessions. Patients were assessed at baseline, post-treatment, and 3 months after the treatment. VAS, range of motion, 15-m walking time, WOMAC index, Nottingham Health Profile, serum YKL-40, and hsCRP levels were the outcome measures. Pain intensity and joint stiffness decreased in both groups at all follow-ups. Physical activity status was found to persist for 3 months after treatment only in mud pack group. Serum mean YKL-40 and hsCRP levels of the patients were higher compared to healthy control group. Serum YKL-40 level increased significantly only in hot pack group 3 months after the treatment (P < 0.017). No significant change was observed in hsCRP levels in both groups during the whole follow-up periods (P > 0.05). Mud pack and hot pack therapy were both demonstrated to be effective in symptomatic treatment of knee OA until the end of the 2-week treatment period, whereas only mud pack therapy was shown to be effective in functional status over time. In the hot pack group, increased serum YKL-40 level 3 months after the treatment might indicate persistence of cartilage degradation. Maintenance of YKL-40 level in mud pack therapy seems to slow down the progression of knee OA.

YKL-40 expression in CD14+liver cells in acute and chronic injury

To demonstrate that CD14⁺ cells are an important source of the growth factor YKL-40 in acute and chronic liver damage. Rats were inoculated with one dose of CCl(4) to induce acute damage. Liver biopsies were obtained at 0, 6, 12, 24, 48 and 72 h. For chronic damage, CCl(4) was administered three days per week for 6 or 8 wk. Tissue samples were collected, and cellular populations were isolated by liver digestion and purified by cell sorting. YKL-40 mRNA and protein expression were evaluated by real-time polymerase chain reaction and western blot. Acute liver damage induced a rapid increase of YKL-40 mRNA beginning at 12 h. Expression peaked at 24 h, with a 26-fold increase over basal levels. By 72 h however, YKL-40 expression levels had nearly returned to control levels. On the other hand, chronic damage induced a sustained increase in YKL-40 expression, with 7- and 9-fold higher levels at 6 and 8 wk, respectively. The pattern of YKL-40 expression in different subpopulations showed that CD14⁺ cells, which include Kupffer cells, are a source of YKL-40 after acute damage at 72 h [0.09 relative expression units (REU)] as well as after chronic injury at 6 wk (0.11 REU). Hepatocytes, in turn, accounted for 0.06 and 0.01 REU after 72 h (acute) or 6 wk (chronic), respectively. The rest of the CD14⁻ cells (including T lymphocytes, B lymphocytes, natural killer and natural killer T cells) yielded 0.07 and 0.15 REU at 72 h and 6 wk, respectively. YKL-40 protein expression in liver was detected at 72 h as well as 6 and 8 wk, with the highest expression relative to controls (11-fold; P ≤ 0.05) seen at 6 wk. Macrophages were stimulated by lipopolysaccharide. We demonstrate that under these conditions, these cells showed maximum expression of YKL-40 at 12 h, with P < 0.05 compared with controls. Hepatic CD14⁺ cells are an YKL-40 mRNA and protein source in acute and chronic liver injury, with expression patterns similar to growth factors implicated in inflammation-fibrogenesis.

Angiogenic activities of YKL-40 in cancer development: A potential biomarker and target for cancer diagnosis and therapy

