The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer

Esophageal cancer (EC) is one of the most aggressive malignant tumors of the gastrointestinal tract. There are two distinct histological types of EC: esophageal squamous cell carcinoma and adenocarcinoma of the esophagus. Etiologic factors and the patterns of incidence of both subtypes are different. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play an important role in esophageal carcinogenesis. Gellatinases MMP-2 and MMP-9 are able to degrade collagen IV from basement membranes and extracellular matrix which is related to tumor progression, including invasion, metastasis, growth and angiogenesis. It has been shown that increased expression of MMPs plays a crucial role in the development of several human malignancies, including esophageal cancer. The activity of MMPs is regulated by their endogenous natural inhibitors (TIMPs). Among these, the roles of TIMP-1 and TIMP-2 in EC development, tumor progression and formation of metastases have been most extensively characterized and best recognized

Matrix metalloproteinase 2 and tissue inhibitor of matrix metalloproteinases 2 in the diagnosis of colorectal adenoma and cancer patients.

The aim of the study was to assess the importance of the measurement of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of matrix metalloproteinases 2 (TIMP-2) in patients with colorectal cancer (CRC) in relation to clinicopathological features of tumor and patients' survival. Additionally, we determined serum MMP-2 and TIMP-2 in colorectal adenoma (CA) patients and healthy controls and compared them with tumor markers, CEA and CA 19-9. The serum levels of MMP-2 and TIMP-2 in 91 CRC patients, 28 CA subjects and 91 healthy controls were determined by ELISA method, but concentrations of CEA and CA 19-9 using MEIA method. Nonparametric statistical analyses were used. Serum levels of MMP-2 and TIMP-2 were significantly lower in CRC patients than in healthy subjects and decreased with tumor stage. Additionally, MMP-2 concentrations were significantly lower in patients with CRC than in CA group. Diagnostic sensitivity of TIMP-2 (59%) was the highest among biomarkers tested and increased in combined use with CEA (79%). Moreover, the area under ROC curve (AUC) of TIMP-2 was larger than AUC of MMP-2 in differentiation between CRC and healthy subjects, but lower than AUC of matrix metalloproteinase 2 in differentiation between colorectal cancer and adenoma. Our findings suggest clinical usefulness of TIMP-2 as a biomarker in the diagnosis of CRC, especially in combination with CEA. However, further investigation is necessary

Expression of matrix metalloproteinase-9 in the neoplastic and interstitial inflammatory infiltrate cells in the different histopathological types of esophageal cancer.

Metalloproteinase-9 (MMP-9) is the proteolytic enzyme degrading type IV collagen, and plays important role in the invasiveness and metastatic potential of tumor cells. The aim of the current study was to compare the association between the intensity of MMP-9 expression in neoplastic cells and in the interstitial inflammatory infiltrate cells in esophageal cancer with clinicopathological features of esophageal cancer (EC) and in different histopatological types of EC, e.g. adenocarcinoma and esophageal squamous cell carcinoma. The study included 32 EC patients, 17 cases of squamous cell carcinoma and 15 cases of adenocarcinoma, verified histopatologically. The presence of MMP-9 in cancer tissue was investigated by immunohistochemistry on formalin-fixed, wax-embedded sections of esophageal cancers. The light microscopy was used to evaluate the expression of metalloproteinase-9 in cancer cells and in inflammatory infiltrate in the neoplastic interstitium in semi-quantitative scale. The expression of MMP-9 in cancer cells was positive in 81% of cases whereas in inflammatory cells - in 75% and increased with tumor stage, depth of tumor invasion (T factor) and lymph node metastases (N factor). In squamous cell cancer the MMP-9 expression in cancer cells and in inflammatory infiltrate was higher than those in adenocarcinoma. Mean value of MMP-9 expression in inflammatory cells was higher in early stages of EC, whereas mean expression of this enzyme in cancer cells increased with tumor stage. In conclusion, this is the first study comparing the expression of metalloproteinase-9 in cancer and inflamatory infiltrate cells in different histopatological types of esophageal cancer. We proved the synthesis of MMP-9 by cancer cells as well as by inflammatory cells and its correlation with tumor stage, tumor size, depth of tumor invasion and lymph node metastases. The results suggest the role of MMP-9 in esophageal tumorigenesis, although this issue requires further investigations

Expression of tissue inhibitors of metalloproteinase 1 (TIMP-1) in gastric cancer tissue.

Degradation of extracellular matrix (ECM) is an essential step of invasion and metastasis of gastric cancer. The proteolysis of basement membranes depends on the balance between activities of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). The aim of the study was to assess the expression of TIMP-1 in gastric cancer (GC) and interstitial inflammatory infiltrate cells within GC tissue in relation to clinico-pathological features of tumor and to estimate the prognostic significance of TIMP-1 expression for patients' survival. The presence of TIMP-1 in 54 cases of gastric cancer samples was investigated by immunohistochemistry. The expression of TIMP-1 in cancer and interstitial inflammatory infiltrate cells was evaluated in semi-quantitative scale. The immunoreactivity of TIMP-1 in cancer and inflammatory cells was positive in 100% of cases and varied from weak to intense reaction. The intensity of TIMP-1 expression increased with more advanced tumor stages and in patients who died of cancer during 2-year observation. TIMP-1 expression in interstitial inflammatory infiltrate cells was the independent prognostic factor for patients' survival. The results suggest the role of TIMP-1 in gastric tumorigenesis, although this issue requires further investigtions

