Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breakdown of basement membrane (BM) is believed to be an essential step for tumor invasion and metastases. We have previously demonstrated that matrix metalloproteinase-9 (MMP-9), the 92 kDa collagenase expression correlates with metastases in human colorectal cancer (CRC). This study explores the relationship between the 72 and 92 kDa type IV collagenase (MMP-2 and MMP-9) activities and pattern of type IV collagen expression during human colorectal tumorigenesis. Thirty-four CRC patients, including four synchronous adenomas and one synchronous liver metastases, were involved in this study. By immunohistochemical staining, type IV collagen expression was noted to be continuous in the BM of normal mucosa, adenoma and in two cases of carcinoma in situ. Limited or absent type IV collagen staining pattern was seen in 100 (19/19) and 23% (3/13) of CRC with and without metastases, respectively. By double immunostaining, MMP-9 protein expression was noted to localize within areas of limited type IV collagen staining. Similarly, type IV collagen staining was noted to be greatest in areas devoid of MMP-9 expression. Gelatin zymography detected both 92 and 72 kDa proenzyme forms in all CRC and normal mucosa extracts examined. The mean tumor/normal fold increases of the proMMP-2 and proMMP-9 enzyme forms were 1.6+/-0.1 (mean +/- SE) and 2.4+/-0.5 in adenomas, and 2.1+/-0.2 and 4.1+/-0.7 in CRC, respectively. The 62 and 82 kDa bands were present in 63 (12/19) and 74% (14/19) of CRC with metastases, compared with only 20 (3/15) and 33% (5/15) of CRC without metastases, respectively. These differences were significant (P = 0.045 and P = 0.030, respectively). Our results demonstrate that loss of BM type IV collagen along with elevations in MMP-2 and MMP-9 expression, especially the activated forms, occur during colorectal tumorigenesis. Our data suggest that control of type IV collagenase activation may be beneficial in preventing human colorectal tumor progression.
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PMID:Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis. 1033 90

The rate of membrane vesicle shedding by tumor cells is probably related to their invasive capability. In order to verify whether the vesicle amount could be utilized as a marker of different pathologies, we analyzed biological fluids obtained from 33 patients with gynecological diseases. In fluids of benign serous cysts, vesicle content was extremely low; in cystoadenomas and fibromas generally it was low. On the contrary, large amounts of vesicles were found in malignant tumor fluids. Gelatin zymographies showed the presence of MMP-2 and MMP-9 in all vesicles except in those recovered from fluids of some serous cysts. A positive correlation between tumor malignancy and both vesicle-amount and vesicle-associated MMP-2 activity was noticed. We also analyzed vesicle content in ascitic fluids recovered from two carcinomas at different times during clinical treatment. In both cases, tumor progression, not monitored by Ca 125 levels, was pointed out by an increased amount of vesicles in ascites. These findings suggest that vesicle content in biological fluids could represent a new useful marker of tumor aggressiveness and tumor progression.
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PMID:Membrane vesicles in ovarian cancer fluids: a new potential marker. 1062 32

The non-receptor tyrosine kinase c-Src has been implicated in the development of numerous human cancers. c-Src is activated in colon cancers, particularly in highly metastatic cells, and its overexpression strongly correlates with tumor progression. C-terminal Src kinase (Csk) has been demonstrated to negatively regulate Src family tyrosine kinases through tyrosine phosphorylation at the C-terminal regulatory site (Tyr-527). We report herein that down-regulation of Src kinase activity by adenovirus-mediated csk gene transfer abrogated the highly metastatic phenotype of colon cancer cells. Overexpression of Csk decreased Src tyrosine kinase activity in NL-17 cells, the highly metastatic clone of mouse colon adenocarcinoma 26. Importantly, Csk overexpression in NL-17 cells resulted in significant suppression of in vivo metastasis, without affecting its tumorgenicity. Csk overexpression decreased the invasiveness of NL-17 cells through Matrigel, in vitro reconstituted basement membrane. Gelatin zymography confirmed the decreased protein levels of MMP-2 (gelatinase A) in the supernatants of Csk-overexpressed NL- 17 cells. These results provide a therapeutic basis for interfering with metastasis of colon cancer by csk gene-mediated down-regulation of Src kinase activity.
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PMID:Overexpression of the csk gene suppresses tumor metastasis in vivo. 1105 67

