Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005684 (bladder cancer)
 16,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Connective tissue matrix-degrading metalloproteinases play an important role in cancer invasion. In this report we describe the isolation of a metalloproteinase exhibiting both type IV collagenolytic and gelatinolytic activities from the conditioned medium of NIH-3T3 fibroblasts transformed with DNA containing an activated c-Harvey-ras oncogene from T24 bladder cancer cells. This tumor proteinase was purified by anion exchange chromatography, zinc-chelate Sepharose chromatography, and gel permeation chromatography. The final product was homogeneous on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (relative molecular mass = 67,000). Gelatin zymography revealed two bands of gelatinolytic activity, corresponding to molecular weights of 67,000 and 62,000. Upon immunoblotting with the use of an affinity-purified polyclonal rabbit antibody to a peptide region of type IV collagenase that lacks homology with interstitial collagenase or stromelysin, the purified tumor enzyme was identified as type IV collagenase.
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PMID:Purification of a gelatin-degrading type IV collagenase secreted by ras oncogene-transformed fibroblasts. 284 10

The balance between production and activation of MMPs and their inhibition by TIMPs is a crucial aspect of cancer invasion and metastasis. On the basis of the concept that MMPs synthesized in tissues seep into the bloodstream, we have examined MMP levels in the plasma of patients with cancer. In colorectal, breast, prostate, and bladder cancer, most patients with aggressive disease have increased plasma levels of gelatinase B. In patients with advanced colorectal cancer, high levels of either gelatinase B or TIMP complex were associated with shortened survival. We propose that these assays may be clinically useful in characterizing metastatic potential in selected kinds of cancer. In rheumatoid arthritis and systemic lupus erythematosus (SLE), serum and plasma levels of stromelysin-1 were approximately 3-5-fold increased. Fluctuating serum stromelysin-1 levels in SLE did not correspond with change in disease activity. In SLE, stromelysin-1 may be a component of the chronic tissue repair process rather than being responsible for inciting tissue damage. On the basis of these observations, we conclude that measurement of plasma/serum MMP and TIMP levels may provide important data for selecting and following patients considered for treatment with drugs that interfere with MMP activity.
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PMID:Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues. Clinical and experimental applications. 1041 33

Matrix metalloproteinases (MMPs) are proteolytic enzymes important at several points during multistep neoplastic progression. Although MMP-1 and MMP-3 have been implicated in the progression of various human cancers, their expression in bladder cancer has not been addressed. Immunohistochemistry (Strept-ABC-HRP method) and in situ hybridization were performed to detect MMP-1 protein, MMP-3 protein, and MMP-3 mRNA, respectively, in 59 transitional cell bladder carcinomas. To assess the role of these MMPs in bladder cancer, their expression was evaluated in relation to known clinicopathologic parameters and patients' disease-free and overall survival. Immunoreactivity for MMP-1 and MMP-3 proteins was observed in the cytoplasm of cancer cells in 30.5% and 24% of samples, respectively. Transcripts for MMP-3 mRNA were localized in stromal cells in 71.2% of cases and in cancer cells in 49% of cases. MMP-1 immunoreactivity demonstrated a statistically significant association with deeply invasive and grade III tumors versus superficial and lower grade tumors. MMP-3 protein immunoreactivity and MMP-3 mRNA immunolocalization did not associate with the parameters studied. However, MMP-3 mRNA localization in stromal cells demonstrated a borderline association with poor patients' disease-free and overall survival. In conclusion, the authors' results demonstrate a differential expression between MMP-1 and MMP-3 in bladder cancer; MMP-1 appears to participate in invasiveness and possibly in loss of differentiation in urothelial carcinomas in contrast to MMP-3.
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PMID:MMP-3 mRNA and MMP-3 and MMP-1 proteins in bladder cancer: a comparison with clinicopathologic features and survival. 1139 30

