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  • 1
    Electronic Resource
    Electronic Resource
    Tumor specific activation of the VEGF/KDR angiogenic pathway in a subset of locally advanced squamous cell head and neck carcinomas (2000)
    Springer
    Clinical & experimental metastasis 18 (2000), S. 313-319 
    Details
    ISSN: 1573-7276
    Keywords: angiogenesis ; flk-1 (KDR) ; head and neck cancer ; p53 ; thymidine phosphorylase ; VEGF
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Vascular endothelial growth factor (VEGF) and its receptors, Flt-1 and flk-1(KDR), constitute an important angiogenic pathway which, under hypoxic conditions, is up-regulated in many solid tumours. We used the monoclonal antibody 11B5, specific for recognizing VEGF expression and the `VEGF/flk-1(KDR) complex' on tumour endothelium, to assess free VEGF protein expression and VEGF/receptor activated microvessel density (aMVD) in a series of 104 inoperable locally advanced squamous cell carcinomas of the head and neck, treated with chemo-radiotherapy. High VEGF expression in cancer cells was strongly associated with high VEGF/receptor expression in the vasculature. The high VEGF expression and the aMVD were not associated with the standard microvessel density (sMVD), as assessed with the monoclonal antibody anti-CD31 and, were not detected in normal tissue. An increased sMVD, however, was significantly related with the expression thymidine phosphorylase (TP), and also with the nuclear accumulation of the oncoprotein p53, but neither p53 nor TP was associated with VEGF expression by cancer cells or VEGF/receptor complex aMVD. In 35% of cancer cases examined, more than 20% of the microvessels assessed with anti-CD31 also expressed the VEGF/KDR complex. The vasculature of the normal head and neck mucosa did not express the VEGF/KDR complex. There was no association between VEGF expression or VEGF/receptor complex aMVD and response to chemo-radiotherapy or patient's survival. It is concluded that activation of the angiogenic pathway VEGF/flk-1(KDR) is tumor specific in a subgroup of locally advanced squamous cell carcinomas of the head and neck. Selective destruction of this type of vasculature, using immunoconjugates directed against the VEGF/receptor complex, may prove therapeutically useful for patients with a high tumoral VEGF/flk-1(KDR) activated microvessel fraction.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011083121295
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  • 2
    Electronic Resource
    Electronic Resource
    Neoplastic stroma and epithelium show up-regulation of platelet-derived endothelial cell growth factor/thymidine phosphorylase in colorectal carcinomas but not adenomas (1998)
    Springer
    Angiogenesis 2 (1998), S. 49-55 
    Details
    ISSN: 1573-7209
    Keywords: Adenoma ; carcinoma ; colorectal cancer ; macrophage ; thymidine phosphorylase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tumor angiogenesis, a crucial step in tumor growth and progression, is regulated by an increasing number of angiogenic factors. One of those is platelet-derived endothelial cell growth factor, recently shown to bethymidine phosphorylase (TP), which reversibly catalyzes the phosphorylation of thymidine to deoxyribose-1-phosphate and thymine. TP overexpression in tumors has been reported, but the differential expression of this enzyme in the colorectal adenoma–carcinoma sequence has not been examined in detail. In this study we analyzed 16 hyperplastic polyps, 37 solitary tubular and tubulovillous adenomas (ranging from 1 to 7.5cm, median 3.2cm), and 47 cases of colorectal carcinomas arising on the basis of pre-existing adenomas (25 cases were Dukes' A, 10 Dukes' B and 12 Dukes' C). Non-neoplastic colonic mucosa was also examined separately from all the above carcinoma cases. All samples were stained for TP and assessed for vascularity. Normal mucosa, hyperplastic polyps, and all but three adenomas and the adenomatous parts of the invading tumors did not show any epithelial cell positivity, and only occasional macrophages and fibroblasts showed weak cytoplasmic immunoreactivity for TP. Neoplastic cells in the carcinomatous part of the tumors were positive for TP in 18 out of 47 (36%) cases. Both nuclear and cytoplasmic staining was detected but in a few cases only one of these was present. There was a highly significant difference between TP expression in neoplastic epithelial cells in adenomas compared with carcinomas (p=0.0001). The same was true when the immunoreactivity of the stromal cells was compared (p=0.0001). Areas with high angiogenesis such as those at the invading edge of the tumor showed intense epithelial, endothelial and stromal TP immunoreactivity. These results show up-regulation of a major angiogenic pathway in both the tumor epithelium and stromal cells with progression from adenoma to carcinoma, and suggest TP may be a candidate target for therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009002426554