We previously showed that enhanced expression of MMP-9, an endopeptidase that digests basement-membrane type IV collagen, is related to tumor progression in vitro and in vivo; antisense-MMP-9 stably transfected clones were less invasive than untransfected parental cells and did not form tumors in nude mice. In this study, we examined the role of ERK-1 in the regulation of MMP-9 production and the invasive behavior of the human glioblastoma cell line SNB19, in which ERK1 is constitutively activated. SNB19 cells were stably transfected with mt-ERK, a vector encoding ERK-1 cDNA in which the conserved lysine at codon 71 was changed to arginine, thus impairing the catalytic efficiency of this enzyme. Gelatin zymography showed reduced levels of MMP-9 in the mt-ERK-transfected cell lines relative to those in vector-transfected and parental control cells. Reductions in MMP-9 protein mRNA levels were also detected in the mt-ERK-transfected cells by Western and Northern blotting. The mt-ERK-transfected cells were much less invasive than parental or vector control cells in a Matrigel invasion assay and in a spheroid coculture assay. Thus an ERK-dependent signaling pathway seems to regulate MMP-9 mediated glioma invasion in SNB19 cells; interfering with this pathway could be developed into a therapeutic approach, which aims at a reduction of cancer cell invasion.
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PMID:Downregulation of MMP-9 in ERK-mutated stable transfectants inhibits glioma invasion in vitro. 1216 59

Overexpression of insulin-like growth factor binding protein-2 (IGFBP-2) has been shown to be associated with tumor progression in several human malignant tumors; however, the significance of IGFBP-2 expression in bladder cancer remains poorly defined. The objective of this study was to investigate the effect of IGFBP-2 overexpression in human bladder cancer KoTCC-1 cells on their phenotype associated with tumor progression. We introduced IGFBP-2 cDNA into KoTCC-1 cells, which do not express a detectable level of IGFBP-2 protein, thus generating an IGFBP-2 overexpressing cell line (KoTCC-1/BP2). We also generated a vector-only-transfected cell line (KoTCC-1/C) as a control. Despite the absence of a significant difference in in vitro cell growth rates and motilities among KoTCC-1 sublines, KoTCC-1/BP2 exhibited significantly higher invasive ability than KoTCC-1/C. Gelatin zymography showed a marked increase in matrix metalloproteinase-2 (MMP-2) production by KoTCC-1/BP2 compared with that by KoTCC-1/C. Furthermore, there was no significant difference in sub-cutaneous tumor growth among KoTCC-1 sublines; however, more advanced tumor progression, including lymph node metastasis and hemorrhagic ascites formation, was observed after the implantation of KoTCC-1/BP2 into the bladder wall of nude mice than after the implantation of KoTCC-1/C. These findings suggest that overexpression of IGFBP-2 induces an increase in MMP-2 production, resulting in the enhanced metastatic potential of bladder cancer.
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PMID:Introduction of insulin-like growth factor binding protein-2 gene into human bladder cancer cells enhances their metastatic potential. 1564 22