Comparison between clinical significance of serum proinflammatory proteins (IL-6 and CRP) and classic tumor markers (CEA and CA 19-9) in gastric cancer

Gastric cancer (GC) is a second most common cause of cancer-related death and represents an inflammation-driven malignancy. It has been suggested that interleukin 6 (IL-6) and C-reactive protein (CRP) play a potential role in the growth and progression of GC. The aim of the present study was to compare clinical significance of IL-6 and CRP with classic tumor markers—carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9) in GC patients. The study included 92 patients with GC and 70 healthy subjects. The serum concentrations of IL-6, CEA and CA 19-9 were determined using immunoenzyme assays, whereas CRP using immunoturbidimetric method. We defined the diagnostic criteria and prognostic value for proteins tested. In GC patients, the serum concentrations of all the proteins tested were significantly higher than in healthy subjects. The IL-6, CEA and CA 19-9 levels correlated with nodal metastases, while CRP with tumor stage, gastric wall invasion, presence of nodal and distant metastases. Diagnostic sensitivity of IL-6 was higher (85%) than those of other markers (CRP 66%, CA 19-9 34%, CEA 22%) and increased in combined use with CRP or CEA (88%). The area under ROC curve for IL-6 was larger than those of CRP and classic tumor markers (CEA and CA 19-9). None of the proteins tested was independent prognostic factor for the survival of GC patients. Our findings indicate better usefulness of serum proinflammatory proteins—IL-6 and CRP than classic tumor markers—CEA and CA 19-9 in the diagnosis of GC

CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool?

The search for a suitable biomarker which indicates immune system responses in cancer patients has been long and arduous, but a widely known biomarker has emerged as a potential candidate for this purpose. C-Reactive Protein (CRP) is an acute-phase plasma protein that can be used as a marker for activation of the immune system. The short plasma half-life and relatively robust and reliable response to inflammation, make CRP an ideal candidate marker for inflammation. The high- sensitivity test for CRP, termed Low-Reactive Protein (LRP, L-CRP or hs-CRP), measures very low levels of CRP more accurately, and is even more reliable than standard CRP for this purpose. Usually, static sampling of CRP has been used for clinical studies and these can predict disease presence or recurrence, notably for a number of cancers. We have used frequent serial L-CRP measurements across three clinical laboratories in two countries and for different advanced cancers, and have demonstrated similar, repeatable observations of a cyclical variation in CRP levels in these patients. We hypothesise that these L-CRP oscillations are part of a homeostatic immune response to advanced malignancy and have some preliminary data linking the timing of therapy to treatment success. This article reviews CRP, shows some of our data and advances the reasoning for the hypothesis that explains the CRP cycles in terms of homeostatic immune regulatory cycles. This knowledge might also open the way for improved timing of treatment(s) for improved clinical efficacy

Only vulnerable adults show change in chronic low-grade inflammation after contemplative mental training: evidence from a randomized clinical trial.

Growing evidence suggests that chronic low-grade inflammation can be reduced through mindfulness-based mental training interventions. However, these results are inconsistent and based on patient populations with heterogeneous conditions. Similar research in healthy adults is lacking. Moreover, common intervention protocols involve varying combinations of different contemplative practices, such that it remains unclear which types of training most effectively influence biomarkers of inflammation. The present study investigated the effect of three distinct 3-month training modules cultivating a) interoception and present-moment focus (Presence), b) socio-affective skills (Affect), or c) socio-cognitive skills (Perspective) on the inflammatory biomarkers interleukin-6 (IL-6) and high sensitive C-reactive protein (hs-CRP) in 298 healthy adults. We observed no group-level effect of training on either biomarker, but trend-level interactions of training type and participant sex. In additionally exploring the influence of participants' baseline inflammation, a selective training effect emerged: Following the Presence module, participants with relatively higher inflammatory load showed stronger reduction in IL-6 on average, and in hs-CRP if they were male. Mindfulness- and attention-based mental practice thus appears most effective when targeting chronic low-grade inflammation in healthy adults, particularly in men. Overall, our data point to a floor effect in the reduction of inflammatory markers through contemplative mental training, suggesting that mental training may be less effective in improving basal biological health outcomes in healthy, low-stressed adults than in vulnerable populations

Gender, Obesity and Repeated Elevation of C-Reactive Protein: Data from the CARDIA Cohort

C-reactive Protein (CRP) measurements above 10 mg/L have been conventionally treated as acute inflammation and excluded from epidemiologic studies of chronic inflammation. However, recent evidence suggest that such CRP elevations can be seen even with chronic inflammation. The authors assessed 3,300 participants in The Coronary Artery Risk Development in Young Adults study, who had two or more CRP measurements between 1992/3 and 2005/6 to a) investigate characteristics associated with repeated CRP elevation above 10 mg/L; b) identify subgroups at high risk of repeated elevation; and c) investigate the effect of different CRP thresholds on the probability of an elevation being one-time rather than repeated. 225 participants (6.8%) had one-time and 103 (3.1%) had repeated CRP elevation above 10 mg/L. Repeated elevation was associated with obesity, female gender, low income, and sex hormone use. The probability of an elevation above 10 mg/L being one-time rather than repeated was lowest (51%) in women with body mass index above 31 kg/m2, compared to 82% in others. These findings suggest that CRP elevations above 10 mg/L in obese women are likely to be from chronic rather than acute inflammation, and that CRP thresholds above 10 mg/L may be warranted to distinguish acute from chronic inflammation in obese women