Angiogenesis in Cervical Neoplasia: Microvessel Quantitation in Precancerous Lesions and Invasive Carcinomas with Clinicopathological Correlations

Dellas, Athanassios; Moch, Holger; Schultheiss, Elisabeth; Feichter, Georg E.; Almendral, Alfonso C.; Gudat, F; Torhorst, J.

doi:10.1006/gyno.1997.4835

Cited by 92 publications

(65 citation statements)

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“…Many authors have reported that a high microvessel density correlates with poor patient prognosis in uterine cervical cancers (Kainz et al, 1995;Rutgers et al, 1995;Wiggins et al, 1995;Bremer et al, 1996;Dinh et al, 1996;Dellas et al, 1997;Obermair et al, 1998). In the present study, the prognosis of the patients with high PD-ECGF squamous cell carcinomas was worse than those with low PD-ECGF squamous cell carcinomas, and PD-ECGF expression correlated with Ki-67 index as an indicator of cellular proliferation (Sawhney and Hall, 1992), microvessel density and vascular invasion.…”

Section: Discussionsupporting

confidence: 58%

Expression of platelet-derived endothelial cell growth factor (PD-ECGF) and its mRNA in uterine cervical cancers

et al. 1999

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Angiogenesis contributes to the growth and secondary spreading of solid tumours. Platelet-derived endothelial cell growth factor (PD-ECGF) is identified as such an angiogenic factor. In the present study, the prognosis of the patients with high PD-ECGF uterine cervical cancers was worse than those with low PD-ECGF cancers, and PD-ECGF expression correlated with cellular proliferation and with vascular density and venous invasion in uterine cervical cancers. Therefore, PD-ECGF might contribute to the growth of uterine cervical cancers via angiogenesis related to vascular spreading. Furthermore, PD-ECGF and its mRNA had a wide range and were highly expressed in uterine cervical cancers, especially squamous cell carcinoma, regardless of clinical stage. Therefore, PD-ECGF in uterine cervical cancers might play a role of basic angiogenesis in all processes of advancing of uterine cervical cancers. This indicates that 5′-deoxy-5-fluorouridine might be highly effective in squamous cell carcinoma of the cervix, which possesses a high activity of thymidine phosphorylase to convert 5′-deoxy-5-fluorouridine to 5-fluorouracil, and that some angiogenic inhibitors of new capillary formation might be effective in the inhibition of tumour growth and spreading associated with angiogenesis. © 1999 Cancer Research Campaign

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Section: Discussionsupporting

confidence: 58%

Expression of platelet-derived endothelial cell growth factor (PD-ECGF) and its mRNA in uterine cervical cancers

et al. 1999

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“…Dellas and co-workers observed a significant increase in microvessel counts in dysplastic and invasive lesions compared to normal cervical epithelium [18]. In our model, dual species-specific CD31 immunostaining revealed that the establishment of a blood supply to the implant occurred via anastomotic vascular channels.…”

Section: Summary Of Observations: Experiments I-viisupporting

confidence: 50%

Development and Assessment of a General Theory of Cervical Carcinogenesis Utilizing a Severe Combined Immunodeficiency Murine–Human Xenograft Model

