UMLS:C0178874 - FACTA Search

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Barrett's esophagus is a premalignant condition arising in response to chronic reflux esophagitis. Inducible nitric oxide synthase (iNOS; NOS-2) and cyclooxygenase-2 (COX-2) are mediators of inflammation and regulators of epithelial cell growth. Expression levels of iNOS and COX-2 are high in colorectal adenomas and carcinomas, and COX-2 expression is elevated in gastric cancers. To determine the involvement of iNOS and COX-2 in Barrett's-associated neoplasia, we measured expression of these genes in metaplastic Barrett's and esophageal adenocarcinomas. We detected elevated iNOS and COX-2 mRNA levels in Barrett's mucosa compared with paired gastric control tissues in 16 of 21 (76%) and 17 of 21 (80%) patients, respectively (P < 0.001 for both genes). In esophageal adenocarcinomas, iNOS and COX-2 mRNA levels were increased in four of five and five of five cases, respectively. Furthermore, in 10 of 10 Barrett's patients, immunohistochemical staining for iNOS and COX-2 expression was strongly positive and higher than in matched gastric controls. Increased COX-2 expression was confirmed by Western blotting. These findings support the hypothesis that iNOS and COX-2 are involved early and often in Barrett's-associated neoplastic progression.
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PMID:Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in Barrett's esophagus and associated adenocarcinomas. 967 48

Vascular endothelial growth factor (VEGF) expression and mutations of cancer-related genes increase with cancer progression. This correlation suggests the hypothesis that oncogenes and tumour suppressors regulate VEGF, and a significant correlation between p53 alteration and increased VEGF expression in human lung cancer was reported recently. To further examine this hypothesis, we analysed VEGF protein expression and mutations in p53 and K-ras in 27 non-small-cell lung cancers (NSCLC): 16 squamous cell, six adenocarcinomas, one large cell, two carcinoids and two undifferentiated tumours. VEGF was expressed in 50% of the squamous cell carcinomas (SCC) and carcinoids but none of the others. p53 mutations occurred in 14 tumours (52%), and K-ras mutations were found in two adenocarcinomas and one SCC; there was no correlation between the mutations and VEGF expression. As nitric oxide also regulates angiogenesis, we examined NOS expression in NSCLC. The Ca2+-dependent NOS activity, which indicates NOS1 and NOS3 expression, was significantly reduced in lung carcinomas compared with adjacent non-tumour tissue (P < 0.004). Although the Ca2+-independent NOS activity, which indicates NOS2 expression, was low or undetectable in non-tumour tissues and most carcinomas, significant activity occurred in three SCC. In summary, our data do not show a direct regulation of VEGF by p53 in NSCLC. Finally, we did not find the up-regulation of NOS isoforms during NSCLC progression that has been suggested for gynaecological and breast cancers.
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PMID:Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the relation to p53. 968 99

The relationship between nitric oxide (NO) synthase II (NOS II) expression and the metastatic ability of tumor cells is inconclusive. We determined the role of host NOS II expression in the growth and metastasis of the B16-BL6 murine melanoma and M5076 murine ovarian sarcoma cell lines. The cells were either s.c. or i.v. injected into syngeneic wild-type (NOS H+/+) and NOS II-null (NOS H-/-) C57BL/6 mice. Both cell lines produced slightly larger s.c. tumors in NOS H-/- mice than in NOS II+/+ mice. However, B16- BL6 cells produced more and larger experimental lung metastases in NOS II+/+ mice than in NOS II-/- mice, whereas M5076 cells produced fewer and smaller experimental lung metastases in NOS II+/+ mice than in NOS II-/- mice. After activation with IFN-gamma and lipopolysaccharide, macrophages isolated from NOS II+/+ C57BL/6 mice produced NO-dependent cytotoxicity in sarcoma cells, whereas macrophages from NOS II-/- C57BL/6 mice did not. In contrast, activated macrophages produced little to no NO-mediated cytotoxicity in melanoma cells. Immunostaining analyses indicated that NOS II expression was apparent in the metastases growing in NOS H+/+ mice and correlated with increased cell proliferation in B16-BL6 lung metastases but with decreased cell proliferation in M5076 liver metastases. Our data suggest that disruption of host NOS II expression enhanced the growth and metastasis of NO-sensitive tumor cells but suppressed the metastasis of NO-resistant tumor cells, proposing that host-derived NO may differentially modulate tumor progression.
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PMID:Influence of nitric oxide synthase II gene disruption on tumor growth and metastasis. 1082 24

