Arginine metabolism in soft tissue sarcoma.
ABSTRACT L-Arginine (L-Arg) is a conditionally essential amino acid for humans, which is the substrate for both arginase (ARG) and the inducible form of nitric oxide synthase (iNOS) enzymes. Whether L-Arg metabolism has detrimental or beneficial influence on the tumor growth depends on local up regulation of the NOS or ARG pathways at the tumor site.
To evaluate the expression profile of ARG and iNOS in various histological subtypes of soft tissue sarcomas (STSs).
A series of 81 adult STSs were tested for ARG1, ARG2 and iNOS expression by immunohistochemical analysis.
ARG1, ARG2 and iNOS expression was found in tumor cells of all cases of STSs except dermatofibrosarcoma protuberans (DFSP) in a cytoplasmic pattern. However, there was no significant correlation found between ARG, iNOS expression and histopathological parameters. Conversely, the majority of DFSP were devoid of ARG and iNOS expression, while only two cases showed focal and weak expression.
Overexpression of L-Arg-metabolizing enzymes ARG and iNOS in tumor cells of all of the STS cases except DFSP may have a role in mediating the biological processes which characterize STSs. New knowledge of the regulation of arginine metabolism in tumor tissues is key to designing sound therapeutic means to effectively prevent tumorigenesis. Further studies are needed to clarify the absence of ARG and iNOS staining in DFSP.
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ABSTRACT: Nitric oxide is generated by the NO synthases, a family of isoenzymes expressed in a wide range of mammalian cells. In the vascular and nervous systems distinct isoforms generate NO to act as a signal transduction mechanism. The isoform induced by cytokines, on the other hand, provides a sustained release of NO which mediates some cytotoxic and cytostatic effects of the immune system. Solid tumors are a heterogeneous population of cell types, including tumor, vascular, and infiltrating immune cells. Studies in vitro show that NO synthase can be present in many of these cells. However, its presence in situ in solid human tumors has not been reported. In this study, we have investigated NO synthase activity and its cellular localization in malignant and nonmalignant human gynecological tissue. Nitric oxide synthase activity was observed in malignant tissue, was highest (> or = 250 pmol/min/g tissue) in poorly differentiated tumors, and was below detectable levels in normal gynecological tissue. Furthermore, investigations with a polyclonal NO synthase antibody revealed immunoreactivity only in malignant tissue. This was associated with NO synthase activity and localized to tumor cells. Thus NO synthase is present in human gynecological tumors, and its presence seems to correlate inversely with the differentiation of the tumor.Cancer Research 03/1994; 54(5):1352-4. · 8.65 Impact Factor
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ABSTRACT: Dermatofibrosarcoma protuberans (DFSP) displays chromosomal rearrangements involving chromosome 17 and 22, which fuse the collagen type Ialpha1 (COLIA1) gene to the platelet-derived growth factor (PDGF) B-chain (PDGFB) gene. To characterize the functional and structural properties of the COLIA1/PDGFB fusion protein, we generated a stable NIH3T3 cell line that contained a tumor-derived chimeric gene resulting from a COIA1 intron 7-PDGFB intron 1 fusion. Expression of the fusion protein led to morphological transformation and increased growth rate of these cells. The PDGF receptor kinase inhibitor CGP57148B reversed the transformed phenotype and reduced the growth rate of COLIA1/PDGFB-expressing cells but had no effects on control cells. The presence of dimeric COLIA1/PDGFB precursors was demonstrated through PDGFB immunoprecipitations of metabolically labeled cells and also by PDGFB immunoprecipitations followed by immunoblotting with COLIA1 antibodies. Pulse-chase studies demonstrated that the COLIA1/PDGFB precursor was processed to an end product that was indistinguishable from wild-type PDGF-BB. Finally, COLIA1/PDGFB-expressing cells generated tumors after s.c. injection into nude mice, and tumor growth was reduced by treatment with CGP57148B. We conclude that the COLIA1/PDGFB fusion associated with DFSP contributes to tumor development through ectopic production of PDGF-BB and the formation of an autocrine loop. Our findings, thus, suggest that PDGF receptors could be a target for pharmacological treatment of DFSP and giant cell fibroblastoma, e.g., through the use of PDGF receptor kinase inhibitors such as CGP57148B.Cancer Research 09/1999; 59(15):3719-23. · 8.65 Impact Factor
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ABSTRACT: Recently, the high activity of arginase enzyme has been observed in the sera of malignant neoplasms. In this pathogenic condition, it is said that arginase strongly inhibits lymphocyte proliferation and plays a role in providing ornithine as a substrate for biosynthesis of polyamines, which have been found in various types of cancer. The aim of this study was to examine the arginase activity levels in breast cancer as a marker. We evaluated the serum arginase activity levels in 48 females with breast cancer, in 30 females with benign disease, and in 50 healthy control subjects. The serum arginase activities were determined according to the slightly modified method of Chinard. The mean activity of arginase was found to be high in the early stages (n = 27, stage I + II, P < 0.01), and higher in the advanced states (n = 21, stage III + IV, P < 0.001) of the malignant group in comparison with those of the normal subjects. A high arginase level in breast cancer was observed to possibly be released into the serum: namely, the more advanced the breast cancer, the higher the serum level of arginase enzyme activity. Therefore, this enzyme might serve as a useful biological marker in breast cancer while also being an indicator of breast cancer progression.Surgery Today 01/2003; 33(9):655-61. · 0.96 Impact Factor