BRIEF REPORT |
Correspondence to: L. BenítezBribiesca, Oncological Research Unit, National Medical Center S-XXI, Av. Cuauhtémoc 330, 06725 México DF, México. E-mail: luisbenbri@mexis.com
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Summary |
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Recently, mast cell tryptase has been identified as another potent proangiogenic factor in tumors, along with fibroblast and vascular endothelial growth factors. Its role has been studied in a number of cancers, including carcinoma of the uterine cervix, with discordant results. Our aim was to study the expression of tryptase and bFGF in mast cells (MCs) during development of neoangiogenesis in premalignant and malignant lesions of the cervix. Biopsy specimens from 21 patients without cancer and from 63 patients with dysplasias and squamous cell carcinomas were used. They were stained with Alcian bluesafranin O (ABSO) and immunostained with specific antibodies against factor VIII, CD105, tryptase, and bFGF. Tryptase-positive mast cells increased with tumor progression and were close to newly formed blood vessels. Vascularization showed a linear increase from dysplasia to invasive cancer. We suggest that MC tryptase may upregulate neoangiogenesis in carcinogenesis of the uterine cervix. (J Histochem Cytochem 49:10611062, 2001)
Key Words: mast cell, tryptase, angiogenesis, cervical cancer
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Introduction |
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IT HAS BEEN WELL ESTABLISHED that tumors require a blood supply for their expansive growth. Newly formed blood vessels comprise a complex network that allows adequate oxygen and metabolic distribution to neoplastic cells. Tumor angiogenesis is driven by positive and negative regulators of endothelial growth and is a potential target for therapy.
Among the many proangiogenic factors identified to date, the fibroblast growth factor (FGF) family (
Paraffin-embedded cervical biopsies from 21 patients without cancer, 19 with cervical dysplasia, eight with carcinoma in situ, and 36 with squamous cell carcinoma in different clinical stages were studied. Sections 5 µm thick were mounted on poly-L-lysine-coated slides. Some were stained with routine H and E and Alcian bluesafranin O (ABSO) for heparin-containing mast cell granules. Other sections were processed for immunolocalization of factor VIII and CD105 as endothelial markers of neovascularization, and bFGF and tryptase for mast cell growth factors, using the following antibodies: mouse monoclonal anti-human factor VIII-related Ag; mouse monoclonal anti-CD105, and mouse antihuman monoclonal mast cell tryptase, all from DAKO (Glostrup, Denmark) and rabbit polyclonal FGF-2 from Santa Cruz Bio-Technology (Santa Cruz, CA). For staining, the DAKO ENVISION System was used. Blood vessels, number of mast cells, and expression of bFGF and tryptase were counted in five high-power fields (h.p.f.) (x400). We found that mast cells differ in their expression of ABSO granules, bFGF, and tryptase. In normal cervical samples, the number of ABSO-stained MCs was 12 ± 3, tryptase-positive MCs 17 ± 5, and bFGF MCs 11 ± 3 per h.p.f. In dysplasias and carcinoma in situ, tryptase-positive mast cells increased to 23 ± 8 and 26 ± 7 per h.p.f., respectively, and in invasive carcinoma they reached 31 ± 9 per h.p.f. In contrast, the numbers of MCs stained with ABSO and bFGF diminished from normal cervix to carcinoma in situ with a slight increase only in invasive cancer. Immunostaining for bFGF was positive in mast cell cytoplasm but was also found occasionally in the malignant cells. The histological location of MCs was in the underlying connective tissue and predominantly around small blood vessels growing into the epithelial lesion (Fig 1). Degranulation was common, and free ABSO and tryptase-positive granules were also seen. Blood vessels were counted only with the factor VIII immunoreaction because CD105 immunostaining showed weak and inconsistent results. The numbers of blood vessels in normal epithelium and in dysplasias were similar (average 9 ± 3 per h.p.f.). In carcinoma in situ and invasive carcinoma, a significant increase in the number of blood vessels was observed (13 ± 4 and 23 ± 6, respectively). Because tryptase-positive mast cells and vascularization showed a parallel increase with progression of the cervical lesions, it appears appropriate to suggest that the mast cell tryptase acts as a neoangiogenic factor in malignant lesions of the cervix rather than heparin, as suggested previously (
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Received for publication November 29, 2000; accepted February 16, 2001.
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