Basigin/CD147, also named extracelluar matrix metalloproteinase inducer (EMMPRIN), has been implicated in playing very important roles in several aspects of tumor progression. In this study, we examined the inhibitory effects of antisense RNA of CD147 on invasion and angiogenesis of human glioblastoma U251 cells in vitro. The U251 cell line was transfected by a plasmid containing antisense CD147 cDNA. Gelatin zymography was used to determine the effect on reducing secretions of MMP-2 and MMP-9 of the transfected cells. Boyden chamber was employed to test the invasion of U251 cells in vitro. We found that downregulation of CD147 resulted in reducing secretions of MMP-2, MMP-9, and VEGF. Moreover, the invasion of stable antisense transfectants was inhibited. Wound-induced migration assay also showed decreased migration in stable antisense transfectants compare to parental- and empty vector-transfected cells. Taken together, these results provide evidence that invasion of human glioblastoma cells can be inhibited by antisense RNA of CD147. Basigin/CD147 may be used as a potential target of drugs for anti-invasion and metastasis of human glioblastoma cells.
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PMID:Inhibition of basigin expression in glioblastoma cell line via antisense RNA reduces tumor cell invasion and angiogenesis. 1597 Jun 88

Hypoxia is a critical event in tumor progression and angiogenesis. Hypoxia can be detected noninvasively by a novel spectroscopic photoacoustic tomography technology (SPAT) and this finding is supported by our molecular biology investigation aimed to elucidate the etiopathogenesis of SPAT detected hypoxia and angiogenesis. The present study provides an integrated approach to define oxygen status (hypoxia) of intracranial tumor xenografts using spectroscopic photoacoustic tomography. Brain tumors can be identified based on their distorted vascular architecture and oxygen saturation (SO2) images. Noninvasive in vivo tumor oxygenation imaging using SPAT is based on the spectroscopic absorption differences between oxyhemoglobin (O2Hb) and deoxyhemoblobin (HHb). Sprague-Dawley rats inoculated intracranially with ENU1564, a carcinogen-induced rat mammary adenocarcinoma cell line, were imaged with SPAT three weeks post inoculation. Proteins important for tumor angiogenesis and invasion were detected in hypoxic brain foci identified by SPAT and were elevated compared with control brain. Immunohistochemistry, Western blotting, and semi-quantitative RT-PCR showed that HIF-1 alpha, VEGF-A, and VEGFR2 (Flk-1) protein and mRNA expression levels were significantly higher (P < 0.05) in brain tumor tissues compared to normal brain. Gelatin zymography and RT-PCR demonstrated the upregulation of MMP-9 in tumor foci compared with brain control. Together these results suggest the critical role of hypoxia in driving tumor angiogenesis and invasion through upregulation of target genes important for these functions. Moreover this report validates our hypothesis that a novel noninvasive technology (SPAT) developed in our laboratory is suitable for detection of tumors, hypoxia, and angiogenesis.
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PMID:In vivo imaging and characterization of hypoxia-induced neovascularization and tumor invasion. 1714 11

Activation of androgen receptor (AR) stimulates the growth of not only androgen-dependent but also of androgen-refractory prostate cancer. However, neither the role of AR in invasion/metastasis nor the relationship between invasiveness and androgen-refractory status has been established. In this study, we used the androgen-dependent prostate cancer cell line MDA PCa 2b, derived from a human bone metastasis, to generate an invasive subline (MDA-I) using a Matrigel chamber. MDA-I cells expressed higher levels of AR and prostate-specific antigen than their less invasive parental cells. Blocking AR function or removal of androgen suppressed the invasion of MDA-I cells, whereas stimulating AR increased invasion. In addition, forced AR overexpression increased the invasiveness of MDA PCa 2b cells. Next, we showed that an androgen-refractory subline (MDA-hr) of MDA PCa 2b cells also expressed higher levels of AR and were more invasive than their parental androgen-dependent cells. Blocking AR function suppressed the invasiveness of MDA-hr cells. Gelatin zymography indicated that matrix metalloproteinase 2 (MMP-2) and MMP-9 activities were regulated by AR signaling and closely correlated with the invasiveness of the androgen-dependent and androgen-refractory prostate cancer cells. These data suggest that AR promotes the invasiveness of both androgen-dependent and androgen-refractory prostate cancer and that a more invasive phenotype might develop through AR activation during cancer progression. These findings potentially support the use of adjuvant hormonal therapy and the future development of more potent androgen blockade therapy.
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PMID:Androgen receptor and invasion in prostate cancer. 1828 88