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been shown to stimulate the growth of a variety of cells in an autocrine or paracrine manner. Although HB-EGF is widely expressed in tumors compared with normal tissue, its contribution to tumorigenicity is unknown. HB-EGF can be produced as a membrane-anchored form (pro-HB-EGF) and later processed to a soluble form (s-HB-EGF), although a significant amount of pro-HB-EGF remains uncleaved on the cell surface. To understand the roles of two forms of HB-EGF in promoting tumor growth, we have studied the effects of HB-EGF expression in the process of tumorigenesis using in vitro and in vivo systems. We demonstrate here that in EJ human bladder cancer cells containing a tetracycline-regulatable s-HB-EGF or pro-HB-EGF expression system, s-HB-EGF expression increased their transformed phenotypes, including growth rate, colony-forming ability, and activation of cyclin D1 promoter, as well as induction of vascular endothelial growth factor in vitro. Moreover, s-HB-EGF or wild-type HB-EGF induced the expression and activities of the metalloproteases, MMP-9 and MMP-3, leading to enhanced cell migration. In vivo studies also demonstrated that tumor cells expressing s-HB-EGF or wild-type HB-EGF significantly enhanced tumorigenic potential in athymic nude mice and exerted an angiogenic effect, increasing the density and size of tumor blood vessels. However, cells expressing solely pro-HB-EGF did not exhibit any significant tumorigenic potential. These findings establish s-HB-EGF as a potent inducer of tumor growth and angiogenesis and suggest that therapeutic intervention aimed at the inhibition of s-HB-EGF functions may be useful in cancer treatment.
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PMID:HB-EGF is a potent inducer of tumor growth and angiogenesis. 1528 34

Signal transducers and activators of transcription (STATs) are latent transcription factors that mediate cytokine- and growth factor-induced transcription. Constitutive activation of STAT3 has been shown in human cancers and transformed cell lines. We report that STAT3, but not STAT1 and STAT5, becomes phosphorylated in response to epidermal growth factor (EGF) and achieves maximal induction of collagenase-1 (MMP-1) transcription by interacting with c-JUN. Phosphorylation of STAT3 protein is biphasic: the first peak within 30 min and the second peak between 4 and 8 h. Association of STAT3 with c-JUN is detected and its constituting STAT3 is increasingly phosphorylated. The STAT and AP-1 elements are necessary for effective induction of MMP-1 promoter by EGF. Mutation of AP-1 element closely located at the STAT site abolishes the binding not only of c-JUN but also of STAT3 to MMP-1 promoter, resulting in the loss of the responsiveness to EGF. By blocking STAT3 activity with the dominant-negative form, we show the requirement of STAT3 for EGF induction of MMP-1 and MMP-10 (stromelysin-2). Furthermore, expression of the dominant-negative STAT3 is sufficient to inhibit the constitutive and EGF-inducible cell migration and invasion and the tumor formation in nude mice. These results demonstrate that STAT3 phosphorylation and its possible interaction with c-JUN are required for the strong responsiveness of MMP-1 to EGF, and STAT3 activation is crucial for exhibition of malignant characteristics in T24 bladder cancer cells.
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PMID:Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells. 1620 32

Matrix metalloproteinases (MMP) contribute to tumor microenvironment and are associated with bladder cancer. A study examining the association between MMP polymorphisms and bladder cancer risk has never been published. We analyzed the association of 11 single nucleotide polymorphisms (SNPs) and one microsatellite polymorphism in MMP genes MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and MMP-12 with bladder cancer risk in 560 Caucasian patients and 560 controls matched on age, gender, and ethnicity. Individual, combination, haplotype, and diplotype analyses were done. No associations between individual MMP polymorphisms and overall bladder cancer risk were seen. The MMP-9 microsatellite > or =24 CA repeat allele and the MMP-12-82 GG polymorphisms were associated with invasive bladder cancer risk [odds ratio (OR), 2.60; 95% confidence interval (95% CI), 1.07-6.26; and OR, 4.59; 95% CI, 1.21-17.32, respectively]. Smoke-stratified analyses revealed several associations between MMP polymorphisms, alone and in combination, with bladder cancer risk, particularly in light smokers. Linkage disequilibrium was seen in all of the MMP-1, MMP-3, MMP-8, and MMP-12 SNPs and in four of five MMP-9 polymorphisms tested. Several MMP-9 haplotype and diplotypes were associated with overall and invasive bladder cancer risk. Our study suggests that genetic variations in the MMP family are associated with bladder cancer risk. Heavy carcinogen exposure may overwhelm some of the genetic effects of MMP polymorphisms. Our study confirms the importance of taking a multigenic pathway-based approach to risk assessment.
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PMID:Matrix metalloproteinase polymorphisms and bladder cancer risk. 1717 58

