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YKL-40—A Protein in the Field of Translational Medicine: A Role as a Biomarker in Cancer Patients?  [PDF]
Nicolai A. Schultz,Julia S. Johansen
Cancers , 2010, DOI: 10.3390/cancers2031453
Abstract: YKL-40 is a 40 kDa glycoprotein produced by cancer cells, inflammatory cells and stem cells. It probably has a role in cell proliferation and differentiation, inflammation, protection against apoptosis, stimulation of angiogenesis, and regulation of extracellular tissue remodelling. Plasma levels of YKL-40 are often elevated in patients with localized or advanced cancer compared to age-matched healthy subjects. Several studies have demonstrated that high plasma YKL-40 is an independent prognostic biomarker of short survival in patients with different types of cancer. However, there is not yet sufficient data to support determination of plasma YKL-40 outside research projects as a biomarker for screening of gastrointestinal cancer and determination of treatment response and poor prognosis before or during treatment and follow-up. Plasma YKL-40 is also elevated in patients with other diseases than cancer, e.g., severe infections, cardiovascular disease, diabetes, chronic obstructive lung disease, asthma, liver fibrosis and rheumatoid arthritis. Co-morbidity should therefore always be considered in patients with cancer, since other sources than cancer cells can increase plasma YKL-40 levels. Future focused translational research projects combining basic and clinical research are needed in a joint effort to answer questions of the complex function and regulation of YKL-40 and the question if plasma YKL-40 is a clinical useful biomarker in patients with cancer.
The efficacy of YKL-40 and CA125 as biomarkers for epithelial ovarian cancer
Zou, L.;He, X.;Zhang, J.W.;
Brazilian Journal of Medical and Biological Research , 2010, DOI: 10.1590/S0100-879X2010007500133
Abstract: our objective was to estimate the efficacy of the measurement of serum ykl-40 alone or with ca125 as biomarkers for the diagnosis of epithelial ovarian cancer (eoc) using the ykl-40 elisa kit. an experimental group of 49 ovarian cancer patients included 42 patients with eoc (53 ± 15 years, range: 19-81 years) and 7 patients (48 ± 13 years, range: 29-36 years) with borderline epithelial ovarian tumor. a control group of 88 non-malignant cases included 42 patients (43 ± 10 years, range: 26-77 years) with benign gynecological disease and 46 healthy women (45 ± 14 years, range: 30-68 years) at a teaching hospital. both ykl-40 (220.1 ± 94.1 vs 61.6 ± 48.4 and 50.1 ± 41.2 ng/ml) and ca125 (524.9 ± 972.5 vs 13.4 ± 7.6 and 28.5 ± 29.6 u/ml) levels were significantly higher (p < 0.05) in patients with ovarian cancer compared to the healthy and non-malignant groups. ykl-40 had 92.9% sensitivity and 94.4% specificity for the diagnosis of eoc. when ykl-40 and ca125 were tested in parallel, the sensitivity was increased to 98.2%, but the specificity was decreased to 81.3%. the correlations between serum ykl-40 and tumor stage, grade histology, performance status, patient age, and extension of debulking surgery were tested. with increasing stage and grade of eoc, preoperative serum ykl-40 levels were significantly increased (p = 0.029, p = 0.05, respectively). serum ykl-40 alone or with serum ca125 levels are useful, although with some limitations, to diagnose ovarian cancer. our study showed that ykl-40 may not be an independent prognostic factor for ovarian cancer. this prospective study may be a new trend in looking for biomarkers that optimize diagnosis of ovarian cancer.
