Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gelatinases (GLs) belong to a family of enzymes known as matrix metalloproteinases (MMPs), which are produced by both normal and neoplastic cells. These enzymes have been implicated in tumor invasion and metastasis, although the mechanism of regulation of tumor MMP production is unknown. Since our previous studies have shown that numerous cytokines are present in the tumor microenvironment, our goal was to establish the effect of selected cytokines on GL production by both established tumor cell lines and primary cultures of head and neck squamous cell carcinoma (HNSCC). Supernatants of HNSCC cell lines SCC-25 and FADU stimulated with interleukin (IL)-1 alpha and IL-1 beta demonstrated modest induction of 92 kd GL production by zymogram analysis when compared with controls; IL-2, IL-6, and interferon-gamma had no consistent effect on MMP production. Stimulation of cell lines with tumor necrosis factor (TNF)-alpha (10(4) to 10 U/mL), however, dramatically enhanced production of 92 kd GL by both cell lines in a dose-dependent fashion, although tissue inhibitor of metalloproteinase (TIMP) expression was unaffected. Northern blot analysis showed that this enhancement of 92 kd GL occurred at the messenger RNA level. Stimulation of short-term primary tumor cultures with TNF-alpha resulted in significant enhancement of 92 kd GL expression in one of four cultures and enhancement of 72 kd GL expression in all cultures. The observed increase in GL expression by TNF-alpha suggests a role for this cytokine in the regulation of GL expression by tumor cells during invasion and metastasis.
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PMID:Cytokine regulation of gelatinase production by head and neck squamous cell carcinoma: the role of tumor necrosis factor-alpha. 787 3

Matrilysin, which is a member of the matrix metalloproteinase family and is implicated in colon cancer invasion, is expressed in human colon adenocarcinoma-derived SW1116 cells. We investigated the effect of alpha-difluoromethylornithine (DFMO) on matrilysin expression in this cell line because others have shown that DFMO can inhibit invasion and carcinogenesis in epithelial tissues, including the colon, in experimental models. DFMO reduced extracellular levels of matrilysin protein after 4 d of treatment. Intracellular levels of matrilysin protein were minimally affected by DFMO treatment. The decrease in extracellular matrilysin protein levels caused by DFMO was not a consequence of lowered steady-state levels of matrilysin mRNA. After 4 d of exposure, the amount of this transcript was higher in DFMO-treated cells than in untreated cultures, whereas the mRNA stabilities were similar. These data show that polyamine depletion by DFMO can suppress the expression of matrilysin, a gene product thought to be involved in tumor invasion. The decrease in extracellular matrilysin protein caused by DFMO treatment appears to be due to a posttranscriptional mechanism, although transcription of this gene also seems to be affected by polyamines in SW1116 cells.
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PMID:Polyamine-dependent expression of the matrix metalloproteinase matrilysin in a human colon cancer-derived cell line. 794 2

The mammary gland, during post-lactational involution, is subjected to extensive tissue reconstruction. This process is governed by the concerted expression of extracellular-matrix-degrading enzymes and their inhibitors. During carcinogenesis, the invasive growth of tumor cells is characterized by the penetration of the basement membrane and stromal invasion. We compared the expression of the tissue-remodeling enzymes stromelysin-1, a matrix metalloproteinase, and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), during mammary gland involution and carcinogenesis in mouse. In involuting mammary glands, stromelysin-1 was expressed in myoepithelial cells, whereas TIMP-1 was confined to the stromal tissue. To analyze the involvement of these tissue-remodeling genes in tumor development, we examined mammary tumors of transgenic mice expressing either the activated Ha-ras or c-myc oncogene under the control of a milk-protein gene promoter. In the undifferentiated and metastasizing Ha-ras-induced tumors, stromelysin-1 expression was comparable to that seen in involution, whereas TIMP-1 expression was greatly elevated. During Ha-ras-induced carcinogenesis, stromelysin-1 expression was first detected in the myo-epithelial cells surrounding preneoplastic lesions. In contrast, in the well-differentiated and non-metastatic mammary tumors induced by c-myc, no expression of either gene was observed. Thus, expression of stromelysin-1 and TIMP-1 is confined to the aggressively growing tumors and is induced in the earliest stages of carcinogenesis.
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PMID:Expression of stromelysin-1 and TIMP-1 in the involuting mammary gland and in early invasive tumors of the mouse. 796 Feb 27

