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)

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

Our previous study showed that genetic disruption of nitric oxide (NO) synthase II (NOS II) expression inhibits the metastatic ability of non-immunogenic B16 melanoma cells in syngeneic mice. In the present study, the mechanisms for this metastasis suppression were determined. B16-BL6 and B16-F10 murine melanoma cells were injected i.v. into syngeneic wild-type (NOS II(+/+)) and NOS II-null (NOS II(-/-)) C57BL/6 mice. Both melanoma cells produced less and smaller experimental pulmonary metastases in NOS II(-/-) mice than in NOS II(+/+) mice. Moreover, less metastatic pleural effusion was observed in NOS II(-/-) mice than in NOS II(+/+) mice. Immunohistochemical analyses indicated that absence of NOS II expression was correlated with decreased vascular endothelial growth factor expression and tumor-associated vascular formation. After activation with lipopolysaccharide and IFN-gamma, neither melanoma cell line produced detectable levels of NO. Our data demonstrate that tumor-induced expression of host NOS II enhances melanoma metastasis and pleural effusion, at least in part, through regulation of vascular formation and vascular permeability.
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PMID:Genetic disruption of host nitric oxide synthase II gene impairs melanoma-induced angiogenesis and suppresses pleural effusion. 1126 68

Synergistic induction of the inducible nitric oxide synthase (NOS II) gene requires a combination of interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). In this study, we determined whether the induction of IFN-gamma was required for NOS II-mediated antitumor activity in vivo. Highly metastatic H7 murine pancreatic adenocarcinoma cells were implanted into the subcutis, footpad, and pancreas of syngeneic IFN-gamma(+/+) and IFN-gamma(-/-) mice. These cells grew and produced metastases and ascites in IFN-gamma(+/+) mice. In sharp contrast, the same tumor cells grew much more aggressively, metastasized more extensively, and produced a larger amount of malignant ascites in IFN-gamma(-/-) mice. Also, induction of IFN-gamma correlated with NOS II gene expression and NO production in IFN-gamma(+/+) injected with the tumor cells but not in IFN-gamma(-/-) mice or IFN-gamma(+/+) mice without tumor challenge. In vitro, only LPS plus IFN-gamma induced a high level of NO production and cytotoxicity against H7 cells. These data suggested that the tumor cells stimulated IFN-gamma secretion from host cells, which in turn stimulated NO production by host cells and suppressed tumor growth and metastasis.
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PMID:Genetic disruption of host interferon-gamma drastically enhances the metastasis of pancreatic adenocarcinoma through impaired expression of inducible nitric oxide synthase. 1168 72

Angiogenesis is intimately related to the growth and progression of tumours and must be induced to facilitate growth beyond a minimum size. It has been implicated in the development of metastases and survival in breast carcinoma. VEGF is a cytokine that plays an important role in angiogenesis. Its expression is increased in solid tumours during induction of angiogenesis and it has been implicated as a prognostic marker in patients with node negative breast carcinoma. We studied VEGF expression, in a series of patients with node positive breast carcinoma and examined histopathological parameters of the tumour and the prognostic value of VEGF expression. Specimens from 108 cases of node positive breast cancer were stained for VEGF using an antibody suitable for use on formalin fixed tissue. VEGF staining was cytoplasmic and was scored by intensity and the percent positive cells. Patients with positive VEGF staining (n=48) were compared with patients with negative VEGF staining (n=60). Demographic criteria were similar in both groups. Only one (12%) patient with lobular carcinoma and one (14%) patient with medullary carcinoma expressed VEGF compared with 46 (49%) patients with ductal carcinoma (NOS). DCIS was present in 60 tumours. There was a strong correlation between staining in DCIS and the adjacent invasive tumours. There was no significant association between VEGF staining and T stage, tumour size or the number of positive lymph nodes. VEGF expression had no prognostic significance either for disease-free or overall survival in patients with node positive disease. This study failed to support a role for VEGF as a prognostic marker in patients with node positive breast carcinoma.
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PMID:An evaluation of the prognostic significance of vascular endothelial growth factor in node positive primary breast carcinoma. 1189 15

