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

As high levels of Prostaglandins E2 were observed in several gastric diseases, the Authors determined the PGE2 levels in gastric cancer patients without recurrences, in pre and post-operative period. PGE levels were correlated with cancer progression and their significance as tumoral markers was also assessed.
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PMID:[Prostaglandins and gastric cancer: a preliminary study]. 251 47

We have earlier shown that Syrian hamster cells spontaneously transformed in vitro during in vivo progression, acquire in 1 step, along with highly increased tumorigenicity, 2 new properties characterizing the [H2O2CA + tPGE(S)] phenotype, i.e., a high H2O2 catabolizing (antioxidant) activity and the ability to release PGE2 upon contact with NK cells. In contrast, RSV-SR-(v-src)-transformed cells acquire the [H2O2CA + PGE(S)] phenotype and high tumorigenicity during in vitro transformation, i.e., without preliminary in vivo selection. In the present study, the possible influence of different transforming genes on the rates of subsequent in vivo tumor progression was studied using cells in vitro transformed by SV40, BAV-3, or transduced by activated genes Ha-ras, p53, myc and bcl-2. The expression of the [H2O2CA + PGE(S)] phenotype, the extent of tumorigenic and spontaneous metastasizing activities were examined before and during in vivo cells selection in s.c. growing tumors. Our results demonstrate that: (1) after in vitro transformation all cell lines (except v-src) were negative for the expression of [H2O2CA + PGE(S)] phenotype and remained equally low-tumorigenic; (2) independently of the types of genes initially transforming the cells, in vivo tumor progression was consistently leading to the replacement of parental cells by cells expressing the [H2O2CA + PGE(S)] phenotype, to 30-200 times increased tumorigenicity and less frequently to metastasizing; (3) the time necessary for selection of cells expressing this phenotype was the same (about 180 days in vivo) for all transformants, except bcl-2; the latter reaching similar values after a significant delay. Thus, common secondary src-like phenotypic cell changes, regardless of initially cell transforming genes are necessarily selected during tumor progression in vivo.
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PMID:Cell transforming genes and tumor progression: in vivo unified secondary phenotypic cell changes. 946 19

Non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to reduce the risk and mortality of colorectal cancer (CRC). Although the exact mechanisms remain unclear, the inhibition of cyclooxygenase (COX) by NSAIDs appears to abort, if not prevent, CRC carcinogenesis or metastatic tumor progression. The aim of our study was to investigate the association between COX-2 expression and CRC tumor cell invasiveness. The differences in immunoblot-detectable COX-2 protein contents in primary CRCs, metastatic hepatic lesions and corresponding normal mucosa from the same individual were evaluated in 17 patients. Three different colon cancer cell lines, SW620, Lovo, HT-29 and a metastatic variant of HT-29, HT-29/Inv3, were employed to evaluate COX-2 expression and prostaglandin E(2) (PGE2) production in relation to their invasive abilities in vitro. The effects of a COX-2-selective inhibitor, etodolac, on cell proliferation and invasive activity were also determined. The results showed that 15 of 17 (88%) metastatic CRC cells from the liver and 14 of 17 (82%) primary CRC tissue exhibited much higher levels of COX-2 than corresponding adjacent normal mucosa from the same patient. Among those patients with relatively high COX-2 expression in the primary tumors, almost all exhibited even higher levels of COX-2 in their hepatic metastases. Among the 4 colon cancer cell lines, HT-29/Inv3 manifested the highest COX-2 expression, PGE2 production and in vitro invasive activity. The selective COX-2 inhibitor, etodolac, could especially exert cytotoxicity and markedly suppress the invasive property and PGE(2) production, although not the COX-2 protein level, in HT-29/Inv3 cells. Our results imply that COX-2 expression may be associated with the invasive and metastatic properties of CRC tumor cells.
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PMID:Tumor invasiveness and liver metastasis of colon cancer cells correlated with cyclooxygenase-2 (COX-2) expression and inhibited by a COX-2-selective inhibitor, etodolac. 1127 97

