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)

Protein A (PA) of Staphylococcus aureus has been demonstrated to possess anti-tumor activity against a wide variety of tumors. In the current study we endeavored to obtain a mechanistic insight into PA-mediated Ehrlich's ascites carcinoma (EAC) killing. Our results indicate that PA stimulates generation of nitric oxide (NO) from murine peritoneal macrophages. Nitric oxide in turn induces cytotoxic damage to the tumor cells. Analysis of the morphological features and cell cycle phase distribution pattern of nuclear DNA revealed an induction of apoptosis (appearance of sub-G0/G1 population) in EAC after PA treatment. We have further elaborated the alterations in the expressions of the proto-oncoproteins p53 and Bax, together with a change in the ratio of Bcl-2/Bax in the treated tumor cells, which favor apoptosis. PA-induced apoptosis and changes in the expression of oncoproteins in the tumor cells was prevented by the suppression of NO release by the addition of L-NAME, the competitive NOS inhibitor, suggesting a possible mechanism by which PA exerts its anti-tumor activities involving nitric oxide through the alteration in the expressions of pro-apoptotic proteins.
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PMID:Protein A-activated macrophages induce apoptosis in Ehrlich's ascites carcinoma through a nitric oxide-dependent pathway. 1177 5

The inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) are overexpressed in colonic tumors of humans, as well as in colon tumors that develop in rats after the administration of the colon-specific carcinogen, azoxymethane (AOM). iNOS may regulate COX-2 production of proinflammatory prostaglandins, which are known to play a key role in colon tumor development. Experiments were designed to assess the potential chemopreventive properties of highly selective iNOS inhibitors, administered individually and in combination with a selective COX-2 inhibitor, on the development of AOM-induced colonic aberrant crypt foci (ACF). F344 rats were fed experimental diets containing one of the following: 0, 10, 30, or 100 parts/million (ppm) of the selective iNOS inhibitor L-N(6)-(1-iminoethyl)lysine tetrazole-amide (SC-51); 1800 ppm of the less potent, selective iNOS inhibitor aminoguanidine (AG); 500 ppm of the COX-2 inhibitor celecoxib; 320 ppm of the nonsteroidal anti-inflammatory sulindac (positive control); or 30 ppm of SC-51 with 500 ppm of celecoxib, and 100 ppm of SC-51 with 500 ppm of celecoxib. One and 2 weeks later, rats received s.c. injections of AOM at a dose of 15 mg/kg of body weight. At 17 weeks of age, all rats were sacrificed. Colons were evaluated for ACF, and colonic mucosae were assayed for COX and NOS isoform enzyme activities. Samples of venous blood, collected at various time points, were analyzed for these agents. SC-51, administered alone, demonstrated dose-dependent inhibition of the incidence of colonic ACF. The highest doses of SC-51 (100 ppm) and AG (1800 ppm) significantly suppressed the incidence of colonic ACF (P < 0.01 and < 0.001, respectively) and crypt multiplicity in terms of numbers of aberrant crypts/focus (P < 0.0001). Importantly, the combination of either low or high effective doses of SC-51 (30 or 100 ppm) and celecoxib (500 ppm) suppressed AOM-induced colonic ACF formation (P < 0.05 and < 0.001, respectively) and reduced multiplicity of four or more aberrant crypts/focus (P < 0.0001) to a greater extent than did these agents administered individually. As expected, sulindac inhibited colonic ACF formation (P < 0.001) and reduced the multiplicity of four or more aberrant crypts (P < 0.0001) to approximately 45%. The enzymatic activities of COX-2 and iNOS were significantly induced in the AOM-treated animals, and administration of the iNOS inhibitors, SC-51 and AG, significantly inhibited the activities of both iNOS and COX-2 in the colonic mucosa. The combined administration of SC-51 and celecoxib inhibited the COX-2 activity to a greater extent than did either of these agents administered alone. These findings support the hypothesis that selective iNOS inhibitors may have chemopreventive properties and that coadministration with a selective COX-2 inhibitor may have additional chemopreventive potential.
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PMID:Chemopreventive properties of a selective inducible nitric oxide synthase inhibitor in colon carcinogenesis, administered alone or in combination with celecoxib, a selective cyclooxygenase-2 inhibitor. 1178 74