Pioneer Valley Life Sciences Institute, University of Massachusetts, USA A evidence has shown that elevated serum levels of a secreted glycoprotein YKL-40 are associated with a worse prognosis from a variety of advanced human cancers, including breast cancer, colorectal cancer, ovarian cancer, and brain tumor. Furthermore, these increased levels correlate with poorer survival of cancer patients, suggesting that serum levels of YKL-40 might be a prognostic biomarker. Yet the role of YKL-40 activity in these cancers is poorly understood. To explore a functional role of YKL-40 in tumor development, we engineered cancer cells with YKL-40 cDNA to express ectopic YKL-40. Over-expression of YKL-40 in these cancer cells led to larger tumor formation with an extensive angiogenic phenotype than did control cancer cells in mice. Affi nity purifi ed recombinant YKL-40 protein promoted vascular endothelial cell angiogenesis in vitro, the eff ects of which are similar to the activities observed using cancer cell conditioned medium aft er transfection with YKL-40. Immunohistochemical analysis of human breast cancer revealed a correlation between YKL-40 expression and blood vessel density. YKL-40 levels were positively correlated with tumor grade and Her2/neu, but negatively correlated with estrogen and progesterone receptor. In complementary approaches, we found that blockade of YKL-40 by YKL40 siRNA gene knockdown and a YKL-40 neutralizing antibody restrained tumor growth, angiogenesis, and progression. Taken together, these fi ndings have shed light on the mechanisms by which YKL-40 promotes tumor angiogenesis and progression; thus pointing to a valuable cancer diagnostic and prognostic biomarker as well as a target for cancer therapy.

Resveratrol represses YKL-40 expression in human glioma U87 cells

BackgroundGlioblastoma multiforme (GBM) is the most malignant intracranial tumour that develops in both adults and children. Microarray gene analyses have confirmed that the human YKL-40 gene is one of the most over-expressed genes in these tumours but not in normal brain tissue. Clinical studies have shown that serum YKL-40 levels are positively correlated with tumour burden in addition to being an independent prognostic factor of a short relapse-free interval as well as short overall survival in patients with various cancers. Our previous study revealed that YKL-40 was closely correlated with the pathological grades of human primary astrocytomas and played a crucial role in glioma cell proliferation. Hence, YKL-40 could be an attractive target in the design of anti-cancer therapies.MethodsCell viability and invasion assays were performed to detect the cell proliferation and invasive ability of U87 cells induced by resveratrol (3, 5, 4'-trihydroxystilbene; Res) or YKL-40 small-interfering RNAs (siRNAs). In addition, the luciferase assay, real-time RT-PCR, western blotting, and ELISA were used to measure YKL-40 promoter activity, mRNA, and protein expression, respectively. The expressions of phosphor-ERK1/2 and ERK1/2 were determined by western blotting.ResultsRes inhibited U87 cell proliferation and invasion in vitro and repressed YKL-40 in U87 cells by decreasing the activity of its promoter and reducing mRNA transcription and protein expression in vitro. YKL-40 siRNA treatment also impaired the invasiveness of U87 cells. When U87 cells were cultured with 20 μM PD98059 (an ERK1/2 inhibitor) alone, with 20 μM PD98059 and 100 μM Res, or with 100 μM Res alone for 48 h, YKL-40 protein expression decreased most significantly in the Res-treated group. PD98059 partially reversed the decrease of YKL-40 protein expression induced by Res. Furthermore, phosphor-ERK1/2 expression was reduced by Res treatment in a time-dependent manner.ConclusionsWe demonstrated for the first time that Res represses YKL-40 expression in vitro; in addition, the ERK1/2 pathway is involved in this repression. This finding could extend the prospective use of Res in glioma research and enlarge the armamentarium for treating gliomas.

Increased Circulating and Visceral Adipose Tissue Expression Levels of YKL-40 in Obesity-Associated Type 2 Diabetes Are Related to Inflammation: Impact of Conventional Weight Loss and Gastric Bypass