Tumor-derived prostaglandins (PGs) have been implicated in the progression of murine and human breast cancer. Chronic treatment with a non-selective PG inhibitor indomethacin was shown in this laboratory to retard the development and metastasis of spontaneous mammary tumors in C3H/HeJ female retired breeder mice. The present study examined the role of endogenous prostaglandins in the proliferation/survival, the migratory and invasive behavior and angiogenic ability of a highly metastatic murine mammary tumor cell line, C3L5, originally derived from a C3H/HeJ spontaneous mammary tumor. This cell line was shown to express high levels of cyclooxygenase (COX) -2 mRNA and protein as detected by Northern and Western blotting as well as immunostaining. PGE(2) production by C3L5 cells was primarily owing to COX-2, since this was blocked similarly with non-selective COX inhibitor indomethacin and selective COX-2 inhibitor NS-398, but unaffected with the selective COX-1 inhibitor valeryl salicylate. C3L5 cell proliferation/survival in vitro was not influenced by PGs, since their cellularity remained unaffected in the presence of PGE(2) or NS-398 or PG-receptor (EP1/EP2) antagonist AH6809; a marginal decline was noted only at high doses of indomethacin, which was not abrogated by addition of exogenous PGE(2). Migratory and invasive abilities of C3L5 cells, as quantitated with in vitro transwell migration/invasion assays, were inhibited with indomethacin or NS-398 or AH6809 in a dose-dependent manner; the indomethacin and NS-398-mediated inhibition was partially reversed upon addition of exogenous PGE(2). An in vivo angiogenesis assay that used subcutaneous implants of growth factor-reduced matrigel inclusive of tumor cells showed a significant inhibition of blood vessel formation in these implants in animals treated with indomethacin compared with animals receiving vehicle alone. These studies show that selective and nonselective COX-2 inhibitors retarded tumor progression in this COX-2-expressing murine mammary tumor model by inhibiting tumor cell migration, invasiveness and tumor-induced angiogenesis. The inhibitory effects were not entirely PG dependent; some PG-independent effects were also noted.
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PMID:Cyclooxygenase inhibitors retard murine mammary tumor progression by reducing tumor cell migration, invasiveness and angiogenesis. 1147 53

Cyclooxygenase-2 (COX-2) is the rate-limiting enzyme in prostanoid biosynthesis and is involved in tumor progression. We investigated expression of COX-1 and COX-2 in cell lines and tumors from ovarian carcinomas. Expression of COX-2 mRNA and protein was detectable in three of five ovarian carcinoma cell lines and was inducible by interleukin-1beta or phorbolester in a subset of cell lines. Prostaglandin E(2) (PGE(2)) production could be inhibited by the selective COX-2 inhibitor NS-398. In malignant ascites of ovarian carcinomas significantly increased levels of PGE(2) were found compared to other carcinomas or nonmalignant ascites (P = 0.03). We investigated expression of COX-2 by immunohistochemistry in 117 ovarian surface epithelial tumors. Expression of COX-2 was detected in 42% of 86 ovarian carcinomas and in 37% of 19 low malignant potential tumors, but not in 12 cystadenomas or 2 normal ovaries. Expression of COX-1 was detected by immunohistochemistry in 75% of 75 invasive ovarian carcinomas and in 75% of 16 low malignant potential tumors, whereas 2 samples from normal ovaries and 8 cystadenomas were positive for COX-1. In univariate survival analysis of invasive carcinomas, expression of COX-2 was associated with a significantly reduced median survival time (log rank test, P = 0.04). For patients younger than 60 years of age, this association was even more significant (P < 0.004). In contrast, expression of COX-1 was no prognostic parameter (P = 0.89). There was no significant correlation between COX-2 or COX-1 expression and other clinicopathological markers. In multivariate analysis expression of COX-2 was an independent prognostic factor for poor survival (relative risk, 2.74; 95% CI, 1.38 to 5.47). Our data indicate that COX-2 expression is an independent prognostic factor in ovarian carcinoma. Based on the results of this study, it would be interesting to investigate whether ovarian carcinoma patients with tumors positive for COX-2 would benefit from treatment with selective COX-2 inhibitors.
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PMID:Expression of cyclooxygenase 2 is an independent prognostic factor in human ovarian carcinoma. 1281 42

Studies concerning the expression of the receptor CD95 (Fas) by tumor cells and the role of this protein in apoptosis induced by the effector host cells that bear Fas-ligand are mainly focused on the membrane-bound form of Fas. There are only a few data about the production of the soluble form of Fas by the tumor cells, its role in the interaction with the effector host cells, and the possible changes in the synthesis of this protein during tumor progression. In the present work, three in vitro transformed parental cell lines of different origin and 24 of their variants isolated after a short cycle of natural selection in vivo were studied. It was demonstrated for the first time that: 1) production of the soluble Fas by all selected in vivo variant tumor cell lines increased significantly (2-10-fold) in comparison to the initial (parental) cell lines and did not depend on the origin of the parental lines. At the same time, the expression of the membrane-bound form of Fas decreased considerably; 2) variations of the balance between membrane-bound and soluble forms of Fas in selected in vivo variant cells and the expression of the [H(2)O(2)(CA) + PGE(S)]-phenotype by these cells (this phenotype determines one of the essential mechanisms of the protection of a tumor cell in vivo) possibly represent independent secondary changes acquired during tumor progression in vivo.
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PMID:Changes in the balance between membrane-bound and soluble forms of CD95 (Fas) during selection of tumor cells in vivo. 1195 21

We described the earliest in vivo changes of in vitro transformed cells of various origin manifested in highly-increased H(2)O(2)-catabolizing and PGE(2)-releasing activities. We designate it as [H(2)O(2)(CA) + PGE(S)]-phenotype. It provided tumor cells with resistance to cytotoxicity of Mph and NK cells and correlated with increased tumorigenicity. Used as a functional marker of the early step of in vivo tumor progression [H(2)O(2)(CA) + PGE(S)]-phenotype allowed to estimate the difference in the rates of natural selection of tumor cells grown locally and/or disseminated and its significant delay related to bcl-2 gene expression. The data suggests that in vivo sublethal damage of tumor cells and activation of src gene are relevant to acquisition of [H(2)O(2)(CA) + PGE(S)]-phenotype.
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PMID:Early phenotypic changes of in vitro transformed cells during in vivo progression: possible role of the host innate immunity. 1232 76