Japan has a lower incidence of vulvar squamous cell carcinoma (VSCC) than Western nations. To pin-point the reasons for this, we reviewed biopsy samples from all cases treated at Nagoya University Hospital over the past 33 years in order to investigate the background lesions for VSCC. Two of 36 VSCC patients had adjacent or coexisting lichen sclerosus (LS), 5 had squamous cell hyperplasia (SCH), and 16 had vulvar intraepithelial neoplasia (VIN). There were 8 cases in which these lesions were thought to be the origin of the VSCC, 1 in which keratinizing squamous cell carcinoma (KSC) was seen in LS, 1 in which verrucous SCH was the origin, and 6 in which 4 basaloid carcinoma and 2 warty carcinoma developed from basaloid VIN and warty VIN, respectively. Although 8 other cases of keratinizing or non-keratinizing squamous cell carcinomas (NSC) coexisted with VIN NOS (not otherwise specified), differentiated VIN or basaloid VIN, we could not be histologically certain of the origin. Among 22 VSCC patients tested for HPV DNA, only an 84-year-old woman presenting a histological feature of KSC tested positive by in situ hybridization (ISH). It was considered that LS and SCH had little and VIN considerable capacity to cause the malignancy of VSCC. We surmise that in Japan the majority of squamous cell carcinoma is unrelated to HPV. One reason for the low incidence of VSCC is largely due to race; the homogeneous, monoethnic Japanese population, as well as the few cases of HPV-related VSCC.
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PMID:Squamous cell carcinoma of the vulva and adjacent lesions treated at Nagoya University Hospital from 1965 to 1997. 1182 Mar 32

NO is produced by macrophages through activation of the inducible enzyme NOS and its production is triggered as an antiviral and antitumoral immune mechanism. Replication of Marek's disease herpes virus (MDV) is inhibited by NO in vitro. MDV induces T-lymphomas in the chicken and a genetic resistance to tumor development has been linked to the B21 major histocompatibility complex. During the first initial week of viral replication after inoculation of the highly virulent RB-1B MDV strain, histocompatible B21/B21 chickens developed strong iNOS expression and NO production capacity in the spleen, in parallel with strong systemic NO production in the serum. Comparable NO response was not seen with the vaccinal strain HVT. In contrast, reduction in spleen macrophage number and delay in iNOS gene expression was observed in genetically susceptible B13/B13 chickens after MDV infection, in addition to suppression of IFN-gamma-inducible NO production. However, vaccination with HVT 3 days before RB-1B inoculation restored strong iNOS gene expression in the spleen 1 week later and inducible NO production 3 weeks later. Following the pattern of iNOS gene expression, early strong expression of cytokines with powerful iNOS-inducing activity such as IFN-gamma and CC chemokines from the MIP family (MIP-1beta, K203) was observed in genetic resistance and resistance acquired after vaccination with HVT. In conclusion, resistance to MDV appeared preferentially linked in both types of resistance to the early establishment of cytokine induction characteristic of a Th1 immune response, thus favoring the development of an early and strong NO response.
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PMID:Similar pattern of iNOS expression, NO production and cytokine response in genetic and vaccination-acquired resistance to Marek's disease. 1186 68

This study concerns the immunohistochemical localization of S-100 alpha, S-100 beta, and whole brain S-100 (wbS-100) in testicular large-cell calcifying Sertoli cell tumor (LCCSCT). We examined 8 LCCSCTs (7 benign and 1 malignant), 6 Sertoli cell tumors not otherwise specified (SCTs-NOS), 6 Leydig cell tumors (LCTs), 5 ovarian Sertoli-Leydig cell tumors (SLCTs), and 7 gonadoblastomas (GBLs). The 8 LCCSCTs showed immunoreactivity for S-100 alpha, S-100 beta, and wbS-100. Five of the 6 LCTs and the Leydig cell components in the ovarian SLCTs stained positively for S-100 alpha and wbS-100 but were negative for S-100 beta. SCTs-NOS and the Sertoli cell components in the SLCTs occasionally showed focal and weak/moderate positivity for S-100 alpha, S-100 beta, and wbS-100. Sex cord cells of the GBLs were positive for S-100 beta and wbS-100 and negative for S-100 alpha. Germ cell elements of the GBLs were negative for S-100 alpha, S-100 beta, and wbS-100. In nonneoplastic testicular parenchyma adjacent to the above-mentioned tumors, there was S-100 alpha reactivity in Leydig cells, rete testis, and a few Sertoli cells. S-100 beta reactivity was seen in a few Sertoli cells, Schwann cells, and some endothelial cells. WbS-100 reactivity was present in Leydig cells, a few Sertoli cells, rete testis, Schwann cells, and some endothelial cells. The results indicate that S-100 alpha and S-100 beta can potentially be used as immunohistochemical markers for LCCSCT, especially when differentiating it from LCT, which may mimic LCCSCT on routine histopathology. Although the biological significance of both S-100 subunits expression in LCCSCT remains unknown, these notable calcium-binding proteins may be associated with the characteristic calcification in LCCSCT through regulation of calcium levels in the tumor cells.
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PMID:Utility of immunostaining for S-100 protein subunits in gonadal sex cord-stromal tumors, with emphasis on the large-cell calcifying Sertoli cell tumor of the testis. 1197 68