Plasma YKL-40 is elevated in patients with type 2 diabetes. The potential role of visceral adipose tissue (VAT) as a significant source of YKL-40 is unknown. In the study circulating and expression levels of YKL-40 were examined in VAT analyzing the contribution of adipocytes and stromovascular fraction cells (SVFCs). We also explored YKL-40's implication in insulin resistance and inflammation and the effect of weight loss on plasma YKL-40 concentrations. Samples obtained from 53 subjects were used in the study. Gene and protein expression levels of YKL-40 were analyzed in VAT as well as in both adipocytes and SVFCs. In addition, circulating YKL-40 concentrations were measured before and after weight loss achieved either by Roux-en-Y gastric bypass (n = 26) or after a conventional dietetic program (n = 20). Circulating concentrations and VAT expression of YKL-40 were increased in obese patients with type 2 diabetes (P < 0.01) as well as associated with variables of insulin resistance and inflammation. No differences in YKL-40 expression levels between adipocytes and SVFCs were detected. Monocyte chemoattractant protein-1 and homeostasis model assessment emerged (P < 0.01) as independent factors predicting circulating YKL-40. Elevated levels of YKL-40 in obese patients decreased after weight loss following a conventional hypocaloric diet (P < 0.05) but not via a surgery-induced negative energy balance mediated by the Roux-en-Y gastric bypass. The association of increased YKL-40 mRNA and protein levels in VAT with its circulating concentrations indicates an important contribution of VAT in YKL-40 regulation. Furthermore, our data suggest a relevant role of glucose metabolism and inflammation on YKL-40 regulation.

The Chitinase-like Protein YKL-40 Is Secreted by Airway Epithelial Cells at Base Line and in Response to Compressive Mechanical Stress

The chitinase-like protein YKL-40, encoded by the CHI3L1 gene, is a biomarker and functional effector of chronic inflammatory and allergic diseases. In the lung it is associated with asthma severity and reduced lung function. The cellular sources of YKL-40 in human airways and the mechanisms regulating YKL-40 expression are poorly understood. We previously showed that mechanical stress similar to that experienced during bronchoconstriction triggers epithelial cell signaling through epidermal growth factor receptor (EGFR), fibrotic mediator release, and goblet cell hyperplasia consistent with airway remodeling in asthma. We now show that well differentiated normal human bronchial epithelial cells express CHI3L1 and secrete YKL-40 under base-line culture conditions. Mechanical stress (30-cm H(2)O transcellular compressive stress) applied for 3 h induces CHI3L1 expression by ∼4-fold compared with time matched controls, resulting in increased secretion of YKL-40 by 3.6-fold 24 h after onset of the 3-h stimulus. Inhibition of EGFR or MEK1/2 (ERK kinase) significantly but incompletely attenuates mechanical stress-induced up-regulation of CHI3L1 expression in normal human bronchial epithelial cells. Direct activation of EGFR utilizing EGF-family ligands induces CHI3L1 expression. Our results reveal that human airway epithelial cells are a source of YKL-40 and demonstrate that mechanical stress potently induces CHI3L1 expression leading to increased secretion of YKL-40 protein in an EGFR and MEK1/2-dependent pathway. In the asthmatic airway mechanical stress may contribute to enhanced YKL-40 levels.

YKL-40 Protein Levels and Clinical Outcome of Human Endometrial Cancer

The secreted glycoprotein YKL-40 is a member of the chitinase family and elevated serum YKL-40 levels have been reported to be associated with reduced survival in several malignancies, including endometrial cancer. This study investigated immunoreactivity to YKL-40 protein and its prognostic implications in endometrial cancer. Levels of YKL-40 protein in normal endometrium (n = 42), endometrial hyperplasia (n = 40) and endometrial adeno carcinoma (n = 68) were examined using immunohistochemistry. YKL-40 immunoreactivity was significantly higher in endometrial adenocarcinoma compared with hyperplastic and normal endo metrium. In addition, high immuno reactivity of YKL-40 protein was associated with advanced stage, high histological grade, lymph node metastasis and lympho vascular invasion. Moreover, positive immunoreactivity for YKL-40 was a significant predictor of poor prognosis, as measured by estimated progression-free survival and estimated overall survival, compared with negative immunoreactivity. In conclusion, high YKL-40 immuno reactivity in endometrial cancer may be associated with poor prognosis.