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  • 3
    Electronic Resource
    Electronic Resource
    Neo-angiogenesis in locally advanced squamous cell head and neck cancer correlates with thymidine phosphorylase expression and p53 nuclear oncoprotein accumulation (1998)
    Springer
    Clinical & experimental metastasis 16 (1998), S. 665-672 
    Details
    ISSN: 1573-7276
    Keywords: angiogenesis ; thymidine phosphorylase ; p53 ; bcl-2 ; head and neck cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Thymidine phosphorylase (Th.P) is an angiogenic factor shown to induce endothelial cell migration and proliferation. On the other hand, loss of wild type p53 function leads to down-regulation of thrombospondin-1, an inhibitor of angiogenesis. In this immunohistochemical study we investigated the intratumoural angiogenesis and thymidine phosphorylase (Th.P) expression in paraffin-embedded bioptical material from 104 locally advanced squamous cell head and neck cancers. The nuclear accumulation of mutant p53 protein and the cytoplasmic expression of bcl-2 protein was also assessed. High vascular grade was observed in 56% and high Th.P tumour cell reactivity in 48% of cases. High microvessel score was associated with an increased percentage of cancer cells expressing thymidine phosphorylase (P = 0.001). Increased p53 nuclear accumulation also corre-lated with high vascular grade (P = 0.001). High histological grade and absence of bcl-2 overexpression were associated with lymph node involvement (P = 0.002 and P = 0.02 respectively). No correlation of clinically detected lymphadenopathy with angiogenesis and p53 was observed. We conclude that intense neo-angiogene-sis in locally advanced squamous cell head neck cancer is a frequent event, which is associated with nuclear p53 accumulation and thymidine phosphorylase overexpression. ©Lippincott Williams & Wilkins
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006554512338
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  • 4
    Electronic Resource
    Electronic Resource
    Thymidine phosphorylase expression in endometrial carcinomas (1999)
    Springer
    Clinical & experimental metastasis 17 (1999), S. 445-450 
    Details
    ISSN: 1573-7276
    Keywords: angiogenesis ; bcl-2 ; endometrial carcinoma ; p53 ; thymidine phosphorylase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Thymidine phosphorylase (TP) is a potent angiogenic molecule shown to induce endothelial cell migration and proliferation. We investigated the expression of TP in a series of 156 endometrial carcinomas, using immunohistochemical methods. Histopathological parameters of known prognostic significance and the molecular factors of p53, bcl-2 and angiogenesis were also assessed. Thymidine phosphorylase was expressed in cancer cells, stromal fibroblasts and myometrial cells. The pattern of TP staining was nuclear or mixed nuclear/cytoplasmic, and only exceptionally was purely cytoplasmic. An exclusively cytoplasmic staining was documented for the tumour-associated foamy macrophages. Cancer cell reactivity was rather limited; only 3.2% of endometrial carcinomas expressed TP in more than 50% of the neoplastic cell population and only 12% expressed the enzyme in more than 10% of the cancer cells. By contrast, TP reactivity was frequent in the fibroblasts of the tumour supporting stroma and the fibroblasts/myometrial cells at the invading tumour front, where approximately 1/3 of the cases expressed TP in more than 50% of the respective constituent cells. A high TP reactivity in the stromal fibroblasts was significantly associated with the presence of foamy macrophages and an intense lymphocytic response. A high TP reactivity at the invading tumour front was significantly associated with an intense lymphocytic response and the adverse prognostic parameters of high tumour grade, deep myometrial invasion, advanced stage of disease and the non-endometrioid carcinomas. There was no significant association of cancer cell TP reactivity with any of the parameters studied, including nuclear p53 accumulation, cytoplasmic/perinuclear bcl-2 expression, microvessel density (MVD) and prognosis. Similarly, no relationship was established between fibroblastic or fibroblastic/myometrial TP reactivity and MVD. It is concluded that TP is not a major angiogenic factor in endometrial carcinomas. However, a prominent TP activity at the invading tumour front, which is probably induced by cytokines of histiocytic and lymphocytic origin, may promote tumour invasion and progression.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006603709248
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