Inhibitory Activity of YKL-40 in Mammary Epithelial Cell Differentiation and Polarization Induced by Lactogenic Hormones: A Role in Mammary Tissue Involution  [PDF]
Steve Scully, Wei Yan, Brooke Bentley, Qing Jackie Cao, Rong Shao
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025819
Abstract: We previously reported that a secreted glycoprotein YKL-40 acts as an angiogenic factor to promote breast cancer angiogenesis. However, its functional role in normal mammary gland development is poorly understood. Here we investigated its biophysiological activity in mammary epithelial development and mammary tissue morphogenesis. YKL-40 was expressed exclusively by ductal epithelial cells of parous and non-parous mammary tissue, but was dramatically up-regulated at the beginning of involution. To mimic ductal development and explore activity of elevated YKL-40 during mammary tissue regression in vivo, we grew a mammary epithelial cell line 76N MECs in a 3-D Matrigel system in the presence of lactogenic hormones including prolactin, hydrocortisone, and insulin. Treatment of 76N MECs with recombinant YKL-40 significantly inhibited acinar formation, luminal polarization, and secretion. YKL-40 also suppressed expression of E-cadherin but increased MMP-9 and cell motility, the crucial mechanisms that mediate mammary tissue remodeling during involution. In addition, engineering of 76N MECs with YKL-40 gene to express ectopic YKL-40 recapitulated the same activities as recombinant YKL-40 in the inhibition of cell differentiation. These results suggest that YKL-40-mediated inhibition of cell differentiation and polarization in the presence of lactogenic hormones may represent its important function during mammary tissue involution. Identification of this biophysiological property will enhance our understanding of its pathologic role in the later stage of breast cancer that is developed from poorly differentiated and highly invasive cells.
Ovarian tissue cryopreservation: An update
Prasath Ethiraj
Journal of Human Reproductive Sciences , 2008,
Abstract: Ovarian tissue cryopreservation and transplantation have been considered as promising means of fertility preservation for women who have survived cancer, with livebirths being reported from this technique. Ovarian tissue cryopreservation can be offered to patients with different types of cancer. Among the cryoprotectants, glycerol appears to give the poorest results. The techniques of cryopreserving ovarian tissue and alternative approaches have been reviewed in this article. The readers are reminded that this technique is still experimental and informed consent to be obtained from patients after counseling with medical information on the risks involved.
Serum YKL-40 Levels in Patients with Gastric Cancer
Veyis Itik, Ozgur Kemik, Ahu Kemik, A. Cumhur Dulger, Aziz Sümer, Yasemin Usul Soyoral, Huseyin Begenik, Sevim Purisa and Cetin Kotan
Biomarkers in Cancer , 2012, DOI: 10.4137/BIC.S7154
Abstract: Aims and background: YKL-40 is secreted by several types of tumors. Increased serum YKL-40 levels have been reported in prostate, glioblastoma, breast and colorectal cancers. Determination of YKL-40 levels may serve as a valuable biomarker for the diagnosis and treatment of gastric cancer. The purpose of this study was to determine the serum YKL-40 levels expressed in gastric carcinomas. Methods: Between 2009 and 2011, we retrospectively reviewed 100 patients with gastric cancer and compared their serum samples to 75 healthy volunteers. YKL-40 levels were determined by an enzyme-linked immunosorbent assay (ELISA). Results: We found significantly higher serum levels of YKL-40 in patients with gastric cancer compared to the healthy population (P < 0.0001). We also found significant differences in serum YKL-40 levels between female and male patients with gastric cancer (P < 0.01). Conclusions: YKL-40 is over-expressed in gastric cancer, suggesting a more aggressive phenotype. YKL-40 may be a useful serum biomarker for gastric cancer identification, and future studies should focus on the role of YKL-40 in the tumorigenesis of gastric cancer and responsiveness toward treatment.