Relationship of YKL-40 protein expression in pulmonary adenocarcinoma and prognosis.

e18129 Background: YKL-40 (CHI3L1) is synthesized both by cancer cells and tumor-associated macrophages and plays a functional role in tumor progression. High YKL-40 serum levels have been associated with poor prognosis in patients with several cancer types including non-small cell lung cancer (NSCLC). YKL-40 protein expression has been investigated by immunhistochemistry in several cancer types but not in NSCLC. The aim of the present investigation was to analyze the expression of YKL-40 of pulmonary adenocarcinoma cells. Methods: YKL-40 protein was assessed by immunhistochemistry using a monoclonal antibody against YKL-40 in primary tumors or lymph node metastases of 83 patients with metastatic adenocarcinoma of the lung who underwent surgery between 1999 and 2002. The immunreactivity was assessed by two independent observers using the immureactive score (IRS) according to Stegner and Remmele. YKL-40 IRS was related to tumor stage, progression-free survival (PFS) and overall survival (OS). Results: In 77 cases (93%), the IRS was positive. In most tissues, the staining intensity of the tumor cells was strong (n = 47, 57%) or moderate (n = 30, 36%). The percentage of positive tumor cells was high; in 66 tissues (80%) > 80% of the tumor cells were positive and in 3 tissues only none or < 10% of the tumor cells were positive. There was no correlation between YKL-40 IRS and tumor stage. For survival analysis, 79 patients were evaluable. Median PFS was 11.7 months (range 10.6-16.7 months) and median OS was 20.3 months (range 16.8-30.8 months). There was no difference in PFS and OS depending on the YKL-40 IRS. Conclusions: In pulmonary adenocarcinomas YKL-40 protein expression was found with a strong staining intensity and a high percentage of positive tumor cells. In contrast to serum YKL-40 levels, YKL-40 expression was not correlated with PFS or OS. This is in accordance with the results of YKL-40 protein expression in breast, ovarian and head and neck cancer. No significant financial relationships to disclose.

Association between YKL‐40 and adult primary astrocytoma

The YKL-40 coding chitinase 3-like 1 gene is 1 of the most overexpressed genes in human glioblastomas. The objectives of this study were to explore YKL-40 protein expression status and World Health Organization (WHO) pathologic grades of primary human astrocytoma and to investigate the role of YKL-40 in the proliferation of both established and primary astrocytoma cells in vitro. WHO grade 1, 2, 3, and 4 primary astrocytomas (210 patients) were evaluated for YKL-40 protein expression status in immunohistochemical analyses. In addition, after transfection with a plasmid that contained YKL-40 small-interfering RNA (siRNA), cell proliferation and the cell cycle were measured with a cell-viability assay and flow cytometry. Expression levels of phosphorylated, total mitogen-activated protein kinase (MAPK) and protein kinase B (AKT) were detected by Western blot analysis. The percentage of positive cells and the staining intensity differed significantly between different pathologic tumor grades (P < .001). The YKL-40 immunoreactivity score increased markedly with increased pathologic grade (F = 18.89; P < .001). In the in vitro experiment, the cell cycle was arrested in G(1) phase. An inhibitor of the p38 MAPK, SB203580, could partially abrogate the cell proliferation inhibition effect by siRNA treatment. The expression levels of phosphorylated extracellular signal-regulated kinase 1/2 and phosphorylated AKT were notably decreased in siRNA-transfected U87 cells. In contrast, the expression levels of phosphorylated p38 and phosphorylated c-jun N-terminal kinase 1 and 2 increased significantly (P < .01). YKL-40 expression status correlated well with the pathologic grade of primary astrocytomas. The current results also indicted that YKL-40 plays a pivotal role in glioma cell proliferation through activation of the MAPK and AKT pathways. YKL-40 may be an attractive target for glioma therapy.