Glycosylation drives critical processes important for mammalian cell-cell and cell-matrix interactions. Alpha-L-fucose (alpha-L-f) is a key monosaccharide component of oligosaccharides that has been found to be overexpressed during tumor progression. Modification of cell surface fucosylation, we hypothesized, alters tumor cell phenotype and function at the end of the neoplastic progression cascade including tumor invasion. Alpha-L-fucosidase (alpha-L-fase) is a glycosidase that specifically removes (alpha-L-f) from oligosaccharide sites. We first verified the effectiveness of the alpha-L-fase to specifically decrease the level of alpha-L-f on the cell surface of several human breast cancer cell lines and also examined the recovery time for these cells to repopulate their surfaces. To investigate the potential effect of defucosylation on tumor functions, we studied the proliferation, and invasion in vitro of human breast cancer MDA-MB-231 cells as the representative cell model. We further examined several fucose-associated molecules previously shown to be involved in tumor progression, including CD44 and CD15 (Lewis X antigen). We found that alpha-L: -fase pretreatment significantly decreased the invasive capability of breast cancer cells. Deoxyfuconojirimycin (DFJ), a specific alpha-L: -fase inhibitor, reversed this effect. After fucosidase treatment, the level of both CD15 and CD44 were found to be reduced as measured by flow cytometry. alpha-L-fase treatment, further, did not affect tumor cell proliferation in vitro under identical experimental conditions. Gelatin zymography of conditioned media from tumor cells treated with alpha-L-fase demonstrated no change in MMP-2 activity while MMP-9 was significantly reduced. In summary, fucose containing glycans were found widely distributed on the cell surface of breast cancer cells and could be effectively removed by alpha-L-fase treatment. This decreased fucosylation, in turn, was seen to impair the interaction between tumor cells and extracellular matrices, and thus affected key cell functions modulating tumor invasion. Further elucidation of the molecular pathways involved in the inhibition of tumor cell invasion may suggest a rationale for the use of glycobiologic therapeutics to deter tumor progression.
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PMID:Cell surface associated alpha-L-fucose moieties modulate human breast cancer neoplastic progression. 1855 63

Angiogenesis, the formation of new capillaries from preexisting vessels, is essential for tumor progression. Ursolic acid inhibited the tumor-associated capillary formation in C57BL/6 mice induced by highly metastatic B16F-10 melanoma cells. The levels of serum vascular endothelial growth factor (VEGF), NO, and proinflammatory cytokines were significantly reduced in ursolic acid-treated animals compared with those in control animals. The diminished expressions of VEGF and iNOS genes in B16F-10 melanoma cells treated with nontoxic concentrations of ursolic acid support these observations; the serum TIMP-1 (tissue inhibitor of metalloproteinase-1) and IL-2 (interleukin-2) levels were significantly elevated after the ursolic acid treatment. Nontoxic concentrations of ursolic acid toward human umbilical vein endothelial cells (HUVEC) were determined by MTT (methylthiazol tetrazolium) assay, and these nontoxic concentrations were selected for the in vitro studies. Nontoxic concentrations of ursolic acid inhibited vessel growth from the rat aortic ring. (3)H-thymidine proliferation assay clearly showed the inhibitory effect of ursolic acid on the proliferation of HUVECs in vitro. Ursolic acid significantly inhibited endothelial cell migration and invasion. The role of metalloproteinases has been shown to be important in angiogenesis; therefore, gelatin zymography was performed to determine whether ursolic acid affected protease activity. Gelatin zymographic analysis showed the inhibitory effect of ursolic acid on the protein expression of matrix metalloproteinases MMP-2 and MMP-9. The above observation shows the antiangiogenic activity of ursolic acid.
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PMID:Antiangiogenic activity of ursolic acid. 2046 55


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