We examined the in situ distribution of basement membrane collagen (Col IV), matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) by immunohistochemistry and their mRNA levels by Northern blot analysis in 14 cases of squamous cell carcinoma of the lung. Elevated mRNA levels of MMP-2 and Col IV were demonstrated in all the cases examined and were associated with in situ disruption of basement membranes around the tumor nests. In contrast, TIMP-1 mRNA levels were not altered. MMP-2, MMP-9 and TIMP-1 were localized in tumor cells, stromal fibroblasts and endothelial cells. There were no significant correlations between these parameters and clinical staging. The results suggest that the degrading enzymes of basement membrane collagen play an important role in the invasion and metastasis of human squamous cell carcinoma of the lung.
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PMID:Expression of type IV collagen and its degrading enzymes in squamous cell carcinoma of lung. 796 Nov 22

Matrix degrading metalloproteinases are enzymes that degrade proteins in tissue extracellular matrices. These proteinases exhibit specific, well defined properties that allow them to be classified into a family of enzymes. They are secreted by various cell types as the cells effect their surrounding extracellular matrix. Such effects occur during normal physiologic tissue remodeling but also during pathologic processes such as tumor cell invasion and metastases. Currently there are seven proteases classified as members of the matrix metalloproteinase family and there are two putative members. Direct correlations can be made between the matrix metalloproteinases and normal tissue functions such as bone remodeling, uterine and mammary gland function and ovulation. The matrix metalloproteinases are also strongly associated with cancer progression in that they function to degrade epithelial basement membrane and stromal matrices in many different malignancies including brain tumors.
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PMID:Matrix degrading metalloproteinases. 796 73

Stromelysin, a member of the matrix metalloproteinase family of enzymes, has been implicated in the pathogenesis of tumor metastasis and inflammatory diseases such as rheumatoid arthritis. To screen prospective inhibitors of this protease, we developed a fluorogenic substrate with excitation and emission spectra compatible with commercially available 96-well plate readers. The substrate is based on the addition of 6-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino] hexanoic acid (NBD) (EX467/EM534) and 7-dimethylaminocoumarin-4-acetate (DMC) (EX368/EM459) to the previously reported peptide substrate for stromelysin, Arg-Pro-Lys-Pro-Leu-Ala-Nva-Trp-NH2. The new substrate, NBD-Arg-Pro-Lys-Pro-Leu-Ala-Nva-Trp-Lys-(DMC)-NH2 is 95% quenched and the fluorescent product, Nva-Trp-Lys(DMC)-NH2 is easily detected (EX350/EM465). In competition assays the new fluorogenic substrate has a relative kcat/Km that is one half that of the parent peptide. The fluorophores NBD and DMC were chosen based on the high fluorescence yield of DMC and the overlap of the emission spectrum of DMC and excitation spectrum of NBD which results in an efficient energy transfer system in the intact substrate. These characteristics make this an excellent substrate for routine determination of in vitro activities of stromelysin inhibitors.
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PMID:A high throughput fluorogenic substrate for stromelysin (MMP-3). 797 5

During early human pregnancy, fetal cytotrophoblasts rapidly invade the uterus. This process has many similarities to tumor invasion, except that the extent and the timing of cytotrophoblast invasion are carefully regulated. Therefore, this system is particularly useful for studying mechanisms that regulate invasive processes. Previously, we showed that production and activation of the 92-kDa type IV collagenase (matrix metalloproteinase(MMP)-9) is necessary for cytotrophoblast invasion in vitro. In other systems, interleukin (IL)-1 beta is an important regulator of matrix-degrading metalloproteinases. Therefore, we investigated trophoblast production of IL-1 beta and its receptors, as well as the effects of this cytokine on cytotrophoblast metalloproteinase activity and invasion. The results showed that release of IL-1 beta parallels the invasive potential of the cytotrophoblasts; the highest levels are produced by first trimester cells and the lowest levels by term cells. Immunoprecipitation showed that cytotrophoblasts express the 80-kDa type I IL-1 receptor, suggesting that autocrine effects are possible. IL-1 beta stimulated trophoblast MMP-9 secretion (by a mechanism that required nascent mRNA and protein synthesis) as well as metalloproteinase activity and invasion of Matrigel. Increasing (by lipopolysaccharide treatment) or decreasing (by glucocorticoid treatment) IL-1 beta production had parallel effects on MMP-9 secretion, metalloproteinase activity, and invasion. Because IL-1 beta and corticosteroids are present in high concentrations at the maternal-fetal interface, normal trophoblast invasion may be regulated, in part, by their opposing actions. In contrast, stimulation of cytotrophoblast IL-1 beta secretion by lipopolysaccharide may play a role in the sequela of infected fetal membranes.
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PMID:Interleukin-1 beta regulates human cytotrophoblast metalloproteinase activity and invasion in vitro. 800 17