Role of breast regression protein-39/YKL-40 in asthma and allergic responses

BRP-39 and its human homolog YKL-40 have been regarded as a prototype of chitinase-like proteins (CLP) in mammals. Exaggerated levels of YKL-40 protein and/or mRNA have been noted in a number of diseases characterized by inflammation, tissue remodeling, and aberrant cell growth. Asthma is an inflammatory disease characterized by airway hyperresponsiveness and airway remodeling. Recently, the novel regulatory role of BRP-39/YKL-40 in the pathogenesis of asthma has been demonstrated both in human studies and allergic animal models. The levels of YKL-40 are increased in the circulation and lungs from asthmatics where they correlate with disease severity, and CHI3L1 polymorphisms correlate with serum YKL-40 levels, asthma and abnormal lung function. Animal studies using BRP-39 null mutant mice demonstrated that BRP-39 was required for optimal allergen sensitization and Th2 inflammation. These studies suggest the potential use of BRP-39 as a biomarker as well as a therapeutic target for asthma and other allergic diseases. Here, we present an overview of chitin/chitinase biology and summarize recent findings on the role of BRP-39 in the pathogenesis of asthma and allergic responses.

Increased serum YKL-40 and C-reactive protein levels are associated with angiographic lesion progression in patients with coronary artery disease

ObjectiveYKL-40 is a pro-inflammatory protein highly expressed in atherosclerotic plaques, and is related to prognosis of patients with coronary artery disease (CAD). This study aimed to assess the possible association between YKL-40 and coronary lesion progression in CAD patients. MethodsA total of 313 patients with CAD, who underwent percutaneous coronary intervention (PCI) and follow-up angiography (mean 13.2±3.2 months) were recruited. Serum YKL-40 and high-sensitivity C-reactive protein (hsCRP) levels were measured using ELISA kits. ResultsBaseline serum YKL-40 and hsCRP levels were higher in those with lesion progression (all p<0.001 vs. patients without lesion progression), and correlated significantly with change of lumen diameter stenosis and cumulative coronary obstruction score (all p<0.01). Multivariable logistic regression analysis revealed that after adjusting for conventional risk factors, number of total coronary artery lesions, YKL-40 and hsCRP levels were independent determinants of lesion progression. An area under the curve of YKL-40 and hsCRP was 0.744 (CI 95% 0.685–0.804, p<0.001) and 0.716 (CI 95% 0.657–0.776, p<0.001), respectively. The optimal values of cut-off point were 74.98ng/ml (sensitivity 70%, specificity 71%) for YKL-40 and 3.21mg/l (sensitivity 66%, specificity 68%) for hsCRP to predict lesion progression. ConclusionIncreased serum YKL-40 and hsCRP levels are independently associated with lesion progression in patients with CAD.

YKL-40, a secreted glycoprotein, promotes tumor angiogenesis

Tumor angiogenesis is of paramount importance in solid tumor development. Elevated serum levels of YKL-40, a secreted heparin-binding glycoprotein have been associated with a worse prognosis from a variety of advanced human cancers. Yet the role of YKL-40 activity in these cancers is still missing. Here, we have shown that ectopic expression of YKL-40 in MDA-MB-231 breast cancer cells and HCT-116 colon cancer cells led to larger tumor formation with an extensive angiogenic phenotype than did control cancer cells in mice. Affinity purified recombinant YKL-40 protein promoted vascular endothelial cell angiogenesis in vitro, the effects similar to the activities observed using MDA-MB-231 and HCT-116 cell conditioned medium after transfection with YKL-40. Further, YKL-40 was found to induce the coordination of membrane-bound receptor syndecan-1 and integrin αvβ3 and activate an intracellular signaling cascade including focal adhesion kinase and MAP kinase Erk1/2 in endothelial cells. Also, blockade of YKL-40 using siRNA gene knockdown suppressed tumor angiogenesis in vitro and in vivo. Immunohistochemical analysis of human breast cancer revealed a correlation between YKL-40 expression and blood vessel density. These findings provide novel insights into angiogenic activities and molecular mechanisms of YKL-40 in cancer development.

