Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic cancer has a dismal prognosis due to the fact that patients present late when metastatic disease is already present. Previous studies have demonstrated that pancreatic cancer cells have decreased levels of MnSOD, which correlates well with increased rates of tumor cell proliferation. Recently, we have found that nude mice injected with MIA PaCa-2 human pancreatic cancer cells in the flank occasionally develop ascites and intra-abdominal metastatic deposits. Mice that developed ascites were sacrificed and the ascites cultured. Necropsy demonstrated metastatic tumors in the retroperitoneum, which were excised, digested, and cultured. Western blots, enzyme activity and enzyme activity gels were performed for manganese superoxide dismutase (MnSOD), copper/zinc (CuZnSOD), catalase, and glutathione peroxidase (GPx) in the ascites cell line, metastatic tumor cell line, MIA PaCa-2 primary pancreatic cancer cell line, and the Capan-1, a metastatic pancreatic cancer cell line. Cell growth, plating efficiency, growth in soft agar and growth in nude mice were determined in the ascites, metastatic tumor, and MIA PaCa-2 cell lines. MnSOD, CuZnSOD, and GPx protein and activity were increased in the ascites, metastatic tumor, and Capan-1 cell lines compared to MIA PaCa-2. The ascites and metastatic tumor cell lines had decreased cell growth, plating efficiency, and growth in soft agar, but the ascites cell line had increased cell growth in 4 and 1% O(2) concentrations in vitro and more rapid growth in vivo. Metastatic disease is associated with changes in the content and activity of antioxidant enzymes with an associated change in growth characteristics depending on the O(2) concentrations.
Clin Exp Metastasis 2005
PMID:Metastatic progression of pancreatic cancer: changes in antioxidant enzymes and cell growth. 1647 22

The risk of metastatic progression for prostate cancer patients who undergo radical prostatectomy is best estimated presently based on prostate-specific antigen (PSA) doubling time (PSADT). However, additional markers of risk are needed to identify patients who may benefit from aggressive salvage treatment. A decrease in zinc-alpha2-glycoprotein (AZGP1) mRNA levels in malignant prostate epithelium was previously shown to predict biochemical recurrence, as defined by rising levels of serum PSA after radical prostatectomy. We assessed the reliability with which AZPG1 expression could predict clinical recurrence and metastatic progression. Using immunohistochemical methods, we analyzed AZPG1 expression in malignant prostate epithelium in prostatectomy specimens from 228 prostate cancer patients. Low (i.e., absent or weak) AZGP1 expression was associated with clinical recurrence (defined as confirmed localized recurrence, metastasis, or death from prostate cancer; hazard ratio [HR] = 4.8, 95% confidence interval [CI] = 2.2 to 10.7, P<.001) and with bony metastases or death from prostate cancer (HR = 8.0, 95% CI = 2.6 to 24.3, P<.001). Among the 17 patients in the cohort in whom clinical recurrence was associated with short PSADT, absent or weak AZGP1 expression was observed in 13 patients. If these preliminary findings are validated in independent cohorts, the measurement of AZGP1 levels in radical prostatectomy specimens may permit an accurate and timely assessment of risk of metastatic progression after radical prostatectomy.
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PMID:Zinc-alpha2-glycoprotein expression as a predictor of metastatic prostate cancer following radical prostatectomy. 1701 89

We recently identified NAC-1, member of the bric-a-brac tramtrack broad complex/poxvirus and zinc domain family, as an overexpressed gene in ovarian serous carcinoma and found more frequent NAC-1 protein expression in recurrent compared to primary tumors. In the present study, we assessed the clinical significance of NAC-1 expression in ovarian carcinoma effusions. Formalin-fixed, paraffin-embedded sections from 176 effusions (137 peritoneal, 39 pleural) and 197 corresponding solid tumors (69 primary tumors, 128 solid metastases) were analyzed for NAC-1 expression using immunohistochemistry. Staining intensity and extent results were analyzed for possible association with clinicopathologic parameters and survival. Nuclear NAC-1 immunoreactivity was found in carcinoma cells in 98% of (173/176) effusions, 94% (65/69) of primary tumors, and 95% (121/128) of metastases. Staining intensity and extent were significantly higher in effusions compared with matched solid tumors (P = .002 for intensity, P = .003 for extent compared with primary tumors; P < .001 for both intensity and extent compared with metastases). Furthermore, NAC-1 expression intensity was significantly higher in specimens obtained after the administration of chemotherapy (P = .002) and correlated with shorter progression-free survival (PFS) in analysis of 62 patients with post-chemotherapy effusions (P = .039). International Federation of Gynecology and Obstetrics stage (IV versus III) was the only clinical parameter associated with PFS in this group (P = .004). In Cox analysis, only the International Federation of Gynecology and Obstetrics stage was an independent predictor of shorter PFS (P = .009). In conclusion, NAC-1 expression is higher in ovarian carcinoma cells in effusions compared with their solid tumor counterparts. NAC-1 is up-regulated in tumor cells after chemotherapy, suggesting a role for this protein in tumor progression and in the development of chemotherapy resistance in ovarian cancer.
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PMID:Expression and clinical role of the bric-a-brac tramtrack broad complex/poxvirus and zinc protein NAC-1 in ovarian carcinoma effusions. 1739 28