Several types of genetic aberrations including microsatellite instability (MSI), allelic imbalance (AI), and chromosomal trisomies have been reported in low-grade (LG) mucosa-associated lymphoid tissue (MALT)-type gastric lymphomas. Presence of such genetic alterations could be a discriminator between de novo large cell lymphoma and high-grade (HG) MALT-type lymphoma. We investigated 17 primary gastric large B-cell lymphomas with and without features of MALT-type lymphoma for MSI, AI, and presence of trisomy of chromosomes 3, 12, and 18. We studied resection specimens from 17 primary gastric extranodal diffuse large B-cell lymphomas. Cases classified as HG MALT-type lymphoma, based on either the presence of LG MALT-type lymphoma component in the background (L/H MALT) or large cell lymphoepithelial lesions (HG MALT), and diffuse large B-cell lymphoma (DLBCL-NOS) when no features of MALT were present. MSI was analyzed using fluorescently labeled polymerase chain reaction primers (D3S11, D6S262, D3S1261, D3S1262, D3S1265). Paired tumor and normal DNA samples were amplified, and PCR products were analyzed on a DNA sequencer (ABI PRISM 373XL) with GeneScan (Applied Biosystems, Foster City, CA). MSI was defined as a gain of a novel-length allele compared with the corresponding normal tissue. AI was assessed at locus 3q27 (D3S1262 and D3S1265). The cases were analyzed for the presence of trisomy of chromosomes 3, 12, and 18 using interphase fluorescence in situ hybridization. MSI was detected in 4 out of 15 (27%) cases from which DNA was amplifiable with all primers and all MALT-type lymphomas. In two cases (13%), MSI was present at two loci sufficient to be classified as high-frequency MSI (MSI-H); this was seen exclusively in HG MALT lymphomas (P = 0.04). In the remaining two cases, MSI was detected at a single locus (low-frequency MSI). Allelic imbalance at the locus D3S1262 was detected in 4 out of 17 (24%) cases. It occurred more commonly in stage IE lymphomas when compared with higher stages (P = 0.03), regardless of lymphoma subtype. Trisomy 12 was detected in 3 out of 17 cases (18%) exclusively in stage IE lymphomas (P = 0.08). MSI was uncommon and was found exclusively in MALT-type lymphomas. MSI-H was even less common but occurred in HG MALT lymphomas only. Allelic imbalance at 3q27 (D3S1262) and trisomy 12 were found more commonly in low-stage disease. The latter two findings are in concordance with the recent suggestion that the published variation in gain of chromosomal material in high-grade gastric lymphomas may be related to stage rather than to the subtype of lymphoma. Because of the relatively low frequency of MSI in the high-grade B-cell lymphomas of the stomach, this feature cannot be used to reliably discriminate between the histologic types of extranodal diffuse large B-cell lymphoma.
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PMID:Diffuse large B-cell lymphoma of the stomach: assessment of microsatellite instability, allelic imbalance, and trisomy of chromosomes 3, 12, and 18. 1204 10

Mucinous bronchioloalveolar carcinomas (BACs) can closely mimic metastatic adenocarcinoma to the lung both clinically and morphologically. Several studies have demonstrated that the differential expression of cytokeratin 7 (CK7) and cytokeratin 20 (CK20) is a valuable diagnostic tool in differentiating primary pulmonary adenocarcinomas (PPAs) (usually CK7 positive/CK20 negative) from metastatic colonic adenocarcinoma (usually CK7 negative/CK20 positive). The present study is designed to correlate the histologic subtypes of PPA with expression of 7 and 20. A total of 113 cases of bonafide PPA were selected and classified according to the 1999 World Health Organization criteria as adenocarcinoma, NOS (n = 80), nonmucinous BAC (n = 14), and mucinous BAC (n = 19). Representive sections of all the tumors were immunohistochemically analyzed for CK7 and CK20 expression. To evaluate the diagnostic utility of CK7 and CK20 expression, 6 cases of colonic adenocarcinoma metastatic to the lung were tested with the same antibodies and compared with mucinous BAC. Results were expressed in a semiquantitative fashion based on the percentage of positive tumor cells: <10%, focal; 10% to 25%, 1+; 26% to 75%, 2+; > or =76%, 3+. All 113 PPAs exhibited strong, diffuse CK7 expression. With respect to CK20 expression, 17 of the 19 cases (89.4%) of mucinous BAC showed moderate to strong expression of this protein, whereas only 10 cases of conventional adenocarcinomas and 4 cases of nonmucinous BAC exhibited expression. All 6 examples of metastatic colonic adenocarcinomas were negative for CK7 and strongly positive for CK20. In summary, mucinous BAC is distinct from other PPAs by virtue of its CK20 expression. Although the CK7/CK20 immunoprofile is a valuable diagnostic marker for differentiating primary lung adenocarcinoma from metastatic colonic adenocarcinoma, caution should be exercised when dealing with mucinous BAC.
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PMID:Expression of cytokeratin 20 in mucinous bronchioloalveolar carcinoma. 1237 17