YKL-40 - an emerging biomarker in cardiovascular disease and diabetes

Several inflammatory cytokines are involved in vascular inflammation resulting in endothelial dysfunction which is the earliest event in the atherosclerotic process leading to manifest cardiovascular disease. YKL-40 is an inflammatory glycoprotein involved in endothelial dysfunction by promoting chemotaxis, cell attachment and migration, reorganization and tissue remodelling as a response to endothelial damage. YKL-40 protein expression is seen in macrophages and smooth muscle cells in atherosclerotic plaques with the highest expression seen in macrophages in the early lesion of atherosclerosis. Several studies demonstrate, that elevated serum YKL-levels are independently associated with the presence and extent of coronary artery disease and even higher YKL-40 levels are documented in patients with myocardial infarction. Moreover, elevated serum YKL-40 levels have also been found to be associated with all-cause as well as cardiovascular mortality. Finally, YKL-40 levels are elevated both in patients with type 1 and type 2 diabetes, known to be at high risk for the development of cardiovascular diseases, when compared to non-diabetic persons. A positive association between elevated circulating YKL-40 levels and increasing levels of albuminuria have been described in patients with type 1 diabetes indicating a role of YKL-40 in the progressing vascular damage resulting in microvascular disease.This review describes the present knowledge about YKL-40 and discusses its relation to endothelial dysfunction, atherosclerosis, cardiovascular disease and diabetes and look ahead on future perspectives of YKL-40 research.

Subcellular Localization of YKL-40 in Normal and Malignant Epithelial Cells of the Breast

YKL-40 is a new prognostic biomarker in cancer. The biological function is only poorly understood. This study aimed at determining the subcellular localization of YKL-40, using immunogold labeling, in normal epithelial cells and in malignant tumor cells of the breast by immunoelectron microscopy. YKL-40 protein expression was redistributed in carcinoma versus normal glandular tissue of the breast. A reduced expression of YKL-40 in relation to intermediate filaments and desmosomes was found in tumor cells. Changes in YKL-40 expression suggest that the function of YKL-40 in cells of epithelial origin may be related to cell motility and cell–cell adhesion, features associated with invasion and migration potential of tumor cells.

YKL-40 protein expression is not a prognostic marker in patients with primary breast cancer

YKL-40 is a new biomarker in serum with a prognostic value in several localized and metastatic malignancies. The current knowledge regarding the biological functions of YKL-40 in cancer links YKL-40 to increased aggressiveness of the tumor. Utilizing tissue microarrays, YKL-40 protein expression in tumor tissue was assessed by immunohistochemistry in a cohort of 630 high-risk breast cancer patients with a median estimated potential follow-up time of 10 and 13 years for disease-free (DFS) and overall survival (OS), respectively. YKL-40 protein expression was found in malignant tumor cells and in inflammatory cells. High expression was associated with positive estrogen and progesterone receptor status and high tumor differentiation. Contrary to studies on serum YKL-40 as a prognostic biomarker, a high YKL-40 expression in tumor cells was not significantly associated with DSF and OS in univariate and multivariate analyses.

YKL-40 Protein Expression in the Early Developing Human Musculoskeletal System

YKL-40 is a growth factor for chondrocytes and fibroblasts. The aim was to evaluate YKL-40 expression in the musculoskeletal system during early human development. We studied sections from 15 human embryos [weeks 5.5-8; 7- to 31-mm crown-rump length (CRL)] and 68 fetuses (weeks 9-14; 33- to 105-mm CRL) for YKL-40 protein expression by immunohistochemistry. YKL-40 mRNA expression was evaluated in two human embryos (days 41 and 51). Initially YKL-40 is expressed in all germ layers: ecto-, meso-, and endoderm. YKL-40 mRNA and protein expression are found in tissues of the ecto-, meso-, and endoderm, and YKL-40 protein expression is present during development of cartilage, bone, joints, and muscles. At the cellular level, YKL-40 protein expression is high in tissues characterized by rapid proliferation, marked differentiation, and undergoing morphogenetic changes. Examples of rapid cell proliferation include the chondrogenic inner layer of perichondrium and the osteogenic inner layer of periosteum. Differences in YKL-40 expression during differentiation are found in the chondrogenic and osteogenic cell lineages. The initial shaping of cartilage and bone models and joints is concomitant with a strong outline of YKL-40-positive cells. This indicates that YKL-40 is associated with cell proliferation, differentiation, and tissue morphogenesis during development of the human musculoskeletal system.