Tumor progression and metastasis contribute to the great majority of breast cancer deaths. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are thought to be involved in tumor progression and metastasis. Thus, we determined whether the expression of MMP-9 and TIMP-1 is associated with prognosis in breast cancer patients. We measured serum MMP-9 and TIMP-1 by enzyme-linked immunosorbent assay in 60 breast cancer patients, 18 benign breast disease patients and 15 healthy controls. We also evaluated the expression of MMP-9 and TIMP-1 protein and mRNA in paraffin-embedded tumor tissues from the 60 breast cancer patients by immunohistochemistry and in situ hybridization. We then correlated serum and tissue levels of MMP-9 and TIMP-1 in breast cancer samples and their expression with patients' clinicopathologic characteristics. We found that serum levels of MMP-9 and TIMP-1 were significantly higher in breast cancer patients than in benign breast disease and in healthy controls. High serum levels of MMP-9 and TIMP-1 were associated with lymph node metastasis, higher tumor stage and lower relapse-free and overall survival (OS) rates. Compared to low expression, high tissue expression of MMP-9 protein was associated with lymph node metastasis and higher tumor stage; and high tissue expression of TIMP-1 was associated with a lower OS rate. Our findings suggest that MMP-9 and TIMP-1 may further be evaluated as biomarkers for predicting progression and prognosis of breast cancer. ' 2008 Wiley-Liss, Inc.Key words: MMP-9; TIMP-1; breast cancer; serum biomarker; patient survival Breast cancer is one of the most common neoplasias in women worldwide. However, despite considerable diagnostic and therapeutic advances in recent years, it is still the most common cause of cancer death in women aged 40-49 years in the United States. 1 Approximately 40% of patients with localized breast cancer have micrometastatic disease that is difficult to detect at the time of diagnosis and treatment (especially during adjunctive therapy after surgery) and results in disease recurrence and death several years after diagnosis. 2-4 Serum biomarkers would be valuable in the early diagnosis of breast cancer; they would also be useful to clinicians in detecting micrometastasis and determining the risk of recurrence. This information would also help clinicians determine suitable therapy.Matrix metalloproteinases (MMPs) are a large family of highly homologous, zinc-and calcium-dependent extracellular enzymes that can be loosely categorized as matrilysin, gelatinases, stromelysin, collagenases or membrane-type MMPs on the basis of substrate specificity, protein domain structure, sequence homologic characteristics and ability to be secreted. 5-7 MMP-9 is one of the 2 gelatinases that has been implicated in tumor cell invasion and metastasis because of its unique ability to degrade Type IV collagen (a major component of the basement membrane) and other essential extracellular matrix components. 8,9 MMP-9 and its natural...
We used flow cytometry and a DNA-binding dye efflux assay to isolate a side population (SP) of cells with stem cell characteristics from the human pancreatic carcinoma cell line, PANC-1. Non-obese diabetic/severe combined immunodeficiency mouse xenograft experiments showed that SP cells were enriched in tumor initiating capability compared with non-SP cells. Cultured SP cells were able to differentiate into daughter cells and non-SP cells, through asymmetric division. Our study demonstrated that SP cells had high drug-resistance, both in vivo and in vitro. SP cells also showed significantly higher levels of mRNA expression for CD133, ABCG2 and Notch1, when compared to non-SP cells. Furthermore, xenografted tumors derived from injected SP cells and treated with gemcitabine had more CD133+ cells than untreated ones. We therefore suggest that these SP cells from the PANC-1 cell line were enriched with cancer stem cells.
Altered expression of receptor tyrosine kinases contributes to tumorigenic behaviors of epithelial cancers. In this study, the pathogenic roles of receptor tyrosine kinase RON (recepteur d'origine nantais) in regulating oncogenic phenotypes in colorectal epithelial cells were studied. Increased expression of RON and its variants resulted in colony formation and motile activities of colonic epithelial AA/C1 cells as evident in soft-agar and migration assays, respectively. These results suggest that overexpression of wild-type RON mediates the transformed phenotypes in immortalized colon epithelial cells. In colorectal cancer cells (HT-29, HCT116, and SW620) that naturally express RON, the RON gene expression was silenced by RNA interference. The introduction of RON-specific small interfering (si) RNA significantly affected cancer cell proliferation, motility, and led to increased apoptotic cell death. Focus-forming activities and anchorage-independent growth of colon cancer cells were also dramatically reduced. Moreover, it was demonstrated in tumor growth assays that silencing RON gene expression significantly reduces tumorigenic activities of SW620 cells in vivo. By analysing signaling proteins involved in colon carcinogenesis, we found that the effect of RON-specific siRNA is associated with diminished expression of bcatenin, a critical component in the Wnt signaling pathway. Taken together, our results demonstrate that altered expression of RON in colon cancer cells is required to maintain tumorigenic phenotypes. Thus, silencing RON gene expression could have potential to reverse malignant activities of colon tumors in vivo.
Altered expression of GATA factors was found and proposed as the underlying mechanism for dedifferentiation in ovarian carcinogenesis. In particular, GATA6 is lost or excluded from the nucleus in 85% of ovarian tumors and GATA4 expression is absent in majority of ovarian cancer cell lines. Here, we evaluated their DNA and histone epigenetic modifications in five ovarian epithelial and carcinoma cell lines (human 'immortalized' ovarian surface epithelium (HIO)-117, HIO-114, A2780, SKOV3 and ES2). GATA4 and GATA6 gene silencing was found to correlate with hypoacetylation of histones H3 and H4 and loss of histone H3/lysine K4 trimethylation at their promoters in all lines. Conversely, histone H3/lysine K9 di-methylation and HP1c association were not observed, excluding reorganization of GATA genes into heterochromatic structures. The histone deacetylase inhibitor trichostatin A, but not the DNA methylation inhibitor 5 0 -aza-2 0 -deoxycytidine, re-established the expression of GATA4 and/or GATA6 in A2780 and HIO-114 cells, correlating with increased histone H3 and H4 acetylation, histone H3 lysine K4 methylation and DNase I sensitivity at the promoters. Therefore, altered histone modification of the promoter loci is one mechanism responsible for the silencing of GATA transcription factors and the subsequent loss of a target gene, the tumor suppressor Disabled-2, in ovarian carcinogenesis.
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