Colorectal cancer, the second leading cause of cancer deaths in the United States, has a high probability of metastasizing to the liver. Matrix metalloproteinases (MMPs) are a family of zinc dependent endopeptidases that are implicated in cancer metastasis and many aspects of tumor progression. Using a splenic injection experimental metastasis model, mice that are genetically deficient in MMP-9 demonstrated a nearly 2-fold decrease in liver weight compared with wild type (WT) mice following injection with MC38 syngeneic colorectal cancer cells. Bioluminesence imaging data demonstrates an early negative effect on tumor growth in MMP-9 null mice when compared with WT controls. Reconstitution of the bone marrow in MMP-9-/- mice with cells competent to produce MMP-9 did not recapitulate the WT phenotype of overwhelming burden of metastatic disease in the liver. In situ hybridization revealed the presence of MMP-9 mRNA in both MC38 tumor cells and in surrounding stromal cells, and immunostaining with anti MMP-9 was consistent with MMP-9 expression by resident liver Kupffer cells. Stromal-derived MMP-9 contributes to the establishment and growth of colorectal metastases in the liver. Stromal MMP-9 was derived from resident cells, most likely Kupffer cells, as opposed to infiltrating bone marrow-derived cells and the effect of stromal MMP-9 was independent of expression of MMP-9 by tumor cells. Stromal-derived MMP-9 may represent an important target for selective inhibition in the treatment of metastases. (c) 2007 Wiley-Liss, Inc.
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PMID:Resident stromal cell-derived MMP-9 promotes the growth of colorectal metastases in the liver microenvironment. 1741 72

A captive 33-year-old male white rhinoceros with seasonal dermatitis was diagnosed with a malignant squamous cell carcinoma on the right flank. Staphylococcus aureus was cultured from the skin lesions. No fungal or yeast was isolated. The dermatitis was treated with a combination of oral antibiotics (trimethoprim-sulphadiazine) and topically with weekly chlorhexidine washes and a mixture of a zinc oxide, balsam peru and bismuth oxide cream. Under azaperone and butorphanol anaesthesia, the skin tumour was surgically removed. The tumour was excised with wide margins and allowed to heal by secondary intention as primary wound closure was not possible. A post-mortem performed 2 years later for an unrelated condition revealed no metastases or recurrence of the skin tumour. It was presumed that chronic irritation or trauma may have contributed to the development of the skin tumour. This is the first detailed report of the successful treatment of a squamous cell carcinoma not associated with the horn in a rhinoceros.
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PMID:Successful treatment of a squamous cell carcinoma in a white rhinoceros, Ceratotherium simum. 1799 Nov 66

Matrix Metalloproteinases (MMPs) are zinc-containing proteinases that are responsible for the metabolism of extracellular matrix proteins. Overexpression of MMPs has been associated with a wide range of pathological diseases such as arthritis, cancer, multiple sclerosis and Alzheimer's disease. The excessive and unregulated activity of Matrix Metalloproteinases type 2 (MMP-2), also known as gelatinase A, has been identified in a numbers of cancer metastases. Several MMP inhibitors (MMPi) have been proposed in the literature aiming to interfere in the MMPs activity. In this work we performed long MD simulations in order to study the dynamical behavior of the binding pocket S1' in the apo forms of MMP type 2 and 3, and identify, at the molecular level, the structural properties relevant for the designing of specific inhibitor of MMP-2.
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PMID:Molecular dynamics simulations of metalloproteinases types 2 and 3 reveal differences in the dynamic behavior of the S1' binding pocket. 1822 Jul 84