We investigated the matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) proteins in transitional cell carcinoma (TCC) cell lines and surgical specimens of the bladder neoplasm. The expression level was correlated to the degree of cellular differentiation and invasiveness of bladder cancer. Panels of six TCC cell lines with different degrees of differentiation were tested with monoclonal antibodies (mAbs) to MMP-1, MMP-2, MMP-3, MMP-9a, MMP-9b, TIMP-1 and TIMP-2 by immunocytochemistry. Gelatin zymography was also conducted on the cell lines for MMP-2 and -9. In addition, immunohistochemistry with the mAbs to MMP and TIM molecules was performed on 30 TCC specimens. We found that TCC cell lines were stained positively for MMP-1 (6/6), weakly for MMP-9a (2/6), MMP9b (5/6) and TIMP-1 (3/6), and negatively for MMP-2 (3/6) and MMP-3 (3/6). Zymographic analysis of the cell lines showed a high level of MMP2 in the MGH-U4 cell line. In bladder cancer surgical specimens, all specimens were positive for MMP1 (30/30), 19 were positive for MMP-2 (63.3%), 21 positive for MMP-9a (70%) and 15 positive for MMP-9b (50%). The expression of MMP-2 was found to be positively correlated with higher-grade tumors (p=0.036) and the expression of MMP-9a and -9b was found to be positively correlated with tumor stage (p=0.012 and 0.023, respectively). However, the expression of MMP-1, MMP-3, TIMP-1 and TIMP-2 was not correlated with either tumor staging or grading. In conclusion, the expression of MMP-2 and -9 was correlated with high-grade or high-stage bladder tumors, respectively. However, this correlation was not observed with TCC cell lines in which high- and low-grade tumors are included. Immunohistochemical results on tumor lesions may have more clinical relevance, since in a given tumor microenvironment the interaction among tumor cells in situ and tumor-associated cells, such as neutrophils, macrophages, lymphocytes and endothelial cells, as well as environmental factors (hypoxia and pH), cytokines and growth factors released by these cells may be required for TCC to express selective MMPs and TIMPs. The selective expression of these molecules then regulates tumor progression.
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PMID:Profiling of matrix metalloproteinases and tissue inhibitors of metalloproteinases proteins in bladder urothelial carcinoma. 2296 65

Homeobox genes (HOX genes) have been implicated in many tumors. As a member of HOX genes, HOXB5 is overexpressed in bladder cancer and contributes to the proliferation and invasion of breast cancer cells. However, functions of HOXB5 in retinoblastoma remain elusive. In this study, we found that HOXB5 expression is upregulated in retinoblastoma cell lines and tissues. Overexpression of HOXB5 promoted retinoblastoma cell migration and invasion, but knockdown of HOXB5 suppressed the migration and invasion. Moreover, HOXB5 induced the activation of ERK1/2 and upregulated the production of MMP-3 and MMP-13. In addition, ERK1/2 pathway was required for HOXB5-mediated retinoblastoma cell migration and invasion. Taken together, our study suggests that HOXB5 promotes the migration and invasion of retinoblastoma cells by inducing the activation of ERK1/2 and increasing the production of MMP-3 and MMP-13. Therefore, HOXB5 may represent an effective target for treatment of retinoblastoma.
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PMID:HOXB5 promotes retinoblastoma cell migration and invasion via ERK1/2 pathway-mediated MMPs production. 3001 11