Gelatinase A (type-IV collagenase; M(r) 72,000) is produced by tumour stroma cells and is believed to be crucial for their invasion and metastasis, acting by degrading extracellular matrix macro-molecules such as type IV collagen. An inactive precursor of gelatinase A (pro-gelatinase A) is secreted and activated in invasive tumour tissue as a result of proteolysis which is mediated by a fraction of tumour cell membrane that is sensitive to metalloproteinase inhibitors. Here we report the cloning of the complementary DNA encoding a new matrix metalloproteinase with a potential transmembrane domain. Expression of the gene product on the cell surface induces specific activation of pro-gelatinase A in vitro and enhances cellular invasion of the reconstituted basement membrane. Tumour cells of invasive lung carcinomas, which contain activated forms of gelatinase A, were found to express the transcript and the gene product. The new metalloproteinase may thus trigger invasion by tumour cells by activating pro-gelatinase A on the tumour cell surface.
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PMID:A matrix metalloproteinase expressed on the surface of invasive tumour cells. 801 94

The in vitro invasive ability, the expression of cell adhesion molecule E-cadherin, activity of matrix metalloproteinase (MMP) and K-ras point mutation were investigated in eight human endometrial carcinoma cell lines. 1) In vitro invasive abilities of endometrial carcinoma cell lines depend on the degree of cell differentiation and the origin of cell lines. A poorly-differentiated carcinoma cell line (NUE-1) and a cell line derived from metastatic lymph node (SNG-M) were more invasive than moderately-(HEC-1A, HEC-1BE) and well-differentiated (HEC-6, Ishikawa) cell lines. 2) Immunohistochemically, less or non-invasive cell lines expressed E-cadherin strongly, whereas a highly invasive cell line (NUE-1) expressed E-cadherin weakly. 3) When cultured on Matrigel-coated dishes, the tumor cells derived from moderately- and well-differentiated carcinoma aggregated with each other and did not invade Matrigel in the invasion assay. The aggregated cells expressed E-cadherin more strongly when cultured on Matrigel. 4) 72-kD gelatinase (MMP-2) was secreted in serum-free conditioned medium of all cell lines. In an invasive cell line (NUE-1,SNG-M), the activity of MMP-2 was stronger than in other cell lines. And the activity of 92-kDa gelatinase (MMP-9) was detected in most invasive cell line (NUE-1). 5) Point mutation of K-ras codon 12 was detected in four of eight (50%) cell lines by the PCR-RFLP method. The changes in the DNA sequence were identified, but K-ras point mutation was not correlated with in vitro invasiveness of the tumor cells.
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PMID:[The factors involved in invasive ability of endometrial carcinoma cells]. 804 Jun 23

The synthetic matrix metalloproteinase inhibitor batimastat was tested for its ability to inhibit growth and metastatic spread of the B16-BL6 murine melanoma in syngeneic C57BL/6N mice. Intraperitoneal administration of batimastat resulted in a significant inhibition in the number of lung colonies produced by B16-BL6 cells injected i.v. The effect of batimastat on spontaneous metastases was examined in mice inoculated in the hind footpad with B16-BL6 melanoma. The primary tumor was removed surgically after 26-28 days. Batimastat was administered twice a day from day 14 to day 28 (pre-surgery) or from day 26 to day 44 (post-surgery). With both protocols, the median number of lung metastases was not significantly affected, but there was a significant reduction in the weight of the metastases. Finally, the effect of batimastat was examined on s.c. growth of B16-BL6 melanoma. Batimastat administered daily, starting at day of tumor transplantation, resulted in a significant growth delay, whereas treatment starting at advanced stage tumor only reduced tumor growth marginally. Our results indicate that a matrix metalloproteinase inhibitor can not only prevent the colonization of secondary organs by B16-BL6 cells but also limit the growth of solid tumors.
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PMID:Inhibition of the metastatic spread and growth of B16-BL6 murine melanoma by a synthetic matrix metalloproteinase inhibitor. 805 Aug 28


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