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

Autotaxin (ATX), originally isolated from human melanoma cells, is a novel metastasis-enhancing motogen and angiogenesis factor. In the present study, we compared the expression level of ATX mRNA between normal and breast cancer tissues and found that the expression of ATX mRNA was closely linked to invasiveness of cancer cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemical analysis showed higher cellular ATX mRNA expression in the cancer than normal breast tissues. MDA-MB-435S breast cancer cells, expressing higher amount of ATX mRNA, showed greater relative invasiveness to fibroblast-conditioned medium (FCM) than MCF7, MDA-MB-231, and HBL-100 breast cancer cells. Furthermore, ATX-transfected MCF7 cells showed increased motility and invasiveness than vector-transfected MCF7 cells. Collectively, our results suggest that the expression of ATX is closely linked to the invasiveness of breast cancer cells.
Clin Exp Metastasis 2002
PMID:Expression of autotaxin (NPP-2) is closely linked to invasiveness of breast cancer cells. 1249 89

Prostate cancer cells metastasize to bone causing a predominantly osteosclerotic response. It has been shown that cells from the human prostate cancer cell line PC3 secrete factors that influence the behavior of osteoblast-like cells. Some of these factors with mitogenic activity have been found to be proteins with molecular weights between 20 and 30 kDa, but the identity of the osteoblastic mitogenic factor or factors produced by prostate cancer cells is still unknown. Therefore, the aim of this study was to characterize the protein profile of conditioned medium (CM) from PC3 cells in the molecular weight range from 5 to 30 kDa using proteome analysis. A protein profile of the CM from PC3 cells was performed by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). Thirty protein spots with molecular weights ranging from 5 to 30 kDa were analyzed by matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). One of these spots was identified as galectin-1. We examined whether PC3 CM, recombinant galectin-1 alone, or combined with insulin-like growth factor-I (IGF-I) had any effects on the proliferation or differentiation of human bone marrow stromal (hBMS) cells. Furthermore, we tested whether adhesion of PC3 cells to plastic, laminin, fibronectin, and collagen type I was influenced by lactose, which inhibits galectin-1. Galectin-1 (1000 ng/ml) inhibited the proliferation of hBMS cells up to 70 +/- 12% (treated/control) of control in contrast to PC3 CM, which induced hBMS cell proliferation by 3-fold. This effect was abolished by IGF-I. PC3 CM and galectin-1 in concentrations of 10 and 1000 ng/ml increased the alkaline phosphatase (ALP) activity of hBMS cells up to 175 +/- 27%, 137 +/- 8%, and 131 +/- 11%, respectively, compared with ALP activity of untreated cells, and inhibited the secretion of osteocalcin (OC) up to 81 +/- 3%, 93 +/- 1%, and 58 +/- 2%, respectively, compared with OC secretion of untreated cells. These effects were affected by IGF-I. Lactose inhibited adhesion of PC3 cells to plastic, fibronectin, laminin, and collagen type I up to 58 +/- 4%, 30 +/- 12, 72 +/- 9%, and 86 +/- 4%. In conclusion, galectin-1 modulated osteoblastic proliferation and differentiation. These effects were affected by IGF-I. Thus, galectin-1 is likely be involved in the osteoblastic response, caused by prostate cancer cells metastasizing into bone, by affecting the matrix mineralization.
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PMID:A proteome study of secreted prostatic factors affecting osteoblastic activity: galectin-1 is involved in differentiation of human bone marrow stromal cells. 1256 96

Melanoma invasion is a complex multi stage process involving changes to the cell/extracellular matrix (ECM) and cell/cell interactions. We have previously shown using an in vitro model of reconstructed human skin (consisting of human dermis with a basement membrane [BM] and populated with human skin cells) that some melanoma cells (HBL cell line) invade more actively in the presence of adjacent normal skin cells. The aim of the present study was to further investigate the relationship between melanoma cells, skin cells and ECM proteins during melanoma cell invasion through reconstructed skin, extending this to a study of three melanoma cell lines. We also examined whether such cell/cell induced invasion is due to increased expression and activation of matrix-metalloproteinase-2 (MMP-2) and MMP-9, or due to increases in general protease activity for keratinocytes, fibroblasts or melanoma lines. Addition of skin cells dramatically altered the invasive behaviour of the three metastatic melanoma cell lines (HBL, C8161 and A375SM) used; they increased the invasive ability of HBLs which were unable to invade on their own; they potentiated the invasion of C8161 cells which were invasive in their own right, but reduced the invasion of A375-SM cells which were aggressive invaders in the absence of skin cells. Latent forms of MMP-2, and MMP-9, were clearly expressed by the normal skin cells whereas all three melanoma lines weakly expressed these proteases. Fibroblast and keratinocyte MMPs were activated specifically by culture on type I collagen and on dermis which retained an intact basement membrane. These findings demonstrate that while there is an active communication between melanoma cells and adjacent skin cells, the invasive process is dictated by the melanoma cells and not the skin cells. However, activation of skin cell derived MMPs may play an important role in facilitating invasion by particular melanoma phenotypes.
Clin Exp Metastasis 2003
PMID:Melanoma invasion in reconstructed human skin is influenced by skin cells--investigation of the role of proteolytic enzymes. 1471 3

