Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5?-deoxy-5-fluorouridine

Eda, Hiroyuki; Fujimoto, Kazuya; Watanabe, Shinichi; Ura, Masako; Hino, Ayako; Tanaka, Yutaka; Wada, Kenji; Ishitsuka, Hideo

doi:10.1007/bf00735915

Cited by 181 publications

(100 citation statements)

References 24 publications

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“…In our series, normal/ hyperplastic prostate glands and stroma were persistently unreactive to P-GF-44C, and a strong nuclear/cytoplasmic TP expression became only apparent in areas of intense lymphocytic infiltration, probably in the context of a chronic prostatitis. Lymphocytes produce a variety of lymphokines, such as interferons and interleukins, which are potent stimulators of TP expression (Schwartz et al, 1992;Eda et al, 1993;Goto et al, 2001). Certainly, this would explain our finding that extensive lymphocytic infiltration of the prostatic tumour stroma is related with strong TP expression by cancer and stromal cells.…”

Section: Discussionmentioning

confidence: 99%

Thymidine phosphorylase expression in normal, hyperplastic and neoplastic prostates: correlation with tumour associated macrophages, infiltrating lymphocytes, and angiogenesis

et al. 2002

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Thymidine phosphorylase is an angiogenic factor primarily expressed by cancer cells, stromal cells and tumour-associated macrophages in many human malignancies. These different types of thymidine phosphorylase-expressing cells, however, may have a distinct place in the angiogenic process, and this question was addressed in the present study. A series of 20 normal/ hyperplastic prostate glands and 60 prostate carcinomas was investigated by immunohistochemistry, using specific antibodies for thymidine phosphorylase (P-GF.44C), tumour-associated macrophages (CD68), endothelium (CD31) and prostate specific antigen (ER-PR8). Thymidine phosphorylase expression by normal and hyperplastic epithelial or stromal cells occurred almost exclusively in the context of an intense lymphocytic infiltrate. High thymidine phosphorylase cancer cells and thymidine phosphorylase stromal cells expression was associated with high angiogenesis in prostate carcinomas, and this significant association was extended to include both tumour-associated macrophages and tumour-infiltrating lymphocytes. Thymidine phosphorylase expression and tumour-infiltrating lymphocytes were related inversely with prostate specific antigen reactivity. In conclusion, thymidine phosphorylase is a major angiogenic factor in prostate carcinomas and its up-regulation is likely to occur in the context of a host immune response.

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Section: Discussionmentioning

confidence: 99%

Thymidine phosphorylase expression in normal, hyperplastic and neoplastic prostates: correlation with tumour associated macrophages, infiltrating lymphocytes, and angiogenesis

et al. 2002

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“…As TNF-ca has been shown to up-regulate markedly TP activity in tumour cell lines in vitro (Eda et al, 1993), the purpose of this study was to investigate whether TNF-a may be involved in the regulation of TP in vivo. To do this, we used non-neutralizing antibodies for TNF-x that recognize both unbound and receptor-bound TNF-ax to correlate the cellular distribution of TNF-a protein (both TNF-a expression by TAMs and TNF-a bound to receptors on tumour and endothelial cells) with that of TP protein expression by tumour cells in a consecutive series of primary invasive human breast carcinomas.…”

