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The Role of Mast Cell Tryptase in Neoangiogenesis of Premalignant and Malignant Lesions of the Uterine Cervix
L. Benítez–Bribiesca, A. Wong, D. Utrera, and E. Castellanos
Oncological Research Unit, National Medical Center S-XXI, México DF, México
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 blue– safranin 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 49:1061–1062, 2001)
KEY WORDS mast cell tryptase angiogenesis cervical cancer
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 (Czubayko et al. 1997) and the vascular endothelial growth factor (VEGF) (Nicosia 1998; Kraft et al. 1999) are the most widely studied in malignant growth. Recently, Kankkunen et al. (1997) found that tryptase, a serine proteinase contained in mast cells, is also a potent proangiogenic factor in malignancies. Although the role of mast cells in the development and progression of cancer has not been elucidated, there is evidence that the number of mast cells in various solid cancers increases with tumor progresCorrespondence to: L. Benítez–Bribiesca, Oncological Research Unit, National Medical Center S-XXI, Av. Cuauhtémoc 330, 06725 México DF, México. E-mail: firstname.lastname@example.org Received for publication November 29, 2000; accepted February 16, 2001 (0B5430). © The Histochemical Society, Inc.
sion (Yomita et al. 1999). It has been shown in experimental models that mast cells and their products are capable of inducing tumor angiogenesis (Kessler et al. 1976). The presence of mast cells in cancer of the uterine cervix has been investigated by various authors. Graham and Graham (1966) reported that the number of mast cells in cervical cancer diminishes with cancer progression. Jain et al. (1977) observed an increased number of mast cells only in areas of inflammation around the malignant cells, but a higher number in carcinoma in situ than in invasive cancer. In contrast, Pasternak and Jans (1986) observed an increment of mast cells with cancer progression. The aim of this study was to investigate the expression of FGF and tryptase in mast cells during development of neoangiogenesis in premalignant and malignant lesions of the cervix. 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 m thick were mounted on poly-l-lysinecoated slides. Some were stained with routine H and E and Alcian blue–safranin O (ABSO) for heparin-containing mast cell granules. Other sections were pro1061
In carcinoma in situ and invasive carcinoma. as suggested previously (Roche 1985). Cesk Patol 22:214–216 Roche WR (1985) Mast cells and tumor angiogenesis: the tumormediated release of an endothelial growth factor from mast cells. These findings confirm previous reports on the progressive increase of angiogenesis in cervical neoplasia (Dellas et al. using the following antibodies: mouse monoclonal anti-human factor VIII-related Ag. Almendal A. Surg Gynecol Obstet 123:2–9 Jain PC. Pratap VK. Gynecol Oncol 67:27–33 Graham R. Marmé D. Onitsuka T (1999) Correlation between mast cells and survival rates in patients with pulmonary adenocarcinoma. the number of ABSO-stained MCs was 12 3. Pless NA. Harvima I. Utrera. Precancerous conditions and carcinomas of the uterine cervix. Unger C. Double immunocytochemical staining for Factor VIII and tryptase. 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. tryptase-positive MCs 17 5. Original magnification 400. Folkman J (1976) Mast cells and tumor angiogenesis. Matsuzaki Y. it appears appropriate to suggest that the mast cell tryptase acts as a neoangiogenic factor in malignant lesions of the cervix rather than heparin.).1062 Benítez–Bribiesca. cessed for immunolocalization of factor VIII and CD105 as endothelial markers of neovascularization. The numbers of blood vessels in normal epithelium and in dysplasias were similar (average 9 3 per h. In dysplasias and carcinoma in situ.f. respectively. Tuveson A. and expression of bFGF and tryptase were counted in five high-power fields (h. and bFGF and tryptase for mast cell growth factors. Wong. Marth C. The histological location of MCs was in the underlying connective tissue and predominantly around small blood vessels growing into the epithelial Literature Cited Czubayko F. In normal cervical samples. Lahiri B (1977) Connective tissue changes and mast cell variations in benign and malignant lesions of the uterine cervix. II. Naukkarinen A (1997) Quantitative analysis of tryptase and chymase containing mast cells in benign and malignant breast lesions. and bFGF MCs 11 3 per h. Int J Cancer 18:703–709 Kraft A. We found that mast cells differ in their expression of ABSO granules. Moch H.p. Int Surg 62:358–360 Kankkunen J. Figure 1 Invasive carcinoma of the cervix with abundant capillaries in the stroma and tryptase-positive mast cells around blood vessels. Cancer 85:178–187 Nicosia R (1998) What is the role of vascular endothelial growth factor-related molecules in tumor angiogenesis? Am J Pathol 153:11–16 Pasternak A. and free ABSO and tryptase-positive granules were also seen. a significant increase in the number of blood vessels was observed (13 4 and 23 6.p. Lung Cancer 26:103–108 . respectively). Zmija J. and tryptase. Castellanos lesion (Figure 1). Blood vessels were counted only with the factor VIII immunoreaction because CD105 immunostaining showed weak and inconsistent results. all from DAKO (Glostrup. Gidat F.p.f. Because tryptase-positive mast cells and vascularization showed a parallel increase with progression of the cervical lesions. mouse monoclonal anti-CD105.f. For staining. Ochs A. Singh SN. Int J Cancer 36:721–728 Yomita M. and in invasive carcinoma they reached 31 9 per h. tryptase-positive mast cells increased to 23 8 and 26 7 per h.f. Blood vessels.. Immunostaining for bFGF was positive in mast cell cytoplasm but was also found occasionally in the malignant cells. Liaudet–Coopman E. Jans P (1986) Mastocytes in the process of cancerogenesis.f. and mouse antihuman monoclonal mast cell tryptase. In contrast. Aigner A. Gasti G (1999) Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. number of mast cells. Graham J (1966) Mast cells and cancer of the cervix. CA). Denmark) and rabbit polyclonal FGF-2 from Santa Cruz BioTechnology (Santa Cruz. Weindel K.) ( 400). Langer RS. the DAKO ENVISION System was used. 1997) and point towards the upregulation of angiogenesis by mast cells during carcinogenesis. Int J Cancer 72:385–388 Kessler DA. Nature Med 3:1137– 1140 Dellas A. Schumacher P.p. Torhorst J (1997) Angiogenesis in cervical neoplasia: microvessel quantitation in precancerous lesions and invasive carcinomas with clinicopathological correlations. Feichter G. Degranulation was common. bFGF. Wellstein A (1997) A secreted FGF-binding protein can serve as the angiogenic switch in human cancer.p. Schultheiss E. Berchem G.
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