Parthenolide, a sesquiterpene lactone, shows antitumor activity in vitro, which correlates with its ability to inhibit the DNA binding of the antiapoptotic transcription factor nuclear factor kappaB (NF-kappaB) and activation of the c-Jun NH(2)-terminal kinase. In this study, we investigated the chemosensitizing activity of parthenolide in vitro as well as in MDA-MB-231 cell-derived xenograft metastasis model of breast cancer. HBL-100 and MDA-MB-231 cells were used to measure the antitumor and chemosensitizing activity of parthenolide in vitro. Parthenolide was effective either alone or in combination with docetaxel in reducing colony formation, inducing apoptosis and reducing the expression of prometastatic genes IL-8 and the antiapoptotic gene GADD45beta1 in vitro. In an adjuvant setting, animals treated with parthenolide and docetaxel combination showed significantly enhanced survival compared with untreated animals or animals treated with either drug. The enhanced survival in the combination arm was associated with reduced lung metastases. In addition, nuclear NF-kappaB levels were lower in residual tumors and lung metastasis of animals treated with parthenolide, docetaxel, or both. In the established orthotopic model, there was a trend toward slower growth in the parthenolide-treated animals but no statistically significant findings were seen. These results for the first time reveal the significant in vivo chemosensitizing properties of parthenolide in the metastatic breast cancer setting and support the contention that metastases are very reliant on activation of NF-kappaB.
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PMID:The sesquiterpene lactone parthenolide in combination with docetaxel reduces metastasis and improves survival in a xenograft model of breast cancer. 1595 58

The immune system recognizes diverse melanoma antigens. However, tumors can evade the immune response, therefore growing and progressing. It has been reported that galectin-3 and galectin-1 can induce apoptosis of activated lymphocytes. However, there is strong evidence indicating that the regulation of galectins function in the human tumor microenvironment is a complex process that is influenced by diverse biological circumstances. Here, we have investigated 33 biopsies (eight primary and 25 metastases) from 24 melanoma patients (15-72 years old) and describe the correlation between the expression of galectin-3 or galectin-1 and the level of apoptosis of tumor-associated lymphocytes using immunohistochemistry and an in situ nick translation assay. The range of galectin-3-positive tumor cells varied between 0% and 93% and that of galectin-1-positive tumor cells varied between 5% and 97%. In addition, 23 +/- 27% of tumor-associated lymphocytes were apoptotic. Although our results show a correlation between galectin-3 expression and apoptosis of tumor-associated lymphocytes, we could not find such correlation with galectin-1. Considering the complex process of cancer immunoediting, various interacting factors must be considered.
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PMID:Galectin-3 expression correlates with apoptosis of tumor-associated lymphocytes in human melanoma biopsies. 1665 32

The major role of matrix metalloproteinases (MMPs) is for homeostatic regulation of the extracellular environment, not simply to degrade matrix as their name suggests. We designed and printed a dedicated, focused DNA microarray, the CLIP-CHIP, that enables the analysis of every human and murine protease, protease homologue and inhibitor on a system-wide basis in cancer. We have also developed novel proteomic approaches to identify cleaved substrates of proteases in complex milieu. Isotope coded affinity tag (ICAT) and iTRAQ labeling of conditioned medium proteins secreted by MDA-MB-231 breast carcinoma cells and Mmp2 -/- murine fibroblasts transfected with protease (MT1-MMP or active MMP-2) or their inactive mutant forms enabled quantitative proteomics to be performed. Comparison of the relative abundance ratios of identical peptides from the two samples identified proteins in the conditioned medium that may have been degraded (low ratios) and those that were shed from the cell membrane (high ratios). MS/MS was used to sequence and identify the potential substrates. These analyses have revealed a plethora of new bioactive substrates and biological roles for MMPs. Biochemical confirmation of cleavage of the potential substrates was performed and the cleavage sites identified by MALDI-TOF. In these studies we discovered and confirmed that CTGF, galectin-1, death receptor-6, HSP90alpha, procollagen C-proteinase enhancer protein, the chemokine fractalkine, and cystatin C were novel MT1-MMP or MMP-2 substrates. These sophisticated cellular control functions highlight new intervention points in multiple pathways to treat early stage cancer.
Cancer Metastasis Rev 2006 Mar
PMID:Degradomics: systems biology of the protease web. Pleiotropic roles of MMPs in cancer. 1668 May 73

