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. 2008 Jan;172(1):236-46.
doi: 10.2353/ajpath.2008.070602. Epub 2007 Dec 21.

Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer

Teresa Chiaverotti  1 , Suzana S Couto, Annemarie Donjacour, Jian-Hua Mao, Hiroki Nagase, Robert D Cardiff, Gerald R Cunha, Allan Balmain
Affiliations

Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer

Teresa Chiaverotti et al. Am J Pathol. 2008 Jan.

Abstract

The transgenic adenocarcinoma of mouse prostate (TRAMP) model is widely used in prostate cancer research because of rapid tumor onset and progression. The transgenic mouse is on a C57BL/6 (B6) background and expresses SV40 T-antigen under the probasin promoter. The strong genetic component of susceptibility to prostate cancer in humans prompted us to investigate the effect of mouse strain background (FVB and B6) on incidence, progression, and pathology of prostate cancer in this model. Because TRAMP lesions are unique but differ from conventional prostatic intraepithelial neoplasia because the epithelium and stroma are affected diffusely, we designated them as "atypical hyperplasia of Tag." Although the incidence and severity of atypical hyperplasia of Tag is similar, FVB-TRAMP mice live significantly shorter lives than B6-TRAMP mice because of the rapid development and progression of neuroendocrine carcinomas. This is associated with an increased frequency of neuroendocrine precursor lesions in young TRAMP mice, detectable at 4 weeks after birth. These lesions show properties of bipotential stem cells and co-express markers of epithelial (E-cadherin) and neuroendocrine (synaptophysin) lineages, as well as the transcription factors Foxa1 and Foxa2. Transplantation studies using TRAMP prostatic ducts suggested that neuroendocrine carcinomas arise independently from atypical hyperplasias or other epithelial lesions. Adenocarcinomas were not seen in our cohort. Thus, neuroendocrine carcinomas are the principal malignancy in this model and may develop from bipotential progenitor cells at an early stage of prostate tumorigenesis.

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Figures

Figure 1
Figure 1
Survival curves and lesion incidence graphs for FVB, B6, and B6 × FVB F1 TRAMP mice. A: Survival curves for B6, FVB, and B6 × FVB F1 mice. Histograms showing the incidence of neuroendocrine (NE) carcinomas by age for B6, FVB, and B6 × FVB F1 mice (B); severe atypical hyperplasia of Tag by age for B6 and FVB mice (C); and synaptophysin-positive foci by age in B6 and FVB mice (D).
Figure 2
Figure 2
Neuroendocrine carcinoma in the coagulating gland of an FVB mouse. A: Notice discrete tumor (arrow) within the coagulating gland epithelium. The tumor appears hyperchromatic because of the high nuclear:cytoplasmic ratio of neoplastic cells, H&E. B: Detail of neuroendocrine carcinoma cells adjacent to mildly hyperplastic prostatic glandular epithelium indicated by arrows. Note loss of glandular differentiation and marked cell pleomorphism, H&E. C: Positive synaptophysin staining (brown) of tumor cells in contrast to surrounding glandular epithelial tissue (asterisk), anti-synaptophysin antibody and hematoxylin. D: AR staining of glandular epithelial cells (asterisk) is intense and localized to the nucleus in contrast to the diffuse and weak staining seen in the adjacent NE carcinoma, anti-AR antibody, and hematoxylin.
Figure 3
Figure 3
Prostate whole mounts and histology of pregraft tissues. A: Whole mount of prostatic ducts (dorso-lateral prostate) used to isolate tissue for subcapsular renal grafting. Note abnormal duct (box), which is thickened and fails to trans-illuminate. B: Tissue used for grafting was bisected, and half was used for histological and immunohistochemical analysis. This section shows a duct stained for anti-smooth muscle actin (purple) to outline the intact smooth muscle stroma, and anti-Tag (nuclear stain, brown) to highlight the transformed epithelium. Note intact smooth muscle sheath around focus of glandular herniation (inset). C: H&E-stained section of pregraft duct showing atypical hyperplasia of Tag.
Figure 4
Figure 4
Tissue recombinants composed of rUGM and TRAMP prostate epithelium harvested 2 weeks after subcapsular renal grafting. A: Nuclear SV40 Tag expression is turned off in prostatic outgrowths induced by rUGM (left) when compared to original epithelium grafted (right), anti-Tag antibody and hematoxylin. B: The new prostatic outgrowths express nuclear p63 (left) simulating early prostatic duct development. Note that original epithelium grafted (right) is mostly negative for p63. C: Detail of p63 nuclear expression in continuous basal layer of prostatic outgrowths in tissue recombinants. Note cuboidal epithelium characteristic of immature ducts. D: Detail of original prostatic epithelium negative for p63 with the exception of scattered basal cells (arrows). B–D: Anti-p63 antibody and hematoxylin.
Figure 5
Figure 5
Staining of NE precursor foci in the FVB-TRAMP VP with E-cadherin and synaptophysin. A: Normal gland staining brightly for E-cadherin. B: Serial section of the same gland showing small intraepithelial clusters of synaptophysin-positive NE cells (arrows). C: Another glandular duct showing a larger NE precursor focus. Note intense E-cadherin stain of epithelium with the exception of purely NE cells (asterisk) that have a more basal location. Arrow indicates an area of transition between epithelial and neuroendocrine morphology that expresses both E-cadherin and synaptophysin. D: Synaptophysin staining of serial section of the gland depicted in C showing purely neuroendocrine cells (asterisk) and an area of transition that expresses both synaptophysin and E-cadherin (arrow).
Figure 6
Figure 6
NE carcinoma and adjacent hyperplastic gland in FVB TRAMP mouse showing Foxa1, Foxa2, and synaptophysin expression. A: Strong nuclear expression of Foxa1 in NE carcinoma cells (asterisk) and adjacent hyperplastic glandular epithelium (arrows), anti-Foxa1 and hematoxylin. B: Foxa2 expression is limited to neuroendocrine carcinoma cells (asterisk). Note that the glandular epithelium does not express Foxa2 (arrows), anti-Foxa2 and hematoxylin. C: NE carcinoma cells (asterisk) also express synaptophysin in contrast to the negative hyperplastic glandular epithelium (arrows), anti-synaptophysin and hematoxylin.
Figure 7
Figure 7
Schematic representation of dissociation of epithelial and neuroendocrine lineages in early prostatic tumorigenesis in TRAMP mice in our cohort. In the neuroendocrine carcinoma pathway (B1 and B2) a pluripotent stem cell of the normal prostate (A) is transformed by SV40 Tag expression and starts to proliferate. Initially these proliferative foci maintain a transitional epithelial/NE phenotype co-expressing E-cadherin, synaptophysin, and both Foxa1 and Foxa2 (orange cells with solid nuclei). These bipotential cells continue to proliferate, undergo full NE differentiation with loss of E-cadherin, and then progress to an overt NE carcinoma. NE carcinomas quickly invade the surrounding stroma and have the potential to metastasize. NE carcinomas maintain Foxa1 expression reminiscent of this bipotential stem cell origin. In the atypical hyperplasia of Tag pathway (C1 and C2), luminal cells of the normal prostate (A) are transformed by SV40 Tag expression (yellow cells with solid nuclei), proliferate, and form focal areas of hyperplasia. These foci expand and soon involve the entire glandular lumen. These lesions become large, complex, and dysplastic, but they do not invade the surrounding stroma and do not metastasize. Epithelial cells in these lesions continue to express E-cadherin, Foxa1, and SV40 Tag.
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