Journal Article

Interrelationships among angiogenesis, proliferation, and apoptosis in the tumor microenvironment during <i>N</i>-methyl-<i>N</i>-nitrosourea androgen-induced prostate carcinogenesis in rats

Zhiming Liao, Thomas W.-M. Boileau, John W. Erdman and Steven K. Clinton

in Carcinogenesis

Volume 23, issue 10, pages 1701-1712
Published in print October 2002 | ISSN: 0143-3334
Published online October 2002 | e-ISSN: 1460-2180 | DOI:
Interrelationships among angiogenesis, proliferation, and apoptosis in the tumor microenvironment during N-methyl-N-nitrosourea androgen-induced prostate carcinogenesis in rats

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  • Clinical Cytogenetics and Molecular Genetics


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Proliferation, apoptosis and angiogenesis are critical biologic processes altered during carcinogenesis. Surrogate biomarkers of these processes represent potential intermediate endpoints for short-term intervention studies with preventive and therapeutic agents. We examined the interrelationships among these processes during prostate carcinogenesis induced by N-methyl-N-nitrosourea (MNU) in male Wistar-Unilever rats. Immunohistochemical and digital image analysis techniques were used to evaluate the proliferation index, the apoptotic index and microvessel density (MVD) in tissue representing stages of prostate carcinogenesis. The proliferation index in the normal glandular epithelium of the prostate is lower than that observed in hyperplastic foci and atypical hyperplasia (P < 0.01) and is further increased in carcinoma (P < 0.01). Apoptosis in the normal prostate epithelium or hyperplastic lesions is lower than in adenocarcinoma (P < 0.01). In parallel to proliferation index, MVD increases as prostate cancer progresses. As tumors enlarge, we observed a predictable change in biomarker expression within the tumor microenvironment. We examined prostate tumors │1 cm in diameter and biomarker expression was quantified within the peripheral (outer 1–2 mm), central (perinecrotic) and intermediate (remaining) areas of each tumor. The proliferation index is higher (P < 0.01) in the intermediate area than either in the peripheral area or central area. Similarly, the vascular density in the intermediate area is higher (P < 0.01) than either in the peripheral or central area. The apoptotic index is higher (P < 0.05) in the central perinecrotic core than that in either the intermediate or the peripheral area. In conclusion, we observe that angiogenesis, proliferation and apoptosis are linked biological processes predictably altered temporally and spatially during prostate carcinogenesis in the MNU model. These biomarker changes are similar to those reported in human prostate carcinogenesis and represent potential biomarkers for the assessment of dietary, chemopreventive and therapeutic agents.

Keywords: HPF, high power field; H&E, hematoxylin and eosin; MNU, N-methyl-N-nitrosourea; MVD, microvessel density; PCNA, proliferating cell nuclear antigen; PIN, prostatic intraepithelial neoplasia; TUNEL, terminal deoxynucleotidyltransferase (TdT)-mediated deoxyuridine triphosphate-biotin nick-end labeling

Journal Article.  8255 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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