A combination of LC and MS was applied to an isogenic breast tumor metastasis model to identify proteins associated with a cellular phenotype. Chromatofocusing followed by nonporous-RP-HPLC/ESI-TOF MS was applied to cell lysates of a pair of monoclonal cell lines from the human breast carcinoma cell line MDA-MB-435 that have different metastatic phenotypes in immune-compromised mice. This method was developed to separate proteins based on pI and hydrophobicity. The high resolution and mass accuracy of ESI-TOF measurements provided a good correlation of theoretical MW and experimental Mr values of intact proteins measured in mass maps obtained in the pH range 3.8-6.4. The isolated proteins were digested by trypsin and analyzed by MALDI-TOF MS, MALDI-QIT-TOF MS, and monolith-based HPLC/MS/MS. The unique combination of the techniques provided valuable information including quantitation and modification of proteins. We identified 89 selected proteins, of which 43 were confirmed as differentially expressed. Metastasis-associated proteins included galectin-1, whereas annexin I and annexin II were associated with the nonmetastatic phenotype. In this study, we demonstrate that combining a variety of MS tools with a multidimensional liquid-phase separation provides the ability to map cellular protein content, to search for modified proteins, and to correlate protein expression with cellular phenotype.
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PMID:Proteomic profiling identifies breast tumor metastasis-associated factors in an isogenic model. 1720 1

To evaluate galectin-1, -3 and -7 serum levels as diagnostic and/or prognostic markers for head and neck squamous cell carcinomas (HNSCCs). ELISA was employed to test sera from 102 patients with HNSCCs and from 38 healthy control volunteers for galectin-1, -3 and -7 serum levels. Serum galectin levels were assayed by ELISA and the levels of galectin expression in HNSCCs were determined by means of immunohistochemistry. HNSCCs display significant immunohistochemical amounts of galectin-7, but this galectin cannot be detected in the blood of HNSCC patients. Galectin-3 levels differ significantly (p=0.03) in healthy volunteers and HNSCC patients. Using a threshold value of 4.3 ng/ml, galectin-3 serum level enabled a significant level of discrimination (p=0.03) to be established between the cancer patients and the healthy volunteers, with 90% level of specificity and 36% level of sensitivity. The discrimination was even better when using a threshold value of 13.5 ng/ml for galectin-1 (p=0.001), with 100% level of specificity and 22% level of sensitivity. A subgroup of stage IV HNSCC patients displayed significantly reduced levels of circulating galectin-1 (p=0.003) and galectin-3 (p=0.001) after treatment as opposed to before. Galectin-3 concentrations in sera from the patients with a metastatic disease were significantly (p=0.01) higher than in sera from the patients with localized tumors. The determination of circulating levels of galectin-1 and -3 could be used to monitor the progression of their disease or their response to therapy.
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PMID:The determination of the levels of circulating galectin-1 and -3 in HNSCC patients could be used to monitor tumor progression and/or responses to therapy. 1735 Mar 28

Metastasis is a final and eventually fatal step in the progression of oral squamous cell carcinoma (OSCC) and typically accompanies a large primary tumor. Metastasis may also present from a small primary tumor and progress rapidly; therefore, early diagnosis is important for patients with small primary tumors. Galectin-1 is one significantly upregulated tumor-associated protein in many neoplasms. To determine the clinical significance of galectin-1, we analyzed its expression in clinical samples by immunohistochemistry and reverse transcription-quantitative polymerase chain reaction assay. Galectin-1 protein was significantly overexpressed in the tumor-associated stroma as well as the invasion front during early oral carcinogenesis (P<0.05). During the metastatic stage, the only significant immunoreactivity was at the tumor invasion front (P<0.05). Although galectin-1 mRNA was not significantly upregulated in the whole cancerous tissue, it was upregulated in stromal parts during early-stage OSCC and in epithelial parts at the metastatic stage. Survival analysis and a Cox's proportional hazards model showed that synchronous upregulation of galectin-1 protein and mRNA was correlated with worse disease-free survival in early-stage OSCC (P=0.024 and P=0.047, respectively). Our findings suggest that galectin-1 upregulation at the tumor invasion front might be a predictor of early metastasis in oral carcinogenesis.
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PMID:Overexpression of galectin-1 at the tumor invasion front is associated with poor prognosis in early-stage oral squamous cell carcinoma. 1758 3

Although several molecular markers for human breast cancer exist, their versatility is limited. Here we demonstrate, through a differential proteome analysis utilizing the fluorogenic derivatization-liquid chromatography/tandem mass spectrometry (FD-LC-MS/MS) method between seven cancer cells and one normal cell, that the presence of cooperatively expressed annexin-2 and galectin-1 without tropomyosin-1 in a tissue could be used to diagnose metastatic breast cancer. Interestingly, in a metastatic cancer cell, the expression of the former two together with highly expressed cofilin-1 activates the Rho signal pathway to aggressively form disorganized actin filaments. Despite the excess expression of annexin-2 and galectin-1 in the normal cell, the highly expressed tropomyosin-1 counteracted the activity of cofilin-1 and stabilized the filaments, resulting in the restoration of the disorganization. This phenomenon suggests that enhancement of tropomyosin-1 should be used as therapy for metastatic breast cancer.
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PMID:A proteomics study on human breast cancer cell lines by fluorogenic derivatization-liquid chromatography/tandem mass spectrometry. 1882 27


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