60 YEARS OF NEUROENDOCRINOLOGY: Biology of human craniopharyngioma: lessons from mouse models

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   Figure 1

   Histomorphological features of mouse and human ACP. (A) Haematoxylin and eosin staining of mouse and human tumours showing the presence of microcystic changes (stellate reticulum; arrows) and whorl-like nodular structures (cell clusters; arrowheads). (B) Immunohistochemistry with a specific anti-β-catenin antibody showing the presence of cell clusters with nucleo-cytoplasmic accumulation of β-catenin (arrows). Reproduced, with permission, from Gaston-Massuet C, Andoniadou CL, Signore M, Jayakody SA, Charolidi N, Kyeyune R, Vernay B, Jacques TS, Taketo MM, Le Tissier P, et al. (2011) Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans. PNAS 108 11482–11487.
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   Figure 2

   Cell clusters with nucleo-cytoplasmic accumulation of β-catenin are detectable in the embryonic ACP mouse model. Histological sections of the embryonic mouse ACP model (Hesx1^Cre/+/Ctnnb1^+/lox(ex3)), which developed pituitary glands from 10.5 to 17.5 days post coitum (dpc), were immunostained with a specific β-catenin antibody and counterstained with haematoxylin. Magnified views of the boxed regions are shown. Note that the accumulation of β-catenin begins in a few cells within Rathke's pouch epithelium, which contains the anterior pituitary progenitors. These clusters (arrowheads) are observed only in Hesx1^Cre/+/Ctnnb1^+/lox(ex3) but not in control Ctnnb1^+/lox(ex3) pituitaries. al, anterior lobe; il, intermediate lobe; pl, posterior lobe; sph, sphenoid bone. Scale bars: 100 μm. Reproduced, with permission, from Gaston-Massuet C, Andoniadou CL, Signore M, Jayakody SA, Charolidi N, Kyeyune R, Vernay B, Jacques TS, Taketo MM, Le Tissier P, et al. (2011) Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans. PNAS 108 11482–11487.
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   Figure 3

   ACP-like tumours form only when pituitary progenitor/stem cells are targeted to express oncogenic β-catenin. Expression of mutant β-catenin in committed progenitors (Pit1-Cre/Ctnnb1^+/lox(ex3)) (left), terminally differentiated hormone-producing cells (Gh-Cre/Ctnnb1^+/lox(ex3)) (centre) and Prl-Cre/Ctnnb1^+/lox(ex3) (right) is not tumorigenic, and pituitaries from adult mice are normal. Reproduced, with permission, from Gaston-Massuet C, Andoniadou CL, Signore M, Jayakody SA, Charolidi N, Kyeyune R, Vernay B, Jacques TS, Taketo MM, Le Tissier P, et al. (2011) Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans. PNAS 108 11482–11487.
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   Figure 4

   Paracrine model of involvement of pituitary stem cells in tumorigenesis. When targeted to express oncogenic β-catenin, SOX2⁺ cells (green) accumulate nucleo-cytoplasmic β-catenin, proliferate transiently, stop dividing and form clusters. Clusters secrete signals to the surrounding cells to induce cell transformation and tumour growth from a cell that is not derived from the targeted SOX2⁺ stem cell. Reprinted from Cell Stem Cell, 13, Andoniadou CL, Matsushima D, Mousavy Gharavy SN, Signore M, Mackintosh AI, Schaeffer M, Gaston-Massuet C, Mollard P, Jacques TS, Le Tissier P, et al., Sox2(C) stem/progenitor cells in the adult mouse pituitary support organ homeostasis and have tumor-inducing potential, pp 433–445, Copyright 2013, with permission from Elsevier.
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   Figure 5

   Terminal differentiation of growth hormone (GH)-producing cells is severely disrupted in the pre-tumoural pituitary of the embryonic ACP mouse model. Double immunostaining with either β-catenin antibody (green) or terminal differentiation markers (red) on 18.5 dpc WT or Hesx1^Cre/+/Ctnnb1^+/lox(ex3) pituitary sections. Numbers of somatotrophs (GH-positive cells) (A) but not melanotrophs or corticotrophs (ACTH-positive cells) (B) are drastically reduced in the mouse ACP model relative to the control. Note that β-catenin-accumulating cell clusters do not express GH or ACTH (merge image). Bright fluorescent cells are red blood cells. Reproduced, with permission, from Gaston-Massuet C, Andoniadou CL, Signore M, Jayakody SA, Charolidi N, Kyeyune R, Vernay B, Jacques TS, Taketo MM, Le Tissier P, et al. (2011) Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans. PNAS 108 11482–11487.

• © 2015 Society for Endocrinology