Tewari¹,

Taylor²,

Liao³

et al. 2000

Gynecologic Oncology

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Objective. Currently, we lack a theoretical explanation for why squamous cell cervical cancer develops predominantly in specific sites (i.e., along the squamocolumnar junction). We therefore implanted human cervical tissues containing the transformation zone in severe combined immunodeficiency (SCID) mice and studied morphology, steroid effects, gene expression, and human papillomavirus (HPV) factors.Methods. Normal and dysplastic human cervical tissues (3 ؋ 2 mm) were placed subcutaneously in SCID-beige mice and later assessed by in situ hybridization for HPV 16/18 DNA and by immunohistochemistry for expression of CD31, keratin, proliferating-cell nuclear antigen, HPV 16 E6, p53, and Notch-1 (a binary cell fate determination protein). Some normal tissues were implanted with either a 90-day release 1.7-mg 17␤-estradiol pellet or a 5-mg tamoxifen pellet; others were infected prior to implantation with human recombinant adenovirus 5 vector containing a human cytomegalovirus promoter-driven ␤-galactosidase gene and later assessed by X-gal staining.Results. Murine and human vessels formed anastomoses by 3 weeks. For at least 11 weeks, normal tissue retained the transformation zone and normal cell-type-specific keratin expression and exhibited normal proliferation; Notch-1 was present only in the basal cell layer. Dysplastic tissues exhibited koilocytosis, increased levels of cellular proliferation, and aberrant keratin, p53, and Notch-1 expression; HPV 16/18 DNA and HPV 16 E6 protein were detected for at least 6 weeks. Squamous metaplasia of normal cervical epithelium resulted from estrogen exposure, and a predominant columnar differentiation pattern was associated with tamoxifen administration. Through stable adenovirus infection, ␤-galactosidase was expressed for at least 6 weeks.Conclusions. This small manipulatable xenograft model maintains normal and dysplastic human cervical epithelium through neovascularization. Neoplastic tissue retains HPV 16/18 DNA and a premalignant phenotype, including elevated levels of cellular proliferation and aberrant keratin, p53, and Notch-1 expression. These attributes constitute essential features of a biologic model through which one may study HPV-mediated human disease and may be superior to cell culture and transgenic murine systems. Furthermore, this may serve as a model for gene therapy. Finally, we suggest that the normal cervical epithelium is maintained through putative interactions between the Notch locus and cell cycle growth regulators such as p53 and pRb. Neoplastic cervical epithelium may arise through disruption of this pathway. This theory may be testable in our animal model.

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“…Vascularization has been shown in many in vivo systems to be crucial for tumor progression. Reducing neovasculature restrains tumor growth, and increasing microvasculature is associated with progression from low-grade to high-grade CIN and to cervical carcinoma in humans (47,48,54) as well as in estrogen-induced dysplasia in mice (1). This is also consistent with our result in that I3C induces PTEN and retards progression to high-grade dysplasia.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, little or no PTEN was detected in cells in high-grade cervical dysplasia or in invasive squamous cell carcinoma. This observation indicated that elimination of PTEN expression was associated with progression from low-grade to high-grade cervical dysplasia, a transition when increased angiogenesis is required (47)(48)(49)(50). More exact conclusions can be made with lesions found in the K14HPV16 transgenic mouse, the murine model for human cervical cancer, because of its genetic homogeneity.…”

Section: Pten Expression Decreases As Cervical Dysplasia Increases Anmentioning

confidence: 99%

Indole-3-Carbinol Prevents PTEN Loss in Cervical Cancer In Vivo

Anderson

Chen

et al. 2005

Mol Med

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Indole-3-carbinol (I3C) is a phytochemical (derived from broccoli, cabbage, and other cruciferous vegetables) with proven anticancer efficacy including the reduction of cervical intraepithelial neoplasia (CIN) and its progression to cervical cancer. In a breast cancer cell line, I3C inhibited cell adhesion, spreading, and invasion associated with an upregulation of the tumor suppressor gene PTEN, suggesting that PTEN is important in inhibition of late stages in the development of cancer. The goal of this study was to determine the expression of PTEN during the development of cervical cancer and whether I3C affected expression of PTEN in vivo. We show diminished PTEN expression during the progression from low-grade to high-grade cervical dysplasia in humans and in a mouse model for cervical cancer, the K14HPV16 transgenic mice promoted with estrogen. The implication is that loss of PTEN function is required for this transition. Additionally, dietary I3C increased PTEN expression in the cervical epithelium of the transgenic mouse, an observation that suggests PTEN upregulation by I3C is one mechanism by which I3C inhibits development of cervical cancer.

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Angiogenesis in Cervical Neoplasia: Microvessel Quantitation in Precancerous Lesions and Invasive Carcinomas with Clinicopathological Correlations

Cited by 92 publications

References 0 publications

Expression of platelet-derived endothelial cell growth factor (PD-ECGF) and its mRNA in uterine cervical cancers

Expression of platelet-derived endothelial cell growth factor (PD-ECGF) and its mRNA in uterine cervical cancers

Development and Assessment of a General Theory of Cervical Carcinogenesis Utilizing a Severe Combined Immunodeficiency Murine–Human Xenograft Model

Indole-3-Carbinol Prevents PTEN Loss in Cervical Cancer In Vivo

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