The steps required for new vessel growth are biologically complex and require coordinate regulation of contributing components, including modifications of cell--cell interactions, proliferation and migration of endothelial cells and matrix degradation. The observation that in vivo angiogenesis is accompanied by vasodilation, that many angiogenesis effectors possess vasodilating properties and that tumor vasculature is in a persistent state of vasodilation, support the existence of a molecular/biochemical link between vasodilation and angiogenesis. Several pieces of evidence converge in the indication of a role for nitric oxide (NO), the factor responsible for vasodilation, in physiological and pathological angiogenesis. Data originated in different labs indicate that NO can act both as an 'actor' of angiogenesis and as a 'director of angiogenesis', both functions being equally expressed during physiological and pathological processes. NO significantly contributes to the prosurvival/proangiogenic program of capillary endothelium by triggering and transducing cell growth and differentiation via endothelial-constitutive NO synthase (ec-NOS) activation, cyclic GMP (cGMP) elevation, mitogen activated kinase (MAPK) activation and fibroblast growth factor-2 (FGF-2) expression. Re-establishment of a balanced NO production in the central nervous system results in a reduction of cell damage during inflammatory and vascular diseases. Elevation of NOS activity in correlation with angiogenesis and tumor progression has been extensively reported in experimental and human tumors. In the brain, tumor expansion and edema formation are sensitive to NOS inhibition. On this basis, the nitric oxide pathway appears to be a promising target for consideration in pro- and anti-angiogenic therapeutic strategies. The use of NOS inhibitors seems appropriate to reduce edema, block angiogenesis and facilitate antitumor drug delivery.
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PMID:Nitric oxide and angiogenesis. 1124 73

Inducible nitric oxide synthase (iNOS) is one of three key enzymes generating nitric oxide (NO) from the amino acid L-arginine. iNOS-derived NO plays an important role in numerous physiological and pathophysiological conditions, e.g. blood pressure regulation, inflammation, infection, and the onset and progression of malignant diseases. iNOS has been conjectured both as a marker and a therapeutic target in these situations. iNOS is a mediator of unspecific host defence, central in the clearance of bacterial, viral, fungal and parasitic infections. However, excess production of NO appears to be linked to tissue damage and organ dysfunction, e.g. the hypotensive and vasoplegic state characteristic for septic shock. However, the use of iNOS-inhibitors in septic patients should be performed carefully with regard to the essential functions and properties of NO in blood pressure/blood flow regulation. Considering iNOS-derived NO as a multifactorial transmitter of tumorigenesis and tumor progression, it is tempting to speculate on therapeutical interference with iNOS activity, especially in tumors where metastatic activity, host denfence mechanisms and the level of differentiation seem to be correlated to iNOS expression. It is the aim of this review to provide basic insights into the NOS family of enzymes as well as their regulation. In the second part of the review, we will point out the pivotal roles NOS play in inflammation and neoplastic diseases.
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PMID:Inducible nitric oxide synthase--time for reappraisal. 1456 Dec 9