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confidence: 99%

Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma

Leek

Landers²,

Fox³

et al. 1998

Br J Cancer

192

118

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Summary Angiogenesis is an essential requirement for tumour growth and metastasis and is regulated by a complex network of factors produced by both stromal cells and neoplastic cells within solid tumours. The cytokine tumour necrosis factor alpha (TNF-ca) and the enzyme thymidine phosphorylase (TP) are two factors known to promote tumour angiogenesis. We have demonstrated recently that high numbers of tumour-associated macrophages (TAMs) are significantly associated with increased tumour angiogenesis and poor prognosis in invasive carcinoma of the breast. We have also shown that TAMs are a major source of TNF-a in invasive breast carcinomas, and that macrophagelike stromal cells as well as tumour cells synthesize TP in such tumours. However, little is known of the factors that regulate the production or activity of these factors in the tumour microenvironment. As TNF-a has been shown to up-regulate TP expression in tumour cells in vitro we performed an immunohistochemical study to investigate the possibility that TNF-a may be involved in the regulation of TP expression by malignant breast epithelial cells in vivo. To do this, we used a cocktail of non-neutralizing monoclonal anti-TNF-a antibodies to visualize both TNF-a-expressing macrophages and TNF-a bound to its receptors on tumour cells and endothelial cells in a series of 93 invasive carcinomas of the breast. A semiquantitative grading system was then used to compare these staining patterns with that for TP in the same biopsies. TNF-a immunoreactivity was also compared with various important tumour variables known to relate to outcome in this disease (microvessel density, node status, grade, stage, receptor status and macrophage infiltration), as well as relapse-free and overall survival data for these patients. Our data show significant positive correlations between TNF-a bound to its receptors on tumour cells and: (1) TP protein production by tumour cells, and (2) axillary lymph node status (i.e. metastasis). These results suggest that tumour cell responsiveness to TNF-a produced by neighbouring TAMs may play a part in the regulation of TP expression by tumour cells as well as their metastatic behaviour. This may explain, in part, the relationship between increased macrophage infiltration and angiogenesis in breast cancer, and further supports the contention that TAMs may represent an important target for future anti-angiogenic therapies.

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“…Previously, we reported that both UPase and dThdPase mRNAs were upregulated by the inflammatory cytokines, INF-␥, TNF-␣ and IL-1␣. 1,2,25 Although INF-␥ upregulated the expression of both the dThdPase and UPase genes, the level of maximal induction of dThdPase was higher than that of UPase in human carcinoma cell lines. In contrast, TNF-␣ and IL-1␣ induced expression of these genes in a similar manner.…”

Section: Discussionmentioning

confidence: 98%

Expression of uridine and thymidine phosphorylase genes in human breast carcinoma

Kanzaki

Takebayashi

Bando

et al. 2001

Intl Journal of Cancer

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Uridine phosphorylase (UPase) and an angiogenic enzyme, thymidine phosphorylase (dThdPase) are involved in degradation of the pyrimidine nucleosides through phosphorolysis. The expression levels of UPase and dThdPase are higher in human solid tumors including breast carcinomas than in normal tissues. To clarify the correlation between the expression levels of UPase and dThdPase genes and the clinicopathological factors, mRNA levels of these enzymes were examined by RT-PCR in 43 breast carcinomas. UPase gene expression was not correlated with dThdPase gene expression (regression coefficient R ‫؍‬ 0.032). Although the expression level of the dThdPase gene was correlated with angiogenesis, detected by immunostaining endothelial cells (R ‫؍‬ 0.66), that of UPase gene was not (R ‫؍‬ 0.044). These results suggest that UPase does not have a strong angiogenic activity. The UPase gene expression levels in tumors of patients who relapsed were significantly higher than in those from patients who did not (p ‫؍‬ 0.039). Although the expression levels of neither UPase or dThdPase were associated with age, pT, pN, pM, estrogen or progesterone receptor positivity, the patients with the higher levels of UPase gene expression had worse survival (p ‫؍‬ 0.0038) than those with lower levels. In contrast, the expression of dThdPase gene was not related to relapse or survival of these patients with breast carcinoma. Our findings suggest that the expression level of UPase gene may be an independent prognostic marker in human breast carcinoma.

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Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5?-deoxy-5-fluorouridine

Cited by 181 publications

References 24 publications

Thymidine phosphorylase expression in normal, hyperplastic and neoplastic prostates: correlation with tumour associated macrophages, infiltrating lymphocytes, and angiogenesis

Thymidine phosphorylase expression in normal, hyperplastic and neoplastic prostates: correlation with tumour associated macrophages, infiltrating lymphocytes, and angiogenesis

Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma

Expression of uridine and thymidine phosphorylase genes in human breast carcinoma

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