Sentinel lymph node sampling has become an alternative to axillary lymph node dissection to provide prognostic and treatment information in breast cancer patients. The role of immunohistochemistry has yet to be established. A total of 241 sentinel lymph nodes (in 270 slides) from 91 patients with invasive carcinoma (73 ductal, 9 lobular, 8 mixed lobular/ductal, 1 NOS) were studied for presence of macrometastases (> 0.2 cm), identified in hematoxylin and eosin sections, and occult metastases (micrometastases [< or = 0.2 cm], clusters of cells, isolated carcinoma cells), identified only by immunohistochemistry. Intraoperative touch preparations, frozen sections, seven hematoxylin and eosin levels (L1-L7), and two AE1-3 cytokeratin immunohistochemistries (L1, L4-5) of the entire bisected or trisected sentinel lymph node were examined. Thirty-one (34%) patients had 50 positive sentinel lymph nodes. Twenty-six (33%) sentinel lymph nodes had metastatic carcinoma (11 macrometastases, 11 micrometastases, 3 clusters of cells, 1 isolated carcinoma cells) by touch preparations, frozen sections, and one hematoxylin and eosin (L1). Thirty-eight (43%) were positive by AE1-3 immunohistochemistry (L1) (11 macrometastases, 8 micrometastases, 13 clusters of cells, 6 isolated carcinoma cells), significantly more than by touch preparations, frozen sections, hematoxylin and eosin L1, or hematoxylin and eosin L2-7. Cytokeratin immunostain on L4-5 demonstrated 31 (34%) positive sentinel lymph nodes, a similar frequency to cytokeratin immunostain on L1. Size of sentinel lymph node metastasis did not correlate with size, histologic grade, or type of primary breast carcinoma. AE1-3 (L1) immunohistochemistry is highly sensitive in delineating sentinel lymph node metastasis, especially clusters of cells and isolated carcinoma cells. The prognostic significance of clusters of cells and isolated carcinoma cells and the value of AE1-3 immunohistochemistry on frozen sections need to be determined.
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PMID:Immunohistochemical evaluation of sentinel lymph nodes in breast carcinoma patients. 1260 96

Invasive micropapillary carcinoma (IMPCa) of the breast refers to a unique variant of invasive ductal carcinoma, but its biological behavior has not been elucidated well. We analyzed 16 IMPCa cases (10 pure type, six mixed type). The incidence of IMPCa was 1.0% of all primary breast carcinoma. High nuclear grade (75.0%), as well as poorly differentiated histological grade (81.3%), was frequently seen. Lymph node metastases were evident in 92.9% of the examined cases, and about half of them showed more than 10 positive nodes. Comparison between serially experienced invasive ductal carcinoma, not otherwise specified (IDC-NOS), revealed that both high nuclear grade and poor histological grade were significantly more frequent (P < 0001), there was a lower frequency of positive estrogen receptor/progesterone receptor (P < 0.05, P < 0.01), a higher frequency of HER-2 overexpression (P < 0.025), and more frequent lymph node metastases (P < 0.05) in IMPCa. The comparison between lymph node positive IDC-NOS did not show any statistically significant differences in frequency for positive p53, matrix metalloproteinase protein-2 (MMP-2), vascular endothelial growth factor (VEGF) or E-cadherin. However, IMPCa showed a significantly increased number of blood vessels counted by CD34 immunostains (P < 0.05). These results suggest that IMPCa is, at least, the same or more aggressive than lymph node positive cases of IDC-NOS. Hence, not only the high incidence of lymph node metastases but also distant, blood-borne metastases may be important.
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PMID:Invasive micropapillary carcinoma of the breast: clinicopathological and immunohistochemical study. 1472 Jan 38

Lip cancer is the most frequent malignant neoplasm of the oral cavity; however, there is no information available on the incidence of this type of cancer in Mexico. This study provides information about the clinico-pathological features of lip cancer patients admitted at a cancer hospital in Mexico City during an 11-year period and describes the treatment modalities performed and their results. A total of 113 patients were studied. There were 74 men (65.5%) and 39 women (34.5%), ranging in age from 14 to 106 years (mean 70 years). In 53 cases (46.9%) an association was found between the disease and chronic sun exposure. Additionally, positive smoking antecedents were recorded in 58 cases (51.3%). As 15 patients were followed for less than 1 month, they were excluded for further analysis. There were 82 cases (83.7%) of squamous cell carcinoma, 10 (10.2%) basal cell carcinomas, and one case (1%) each of adenocarcinoma NOS, melanoma, adenoid cystic carcinoma, Merkel cell carcinoma, lymphoepithelioma and angiosarcoma. We observed an incidence of malignant neoplasms in the upper lip of 33.7%, which is higher than most of the published series and may be due to the fact that in this series we included all histological types of lip cancers. Fifty percent of the cases were found in stages III and IV. Cervical lymph node metastases were found in 21% of patients with no previous treatment, and they developed in 5.3% after treatment. Our data suggest that tumoral size is directly related to the possibility of developing node metastases, as none of them occurred in patients T1, whereas 10 (62.5%) of the patients in T4 presented them. Seven deaths were documented (7.1%), five of which corresponded to squamous cell carcinoma, one to Merkel cell carcinoma, and one to adenocarcinoma. Deaths were directly related to the disease in six cases, and one patient died due to surgical complications. Distant metastases were found in only two patients, one of which coursed with an adenocarcinoma and the other with a Merkel cell carcinoma. Based on the present results, we suggest that the differences encountered with respect to other series, particularly the higher incidence found in women, the frequent presentation of this type of neoplasms in the upper lip, the wide variety of histopathological diagnoses and the high frequency of cases with cervical lymph node affection, should lead us to search for multi-modal treatment alternatives in this population.
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PMID:Lip cancer experience in Mexico. An 11-year retrospective study. 1550 90