Early and stable upregulation of collagen type II, collagen type I and YKL40 expression levels in cartilage during early experimental osteoarthritis occurs independent of joint location and histological grading
Helga Lorenz, Wolfram Wenz, Mate Ivancic, Eric Steck, Wiltrud Richter
Arthritis Research & Therapy , 2004, DOI: 10.1186/ar1471
Abstract: Osteoarthritis (OA) is a disease with a high prevalence, and it occupies a very important place in orthopedic surgery. It is characterized by progressive degeneration of articular cartilage and damage to subchondral bone. While macroscopic, histological and biochemical features of OA have been extensively studied [1-4], the molecular changes in chondrocyte metabolism underlying the pathophysiological process of cartilage degeneration remain largely unknown. Studies on human articular cartilage are hampered by the difficulty of obtaining normal tissue and early-stage OA tissue. For this reason a number of animal models have been developed in which cartilage degeneration is induced by causing permanent joint instability [5-7]. In the Pond–Nuki model in dogs, anterior cruciate ligament transection (ACLT) leads to joint laxity and altered mechanical loading in the knee joint, resulting in cartilage degeneration over time. This model has the advantage of a fairly slow natural history of OA, since full-thickness loss of articular cartilage does not develop until about 4–5 years after ACLT. The resulting degenerative changes in cartilage and synovial tissue thus closely resemble those in natural canine OA and human OA [1,4,6,8].Recent studies have examined the gene expression levels of collagen type (col) II, aggrecan and small proteoglycans in dogs [9-11] and of several cartilage-related and OA-related molecules in rabbits [12-14] over time after ACLT. However, most of these studies used insensitive methods of RNA detection (northern blot) [9,11], or the methods were only semiquantitative [13,14] or failed to relate specific gene expression to the basic expression level of housekeeping genes [9,10]. This may be one reason why contradictory results have been obtained; for example in rabbits, in which no alteration of col II gene expression [12,13] or upregulation at region-specific sites [14] is reported. Other matrix molecules, such as aggrecan and fibromodulin, seem to b
High YKL-40 Serum Concentration Is Correlated with Prognosis of Chinese Patients with Breast Cancer  [PDF]
Dong Wang, Bo Zhai, Fengli Hu, Chang Liu, Jinpeng Zhao, Jun Xu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051127
Abstract: This study aimed to investigate the association between serum YKL-40 and prognosis of breast cancer in a Chinese population. Expression of YKL-40 of 120 Chinese patients with breast cancer and 30 controls (benign breast lesions) was measured in tumor tissue by immunohistochemistry and in serum by ELISA. Differences in YKL-40 positivity grouped by specific patients’ characteristics were compared using Pearson Chi-square test for rates of intratumoral staining, one-way ANOVA with a Bonferroni post-hoc comparison, or two-sample t-test for mean YKL-40 serum concentrations. Factors associated with overall survival were identified by univariate and multivariate cox-regression analyses. YKL-40 was elevated in approximately 75% of Chinese patients with breast cancer. A significantly higher percentage of patients with YKL-40 positive tumors had larger tumor size, higher TNM stage, and/or lymph node metastasis. Significantly higher mean YKL-40 serum concentrations were observed in patient subgroups with invasive lobular carcinoma (P<0.0167), higher TNM stage (P<0.001), and positive lymph node metastasis (P<0.001). The estimated mean survival time of patients with YKL-40 positive tumors was significantly shorter than for patients with YKL-40 negative tumors (55.13 months vs 65.78 months, P = 0.017). Multivariable Cox-regression analysis identified a significant association of overall survival time with YKL-40 serum concentration. Patients with YKL-40 positive tumors had significantly shorter disease free survival times than those with YKL-40 negative tumors. We propose that the potential utility of YKL-40 intratumoral staining or serum concentration as a biomarker for breast cancer is greatest within 5 years of diagnosis.
Characteristic odour in the blood reveals ovarian carcinoma
Gy?rgy Horvath, H?kan Andersson, Gunnar Paulsson
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-643
Abstract: In a recently published study, we clearly demonstrated that human ovarian carcinoma tissues can be characterized by a specific odour, detectable by a trained dog. Another recent study confirmed these results using an electronic nose.In the present work, we examined whether the cancer-specific odour can also be found in the blood. Two specially trained dogs were used. Both ovarian cancer tissues and blood from patients with ovarian carcinoma were tested.The tissue tests showed sensitivity of 100% and specificity of 95%, while the blood tests showed sensitivity of 100% and specificity of 98%.The present study strongly suggests that the characteristic odour emitted by ovarian cancer samples is also present in blood (plasma) taken from patients with the disease. This finding opens possibilities for future screening of healthy populations for early diagnosis of ovarian carcinoma. A future challenge is to develop a sensitive electronic nose for screening of ovarian carcinoma by testing the blood/plasma to detect the