Prostaglandin E(2) (PGE(2)) receptor subtype EP(2), which is coupled to cAMP metabolism, is known to mediate proliferation of primary human keratinocytes in vitro. The effect of gain or loss of EP(2) receptors in immortalized human keratinocytes (HaCat cells) was examined. HaCat keratinocytes were transfected with sense or anti-sense constructs of the EP(2) receptor. Loss or gain of EP(2) expression was documented by immunoblot and associated changes in agonist-stimulated cAMP production. Loss or gain of EP(2) receptor expression correlated with alterations in plating efficiencies but with modest affects on growth. When cell lines were studied in an organ culture model, anti-sense clones were highly invasive compared with vector controls and sense transfectants. A marked increase in prostaglandin production is commonly seen in malignant lesions. Because prostaglandin receptors are known to undergo ligand-induced receptor down-regulation, we sought to determine whether EP(2) receptor down-regulation results in increased invasiveness. In vector controls, invasiveness was reproduced by ligand-dependent EP(2) receptor down-regulation as assessed by immunohistochemistry. In addition, loss of EP(2) receptor expression was associated with decreased paxillin expression, a critical component of focal adhesion assembly. Thus, down-regulation of EP(2) receptors represents a potential mechanism for neoplastic progression to an invasive phenotype.
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PMID:Loss of the EP2 prostaglandin E2 receptor in immortalized human keratinocytes results in increased invasiveness and decreased paxillin expression. 1246 23

Cytosolic phospholipase A(2) (cPLA(2)) releases arachidonic acid (AA) from intracellular phospholipids. We evaluated the status of cPLA(2) in azoxymethane (AOM)-induced mouse colon tumors. Despite increased expression of cyclooxygenase 2 (3.7-fold) and PGE(2) (3.4-fold) production in tumors, cPLA(2) mRNA levels and enzyme activity were significantly reduced (3.6- and 3-fold, respectively). Reduced levels of cPLA(2) were also observed in pre-neoplastic aberrant crypt foci (ACF), a distinct morphological alteration that represents an early stage in the pathogenesis of colon tumors. Furthermore, the reciprocal expression patterns of these two genes were found to occur in human colorectal cancers (CRC). Examination of the activity of the secretory phospholipases A(2) (sPLA(2)) and expression of the groups V and X sPLA(2)s revealed no compensatory increase in tumor tissue. As cPLA(2) has been shown to be involved in TNF-alpha-induced apoptosis in certain cell types, and TNF-alpha expression is significantly enhanced in AOM-induced tumors (2.8-fold), we examined the role of cPLA(2) in TNF-alpha-induced apoptosis of cultured mouse colonocytes (YAMC). The specific cPLA(2) inhibitor, AACOCF(3) (arachidonoyl trifluoromethyl ketone), was able to protect colonocytes from TNF-alpha-induced apoptosis in vitro. In summary, our data demonstrate an inverse relationship between COX-2 and cPLA(2) expression in both AOM-induced mouse colon tumors and human CRC and suggest that down regulation of cPLA(2) may attenuate TNF-alpha mediated apoptosis during tumorigenesis and facilitate tumor progression.
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PMID:Inverse association between phospholipase A2 and COX-2 expression during mouse colon tumorigenesis. 1258 82

Overexpression of human cyclooxygenase 2 (COX-2) in the mammary glands of transgenic mice induces tissue-specific tumorigenic transformation. However, the molecular mechanisms involved are not yet defined. Here we show that COX-2 expressed in the epithelial cell compartment regulates angiogenesis in the stromal tissues of the mammary gland. Microvessel density increased before visible tumor growth and exponentially during tumor progression. Inhibition of prostanoid synthesis with indomethacin strongly decreased microvessel density and inhibited tumor progression. Up-regulation of angiogenic regulatory genes in COX-2 transgenic mammary tissue was also potently inhibited by indomethacin treatment, suggesting that prostanoids released from COX-2-expressing mammary epithelial cells induce angiogenesis. G protein-coupled receptors for the major product, prostaglandin E(2) (PGE(2)) EP(1-4), are expressed during mammary gland development, and EP(1,2,4) receptors were up-regulated in tumor tissue. PGE(2) stimulated the expression angiogenic regulatory genes in mammary tumor cells isolated from COX-2 transgenic mice. Such cells are tumorigenic in nude mice; however, treatment with Celecoxib, a COX-2-specific inhibitor, reduced tumor growth and microvessel density. These results define COX-2-derived PGE(2) as a potent inducer of angiogenic switch during mammary cancer progression.
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PMID:Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. 1470 64


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