Oxidative modification of low-density lipoprotein (LDL) leads to formation of the atherogenic molecule oxidized LDL (oxLDL), which is considered to be an important mediator for vascular endothelial dysfunction and atherosclerosis. It is speculated that reduced nitric oxide (NO) release/bioavailability and enhanced release of endothelin-1 (ET-1) may contribute to oxLDL-induced endothelial dysfunction. Estrogen may improve lipid profile and inhibit oxLDL-induced endothelial damage. However, estrogen replacement therapy has been suspended due to uncertainty in benefits versus risk (such as cancer progression) in postmenopausal women. This study was designed to evaluate the effect of a novel phytoestrogen, alpha-zearalanol (alpha-ZAL), on oxLDL-induced effect on NO and ET-1 production in human umbilical vein endothelial cells (HUVEC). HUVEC were incubated with oxLDL (50 microg/mL) for 24 h in the absence or presence of alpha-ZAL (0-1000 nM), 17beta-estradiol (E2, 10 nM), or the E2 receptor antagonist ICI182780 (1 microM). Levels of NO and ET-1 were measured by spectrophotometry and enzymatic immunoassay, respectively. NOS activity was evaluated by conversion of 3H-arginine to 3H-citrulline. Protein and mRNA expression of NOS and ET-1 were measured by Western blot and RT-PCR. Our results indicated that oxLDL significantly reduced NO release and NOS activity, and enhanced ET-1 pro-duction associated with reduced NOS3 (but not NOS2) expression and enhanced ET-1 mRNA expression. All these oxLDL-induced alterations were significantly attenuated or abolished by co-incubation with alpha-ZAL or E2, both through an E2 receptor-dependent mechanism. alpha-ZAL, E2, and ICI182780 had no effect on NO/ET-1 release, NOS activity, or expression of NOS and ET-1. These data suggested that the phytoestrogen alpha-ZAL, like E2, may effectively antagonize oxLDL-induced decrease in NO and increase in ET-1, which may be protective for endothelial function.
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PMID:Phytoestrogen alpha-zearalanol antagonizes oxidized LDL-induced inhibition of nitric oxide production and stimulation of endothelin-1 release in human umbilical vein endothelial cells. 1575 51

Ovarian cancer is the fifth most common cause of cancer death in women. Due to a lack of appropriate animal models, studies involving tumorigenicity, tumor progression and immune response at the molecular level are limited. We isolated many clones derived from thesurvivors of a transformed mouse ovarian epithelial cell line IG-10 in immune- competent mice and found that the clones displayed diverse phenotypes. Most clones were deficient in components of the MHC-I antigen presentation pathway. Soft-agarose colony assays showed different growth rates among clones. However, this did not completely correlate with each clone's in vivo tumorigenicity regarding growth, tumor mass and ascites formation, suggesting the possibility that the clones may display contrasting intrinsic gene expression. We therefore performed two types of arrays to evaluate gene expression at transcriptional and translational levels. The results showed differences in expression of COL4alpha5, NOS-2, and SOCS-1 genes at the transcriptional level, MIP-2 gene at the protein level and CCL5, CXCL-10, IL-1alpha genes at both transcriptional and protein levels between low and high tumorigenic clones. Thus, our animal cell model together with the identified genes may provide a useful tool to study ovarian cancer immune response, tumorigenicity and tumor-host cell interactions in the tumor microenvironment.
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PMID:In vivo survivors of transformed mouse ovarian surface epithelial cells display diverse phenotypes for gene expression and tumorigenicity. 1905 85

Female mice transgenic for the rat proto-oncogene c-erb-B2, under control of the mouse mammary tumor virus (MMTV) promoter (neuN), spontaneously develop metastatic mammary carcinomas. The development of these mammary tumors is associated with increased number of GR-1(+)CD11b(+) myeloid derived suppressor cells (MDSCs) in the peripheral blood (PB), spleen and tumor. We report a complex relationship between tumor growth, MDSCs and immune regulatory molecules in non-mutated neu transgenic mice on a FVB background (FVB-neuN). The first and second tumors in FVB-neuN mice develop at a median of 265 (147-579) and 329 (161-523) days, respectively, resulting in a median survival time (MST) of 432 (201 to >500) days. During tumor growth, significantly increased number of MDSCs is observed in the PB and spleen, as well as, in infiltrating the mammary tumors. Our results demonstrate a direct correlation between tumor size and the number of MDSCs infiltrating the tumor and an inverse relationship between the frequency of CD4(+) T-cells and MDSCs in the spleen. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assessment of enzyme and cytokine transcript levels in the spleen, tumor, tumor-infiltrating non-parenchymal cells (NPCs) and mammary glands revealed a significant increase in transcript levels from grossly normal mammary glands and tumor-infiltrating NPCs during tumor progression. Tumor NPCs, as compared to spleen cells from wild-type (w/t) mice, expressed significantly higher levels of arginase-1 (ARG-1), nitric oxide synthase (NOS-2), vascular endothelial growth factor (VEGF-A) and significantly lower levels of interferon (IFN)-gamma, interleukin (IL)-2 and fms-like tyrosine kinase-3 ligand (Flt3L) transcript levels. Transcript levels in the spleens of tumor-bearing (TB) mice also differed from normal mice, although to a lesser extent than transcript levels from tumor-infiltrating NPCs. Furthermore, both spleen cells and NPCs from TB mice, but not control mice, suppressed alloantigen responses by syngeneic control spleen cells. Correlative studies revealed that the number of MDSCs in the spleen was directly associated with granulocyte colony stimulating factor (G-CSF) transcript levels in the spleen; while the number of MDSCs in the tumors was directly correlated with splenic granulocyte macrophage stimulating factor (GM-CSF) transcript levels, tumor volume and tumor cell number. Together our results support a role for MDSCs in tumor initiation and progressive, T-cell depression and loss of function provide evidence which support multiple mechanisms of MDSC expansion in a site-dependent manner.
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PMID:Myeloid-derived suppressor cells in mammary tumor progression in FVB Neu transgenic mice. 1944 84