To evaluate the clinical potential of endothelial nitric oxide synthase (e-NOS) in human breast cancer, we performed immunohistochemical (IHC) staining of paraffin-embedded primary breast cancer tissue of 163 patients for e-NOS using a monoclonal antibody. A correlation was found between e-NOS expression and both the classic prognostic factors and survival rates. Under half the patients were premenopausal (38.5%), 61.5% being postmenopausal. The median tumour size was 2 cm; in 41.7% of the patients there was involvement of the axillary lymph nodes. Most (84.1%) of the tumours were hormone receptor positive. e-NOS staining was positive in 62%, most of the positive tumours having weak (32.5%) or medium (21.5%) staining for e-NOS. The median follow-up time was 42 months, during which 46 (28%) patients had a local recurrence or metastatic disease. A positive correlation of e-NOS with the hormone receptor status was found (P=0.031). However, no impact on survival rates was observed.
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PMID:Immunohistochemical evaluation of endothelial nitric oxide synthase expression in primary breast cancer. 1592 32

Inducible nitric oxide (NO) synthase (NOS) II has been implicated in macrophage-mediated antitumor activity. However, use of the NOS II gene in cancer therapy is problematic because of the double-edged nature of NO action. Herein we show that adenoviral vectors mediated effective NOS II gene transfer into various human tumors. Production of NO significantly up-regulated multiple angiogenic molecules. However, the NO-producing tumor cells did not form tumors or metastases in ectopic or orthotopic xenograft nude mouse models. The dramatic loss of malignancy was due to NO-mediated apoptosis. We also generated a series of adenoviral vectors harboring mutant NOS II genes that expressed mutant NOS II proteins with defined levels of enzymatic activity. Tumor cells transduced with these NOS II genes produced NO at different levels, which directly correlated with the antitumor activity in vitro and in vivo. This demonstration using a relevant biological system shows that NO produces dose-dependent antitumor activity in vitro and in vivo, regardless of its up-regulation of protumor factors.
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PMID:Nitric oxide synthase II suppresses the growth and metastasis of human cancer regardless of its up-regulation of protumor factors. 1593 86

Nitric oxide (NO) is a diatomic free radical molecule that has been implicated in tumour angiogenesis and progression of head and neck squamous cell carcinoma (HNSCC). However, the mechanism underlying the effect of NO on tumour spread remains largely unknown. Tumour lymphangiogenesis has recently received considerable attention and there is increasing evidence that it is relevant for metastasis to lymph nodes in HNSCC. Here, we study the correlation between inducible NOS synthase (iNOS) activity and lymphangiogenesis in a series of 60 HNSCCs and the possible involvement of the lymphangiogenic factor vascular endothelial growth factor (VEGF)-C. HNSCC presenting with lymph node metastasis had a significantly higher lymphatic vessel density in both the tumour mass and the peritumour area (p = 0.006 and p = 0.001, respectively). Similarly, tumours with lymph node metastasis showed greater lymphatic vessel area than tumours with no lymph node involvement (p = 0.001 for intratumour lymphatics and p < 0.001 for peritumour lymphatics). iNOS activity measured in specimens from the tumour periphery correlated strongly with both lymphatic vessel density and lymphatic vessel area (p = 0.01, rs = 0.45 and p < 0.001, rs = 0.725, respectively). Conversely, these correlations were not observed in specimens from the tumour core. In addition, VEGF-C mRNA expression was significantly elevated in tumours with high iNOS activity (p = 0.008, rs = 0.563), and VEGF-C expression correlated positively with the presence of lymph node metastases (p = 0.03). In vitro, in the A431 human squamous carcinoma cell line, exogenous and endogenous stimulation of the iNOS pathway led to up-regulation of VEGF-C, which was blocked by the NOS inhibitor L-NNA. Taken together, our results indicate that iNOS activity may promote lymphangiogenesis and spread to lymph nodes in HNSCC, with the possible involvement of VEGF-C.
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PMID:Inducible nitric oxide synthase activity correlates with lymphangiogenesis and vascular endothelial growth factor-C expression in head and neck squamous cell carcinoma. 1627 21


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