Reactive oxygen species are now widely recognized as important players contributing both to cell homeostasis and the development of disease. In this respect nitric oxide (NO) is no exception. The discussion here will center on regulation of the inducible form of nitric oxide synthase (iNOS) for two reasons. First, only iNOS produces micromolar NO concentrations, amounts that are high by comparison with the picomolar to nanomolar concentrations resulting from Ca2(+)-controlled NO production by endothelial eNOS or neuronal nNOS. Second, iNOS is not constitutively expressed in cells and regulation of this isoenzyme, in contrast to endothelial eNOS or neuronal nNOS, is widely considered to occur at the transcriptional level only. In particular, we were interested in the possibility that caveolin-1, a protein that functions as a tumor suppressor in colon carcinoma cells (Bender et al., 2002; this issue), might regulate iNOS activity. Our results provide evidence for the existence of a post-transcriptional mechanism controlling iNOS protein levels that involves caveolin-1-dependent sequestration of iNOS within a detergent-insoluble compartment. Interestingly, despite the high degree of conservation of the caveolin-1 scaffolding domain binding motif within all NOS enzymes, the interaction detected between caveolin-1 and iNOS in vitro is crucially dependent on presence of a caveolin-1 sequence element immediately adjacent to the scaffolding domain. A model is presented summarizing the salient aspects of these results. These observations are important in the context of tumor biology, since down-regulation of caveolin-1 is predicted to promote uncontrolled iNOS activity, genotoxic damage and thereby facilitate tumor development in humans.
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PMID:Caveolin-1-mediated post-transcriptional regulation of inducible nitric oxide synthase in human colon carcinoma cells. 1241 33

Medullary carcinoma (MC) of the breast is considered to carry a more favorable prognosis than other subtypes of infiltrating ductal carcinoma. This is a biological paradox because its clinical behavior contrasts with its anaplastic morphology. MC is characterized by a dense lymphocytic infiltrate. In this study, we determined the immunological profile of tumor infiltrating lymphocytes (TILs) in MC by CD20 (L26), CD8, and CD45RO (UCHL 1) immunostaining on paraffin-embedded sections. We examined 14 cases of typical MC (TMC), 15 cases of atypical MC (AMC) classified according to Ridolfi criteria (1977) and 19 cases of poorly differentiated infiltrating ductal carcinoma (PDC-NOS). TILs were quantified separately into cells infiltrating tumor nests (intraepithelial) and cells infiltrating tumor stroma (stromal). The number of CD8 positive and CD20 positive cells infiltrating tumor nests and tumor stroma were significantly increased in TMC and AMC as opposed to the PDC-NOS group. There was a loss in the number of CD45RO positive cells, both intraepithelial and stromal, in TMC and AMC as opposed to the PDC-NOS group. We conclude that MC tumor lymphocytic infiltrate demonstrates a mixed-T cytotoxic (CD8+) and B cell (CD20+)-immunophenotypic profile. This might in part explain the improved clinical outcome of the disease.
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PMID:Immunophenotypic profile of tumor infiltrating lymphocytes in medullary carcinoma of the breast. 1244 Aug 19

We investigated the interactions between inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) pathways in head and neck squamous cell carcinomas (HNSCCs) and in two carcinoma cell lines. HNSCCs showed an up-regulation of both pathways which were strongly correlated with each other (p=0.02) and with tumor vascularization (p=0.0001 and p=0.008, respectively). In carcinoma cells, Escherichia coli lipopolysaccharide (LPS) and EGF treatment up-regulated both pathways. NOS inhibitor N(G)-monomethyl-L-arginine methyl ester (L-NAME) inhibited this up-regulation. LPS or EGF induced iNOS expression that was not altered by NOS or COX-2 inhibitors. Conversely, LPS or EGF promoted COX-2 expression that was decreased by L-NAME. The NO donor S-nitroso-acetyl-penicillamine (SNAP) up-regulated COX-2 pathway and this effect was reduced by the guanylate cyclase inhibitor methylene blue. Thus, in squamous carcinoma cells, NO increases the activity of COX-2 pathway and this effect is probably mediated by endocellular cGMP level, with potential implications on tumor growth, angiogenesis, and therapy.
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PMID:Correlation between nitric oxide and cyclooxygenase-2 pathways in head and neck squamous cell carcinomas. 1245 68


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