Relationship between Metalloprotease-7 and -14 and Tissue Inhibitor of Metalloprotease 1 Expression by Mucosal Stromal Cells and Colorectal Cancer Development in Inflammatory Bowel Disease.

Colorectal carcinoma (CRC) associated with inflammatory bowel disease (IBD) is an example of an inflammation-related cancer. Matrix metalloproteases (MMP) are known to be associated with both processes. The aim of the study was to compare the expression of MMP-7, MMP-14 and tissue inhibitor of metalloproteases-1 (TIMP-1) in sporadic CRC- and IBD-associated CRC, and to compare the expression in inflamed and non-inflamed colonic tissue samples from IBD patients without or with associated CRC. An immunohistochemical study of MMP-7, -14 and TIMP-1 was performed on sporadic CRC (n = 86), IBD-associated CRC (n = 23) and colorectal mucosa of non-tumor samples from IBD patients without (n = 47) and with (n = 23) associated CRC. These factors were more frequently expressed by cancer-associated fibroblasts (CAF) from IBD-associated CRC than by CAF from CRC not associated with IBD. Regarding the inflamed tissue of IBD patients, Crohn's disease (CD) patients with CRC development showed a higher expression of MMP-14 by fibroblasts and by mononuclear inflammatory cells (MICs) than CD patients without CRC development. In non-inflamed tissue samples, MMP-7 associated with fibroblasts and MICs, and TIMP-1 associated with MICs, were more frequently expressed in CD patients with CRC development than in CD patients without CRC development. Our data suggest that these factor expressions by stromal cells may be biological markers of CRC development risk in IBD patients.

Toll-Like Receptor 4 and Matrix Metalloproteases 11 and 13 as Predictors of Tumor Recurrence and Survival in Stage II Colorectal Cancer.

Current clinical-pathologic stratification factors do not allow clear identification of high-risk stage II colorectal cancer (CRC) patients. Therefore, the identification of additional prognostic markers is desirable. Toll-like receptor (TLR)-4 is activated during tumorigenesis and matrix metalloproteases (MMPs) are involved in invasion and metastasis. We aimed to evaluate the expression and clinical relevance of TLR4, MMP11 and MMP13 for patients with stage II CRC. Immunohistochemistry was used to study the expression of TLR4, MMP11 and MMP13 in 96 patients with stage II CRC. We measured the global expression and the expression by different cell types (tumor cells, cancer-associated fibroblasts (CAFs) and mononuclear inflammatory cells (MICs)). The potential relationship between expressions of factors and different prognostic variables were evaluated. Our results show significant relationships between either TLR4 expression by tumor cells and MMP11 expression by CAFs and high risk of tumor recurrence. In addition, the concurrence of age ≥ 75 years and the non-expression of MMP11 by CAFs identify a subgroup of patients with a good prognosis. Our results show that TLR4 expression by tumor cells and MMP11 expression by CAFs may to improve the identification of patients with stage II CRC with a high-risk of relapse.

Clinical significance of myosin in colorectal cancer.

Myosin has raised an interest in cancer research because of its role in tumor progression. The aim of this study was to investigate the expression and clinical relevance of myosin in colorectal cancer (CC). Myosin was detected in CC tumors with recurrence using matrix-assisted laser desorption/ionization time-of-flight analysis. An immunohistochemical study was performed using tissue arrays and specific antibodies against myosin heavy chain. Determinations on cancer specimens from 91 patients with resectable CCs were performed. The minimum follow-up period was of 12.5 years for these patients without tumor recurrence. Western blot and real-time polymerase chain reaction analysis were also performed. Samples of carcinomas with recurrence showed an increased expression of myosin. Tumors with high myosin expression by tumor cell were significantly associated with higher probability of metastasis. Our results suggest that myosin expression in CCs is associated with tumor progression and metastasis development. Therefore, myosin tumor expression may contribute to an improved prognostic evaluation in patients with CC.

Prognostic value of cytosolyc cathepsin D content in resectable gastric cancer.

BACKGROUND AND AIMS: Cathepsin D (Cath-D) is an aspartyl protease involved in protein catabolism and tissue remodelling. In the present article, we evaluate the tumor content of Cath-D in resectable gastric carcinomas and its relation with clinical and pathological parameters, as well as its prognostic significance. METHOD: This prospective study included a series of 60 patients with primary gastric adenocarcinoma, who first underwent a complete surgical resection of their tumors and then were evaluated for disease recurrence and survival status during a mean follow-up period of 41.5 months. Cath D was measured in cytosolic samples using an immune-radiometric assay which determined the total amount of Cath-D (52K, 48K, and 34K). RESULTS: The tumor content of Cath-D ranged from 4 to 247 pmol/mg protein and from 6.4 to 97.7 pmol/mg protein in adjacent non-neoplastic mucosa samples. Cytosolic Cath-D levels were significantly higher in neoplastic tissues (P < 0.001). Statistical analysis also demonstrated that younger patients showed lower Cath-D tumor levels than older ones. Likewise, patients with lower tumor levels of Cath-D had better survival than those with intermediate or high Cath-D tumor content (P = 0.002). This finding showed an independent prognostic value on survival (P = 0.02). CONCLUSIONS: The present study demonstrates the presence of higher Cath-D content in gastric carcinomas than in adjacent non-neoplastic mucosa, and that high intratumor Cath-D levels identify a subgroup of resectable gastric cancer patients with a high probability of relapse as well as worse survival.