HIV cellular entry is a multistep process that requires the interaction of a viral envelope glycoprotein (gp120) and a host receptor (CD4) followed by binding to a co-receptor. The CC-chemokine receptor 5 (CCR5) and CXC-chemokine receptor 4 (CXCR4) have been identified as the major HIV co-receptors and therefore are promising targets for the development of new anti-HIV drugs. CXCR4 is also involved in several diseases such as angiogenesis, metabolic and neurological disorders, rheumatoid arthritis and in different forms of metastatic cancer. Herein, we present a review focusing on small molecule CXCR4 antagonists. These compounds are divided into 11 classes that include cyclic penta- and tetrapeptides, diketopiperazine mimetics, bicyclams, non-bicyclams, tetrahydroquinolines, thiazolylisothiourea derivatives, benzodiazepines, alkyl amine analogs and non-peptides derivatives, dipicolylamine-zinc(II) complexes, ampelopsin and distamycin analogs. The most advanced CXCR4 antagonists documented are bicyclam derivatives, which are specific CXCR4 antagonists and exhibit potency in the nanomolar range. Further development of selective CXCR4 antagonists continues to be crucial for the design of second generation of anti-HIV drugs. We aim to provide a comprehensive summary of diverse structural templates that could be useful for optimization and discovery of novel CXCR4 antagonists.
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PMID:Small molecules anti-HIV therapeutics targeting CXCR4. 1828 65

In this study, we evaluate whether Snail is expressed in adrenocortical cancer (ACC) and if its expression is related to patient outcome. One of the best known functions of the zinc-finger transcription factor Snail is to induce epithelial-to-mesenchymal transition (EMT). Increasing evidence suggests that EMT plays a pivotal role in tumour progression and metastatic spread. Snail and E-cadherin expression were assessed by immunohistochemistry in 26 resected ACCs and real-time quantitative RT-PCR expression analysis was performed. Data were correlated with clinical outcome and in particular with overall patient survival. Seventeen of 26 (65%) ACC tumour samples expressed Snail when assessed by immunohistochemistry. Snail expression was neither detected in normal adrenocortical tissue, nor in benign adrenocortical adenomas. Expression levels were confirmed on the mRNA level by Real-Time-PCR. Survival rates were significantly decreased in Snail-positive tumours compared to Snail-negative tumours: 10 out of 16 vs one out of eight patients succumbed to disease after a median follow up of 14.5 and 28.5 months, respectively (P=0.03). Patients with Snail-expressing ACCs presented in advanced disease (11 out of 12 vs 6 out of 14, P=0.01) and tend to develop distant metastases more frequently than patients with negative staining (7 out of 11 vs two out of eight, P=0.19). In conclusion, we describe for the first time that Snail is expressed in a large subset of ACCs. Furthermore, Snail expression is associated with decreased survival, advanced disease and higher risk of developing distant metastases.
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PMID:Expression of the zinc-finger transcription factor Snail in adrenocortical carcinoma is associated with decreased survival. 1901 64

Phaeochromocytomas are uncommon tumours of adrenal or extra-adrenal chromaffin tissue. About 2-26% of these have been reported to metastasize, but, on histological criteria, it is virtually impossible to predict malignant behaviour of the tumour. Using immunohistochemistry, we analysed the protein expression of SNAIL, a zinc-finger transcription factor, in a series of 50 phaeochromocytoma specimens from 42 patients. We found that SNAIL-expressing cells are frequent in metastatic primary tumours and their metastases, whereas in tumours without metastases, SNAIL expression is commonly absent. We conclude that the expression of SNAIL may be of use in predicting the metastatic potential of phaeochromocytoma.
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PMID:High frequency of SNAIL-expressing cells confirms and predicts metastatic potential of phaeochromocytoma. 1964 Oct 25

Discoidin domain receptors (DDRs) are receptor tyrosine kinases that get activated by collagens in its native triple-helical form. In mammalian cells, DDR family consists of two members, namely DDR1 and DDR2, which mediates migration and proliferation of several cell types. DDR1 is activated by native type IV collagen and overexpressed in human breast cancer. Type IV collagen is the main component of basement membrane (BM), and the ability to degrade and penetrate BM is related with an increased potential for invasion and metastasis. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that collectively are capable of degrading all components of the extracellular matrix, including the BM. In breast cancer cells, denatured type IV collagen induces MMP-9 secretion and invasion. However, the role of DDR1 in the regulation of gelatinases (MMP-2 and -9) secretion and invasion in breast cancer cells remains to be studied. We demonstrate here that native type IV collagen induces MMP-2 and -9 secretions and invasion through a DDR1 and Src-dependent pathway, together with an increase of MMP-2 and -9-cell surface levels. MMP-2 and -9 secretions require PKC kinase activity, epidermal growth factor receptor (EGFR) activation, arachidonic acid (AA) production and AA metabolites in MDA-MB-231 breast cancer cells. In summary, our data demonstrate, for the first time, that DDR1 mediates MMP-2 and -9 secretions and invasion induced by native type IV collagen in MDA-MB-231 breast cancer cells.
Clin Exp Metastasis 2011 Jun
PMID:Role of DDR1 in the gelatinases secretion induced by native type IV collagen in MDA-MB-231 breast cancer cells. 2146 59


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