disease at a stage early enough for treatment to be effective.Worldwide, there are more than 204,000 new cases of ovarian cancer annually, accounting for around 4% of all cancers diagnosed in women. Incidence rates vary considerably, with the highest rates in the United States and Northern Europe and the lowest rates in Africa and Asia. Around 43,000 cases occur each year in Europe, and 22,000 in the USA. In Sweden, the disease represents 3.1% of all cancer cases in women, totalling about 900 cases per year. Despite this relatively low incidence rate, it is the fifth most common cause of cancer death in women.Because of the high mortality rates, ovarian cancer is one of several diseases that fulfil some of the criteria necessary for the introduction of population screening: it is an important health problem, and early detection is associated with improved outcomes. Potential screening tests for ovarian cancer have not yet been shown to reduce mortality, althou
The Eag potassium channel as a new prognostic marker in ovarian cancer
Viren Asher, Raheela Khan, Averil Warren, Robert Shaw, Gerhard V Schalkwyk, Anish Bali, Heidi M Sowter
Diagnostic Pathology , 2010, DOI: 10.1186/1746-1596-5-78
Abstract: To determine the expression of the potassium channels Eag and HERG in ovarian cancer tissue and to assess their role in cell proliferation.The expression of Eag and HERG potassium channels was examined in an ovarian cancer tissue microarray. Their role in cell proliferation was investigated by blocking voltage-gated potassium channels in an ovarian cancer cell line (SK-OV-3).We show for the first time that high expression of Eag channels in ovarian cancer patients is significantly associated with poor survival (P = 0.016) unlike HERG channel expression where there was no correlation with survival. There was also a significant association of Eag staining with high tumour grade (P = 0.014) and presence of residual disease (P = 0.011). Proliferation of SK-OV-3 cells was significantly (P < 0.001) inhibited after treatment with voltage gated K+ channel blockers.This novel finding demonstrates a role for Eag as a prognostic marker for survival in patients with ovarian cancer.Ovarian cancer is the second most common malignancy of the female genital tract in the UK. Cancer statistics from 2007 reveal that 4,317 UK women died from ovarian cancer, accounting for around 6% of all female deaths from cancer [1]. Despite advances in chemotherapy, ovarian cancer mortality rates in the UK since the early 1970 s, have remained stable at ~10-12 per 100,000 women. This is in part due to the asymptomatic nature of the disease with most women presenting at a late stage [1]. Current treatment with platinum based chemotherapy results in clinical remission in 75% of patients but the median progression free survival is only 16 to 21 months [2]. Thus, there is a clear need for the development of novel therapies to improve conventional treatments and identify new prognostic markers for survival.Ion channels are pore-forming proteins that help establish and control voltage gradients across the plasma membranes of all living cells by allowing the flow of ions down their electrochemical gradient
Increased expression of cysteine cathepsins in ovarian tissue from chickens with ovarian cancer
Suzie E Ahn, Jin Choi, Deivendran Rengaraj, Hee Seo, Whasun Lim, Jae Han, Gwonhwa Song
Reproductive Biology and Endocrinology , 2010, DOI: 10.1186/1477-7827-8-100
Abstract: Cancerous (n = 5) and normal (n = 3) ovaries were collected from 2-to 3-year-old hens, and ovarian tissue samples were collected for study. Ovarian cancers were evaluated with hematoxylin and eosin staining. Reverse transcriptase and quantitative PCR analyses, in situ hybridization analysis were performed to examine the mRNA expression pattern of three CTSs in detail, and protein expression of CTSB was evaluated.The CTSB, CTSC, and CTSS genes were highly expressed in cancerous chicken ovaries. Messenger RNAs for the three CTSs were localized to a nodule area, a major characteristic of cancerous ovaries, but the three CTSs showed no specific localization in normal ovaries. Immunoreactive CTSB protein was present in the nodule area of cancerous ovaries.Our results suggest that CTSB, CTSC, and CTSS have important functions in the development of epithelial ovarian cancer.Ovarian cancer has the highest mortality rate of all gynecological cancers and is the fifth leading cause of death among women [1]. About 90% of human ovarian cancers are thought to originate from the ovarian surface epithelium [2]. The rate of epithelial ovarian cancer is high because incessant ovulation causes genomic damage to the ovarian surface epithelium, increasing the possibility of gene mutations [3,4]. The lack of an appropriate animal model has prevented mechanistic studies of ovarian cancer [2].Chickens ovulate almost every day, whereas women ovulate only once a month. Given the prevalent hypothesis that the cause of ovarian cancer is incessant ovulation [5], chickens that spontaneously develop epithelial ovarian cancer may be a good animal model for researching the mechanisms responsible for human ovarian cancer [6,7]. Furthermore, CA125, a well-known marker for human ovarian cancer, is expressed in chicken ovarian cancer cells, but not in normal ovarian cells [6,8,9].There are 11 cysteine cathepsins in human (CTSB, -C, -F, -H, -K, -L, -O, -S, -V, -W, and -X/Z), which all share a conserved
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