Benign prostate hypertrophy (BPH) and prostate cancer (PC) are prostate chronic diseases that require a long period for development from a small lesion to clinical manifestation. PC is the most common cancer in men in Europe and the Americas. Tumor growth and metastasis depend upon the development of neovasculature around the tumor. This process, called angiogenesis, may be regulated by NO, and thus modulation of NO production could play an important role in tumor progression. Recent studies report the involvement of DDAH, an enzyme which metabolizes the endogenous NOS inhibitor ADMA, in the development of tumor vasculature. The aim of the present study was to verify the involvement of the DDAH/NOS pathway in the progression of prostate cancer. The effect of the NOS inhibitor L-NAME was evaluated in the human prostate cancer cell line LnCap and in BPH-1 cells which represent benign prostatic hypertrophy. Higher DDAH-2, eNOS, iNOS and VEGF expression was found in LnCap cells compared to BPH-1 cells. L-NAME treatment of LnCap cells resulted in a reduction in VEGF, iNOS and eNOS expression. VEGF, iNOS and eNOS inhibition is a promising approach for targeting tumor vasculature and certain NOS inhibitors could potentially serve as experimental agents for treatment of certain chemoresistant tumors, including prostate tumors. Moreover, since in our experimental conditions L-NAME was unable to reduce DDAH activity and expression, it is plausible to hypothesize the development of a targeted polypharmacological approach by developing dual and specific inhibitors of DDAH and NOS to better control NO biosynthesis.
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PMID:The DDAH/NOS pathway in human prostatic cancer cell lines: antiangiogenic effect of L-NAME. 2172 Jul 12

Invasive micropapillary carcinoma (IMPC) is a rare variant of ductal carcinoma of the breast, and is characterized by a high metastatic potential and an aggressive clinical course. Studies of CD146 expression and function in breast cancer remain scarce. The aim of this study was to evaluate the role of CD146 and microvessel density (MVD) in breast IMPC. CD146 mRNA expression and immunohistochemistry for CD146 and MVD measured by CD31 were assessed in 82 cases of IMPC and 137 cases of invasive ductal carcinoma, not otherwise specified (IDC-NOS). The mRNA level of CD146 in cancer specimens was higher in IMPC than in IDC-NOS. CD146 expression in tumor cells was up-regulated in IMPC as compared with that in IDC-NOS, and was positively correlated with histological grade, ER, PR status, and P53 expression in IMPC and IDC-NOS. CD146 expression in vascular endothelial cells was significantly higher than that in IDC, and was positively correlated with tumor progression in IMPC and IDC-NOS. MVD in IMPC was significantly higher than that in IDC. CD146 expression in tumor cells was positively correlated with that in vascular endothelial cells of IMPC and IDC-NOS. The association of CD146 expression with MVD and its correlation with progression in breast carcinoma indicated that CD146 is a potentially useful prognostic marker for breast cancer. CD146 could be a new drug target in the treatment of breast cancer.
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PMID:Increased expression of CD146 and microvessel density (MVD) in invasive micropapillary carcinoma of the breast: Comparative study with invasive ductal carcinoma-not otherwise specified. 2205 Nov 46

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