D C Gomes1, S A Jamra2, L F Leal2, L M Colli2, M L Campanini2, R S Oliveira2, C E Martinelli2, P C L Elias2, A C Moreira2, H R Machado2, F Saggioro2, L Neder2, M Castro2, S R Antonini3. 1. School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil. 2. School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil. 3. School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil antonini@fmrp.usp.br.
Abstract
OBJECTIVES: Pituitary stem cells play a role in the oncogenesis of human adamantinomatous craniopharyngiomas (aCPs). We hypothesized that crosstalk between the Wnt/β-catenin and Sonic Hedgehog (SHH) pathways, both of which are important in normal pituitary development, would contribute to the pathogenesis of aCPs. DESIGN: To explore the mRNA and protein expression of components of the SHH signaling pathway in aCPs and their relationship with the identification of CTNNB1/β-catenin mutations and patients outcomes. PATIENTS AND METHODS: In 18 aCP samples, CTNNB1 was sequenced, and the mRNA expression levels of SHH pathway members (SHH, PTCH1, SMO, GLI1, GLI2, GLI3, and SUFU) and SMO, GLI1, GLI3, SUFU, β-catenin, and Ki67 proteins were evaluated by quantitative real-time PCR and immunohistochemistry respectively. Anterior normal pituitaries were used as controls. Associations between molecular findings and clinical data were analyzed. RESULTS: The aCPs presented higher mRNA expression of SHH (+400-fold change (FC); P<0.01), GLI1 (+102-FC; P<0.001), and GLI3 (+5.1-FC; P<0.01) than normal anterior pituitaries. Longer disease-free survival was associated with low SMO and SUFU mRNA expression (P<0.01 and P=0.02 respectively). CTNNB1/β-catenin mutations were found in 47% of the samples. aCPs with identified mutations presented with higher mRNA expression of SMO and GLI1 (+4.3-FC; P=0.02 and +10.2-FC; P=0.03 respectively). SMO, GLI1, GLI3, and SUFU staining was found in 85, 67, 93, and 64% of the samples respectively. Strong GLI1 and GLI3 staining was detected in palisade cells, which also labeled Ki67, a marker of cell proliferation. CONCLUSIONS: The upregulation of SHH signaling occurs in aCPs. Thus, activation of Wnt/β-catenin and SHH pathways, both of which are important in pituitary embryogenesis, appears to contribute to the pathogenesis of aCP.
OBJECTIVES: Pituitary stem cells play a role in the oncogenesis of humanadamantinomatous craniopharyngiomas (aCPs). We hypothesized that crosstalk between the Wnt/β-catenin and Sonic Hedgehog (SHH) pathways, both of which are important in normal pituitary development, would contribute to the pathogenesis of aCPs. DESIGN: To explore the mRNA and protein expression of components of the SHH signaling pathway in aCPs and their relationship with the identification of CTNNB1/β-catenin mutations and patients outcomes. PATIENTS AND METHODS: In 18 aCP samples, CTNNB1 was sequenced, and the mRNA expression levels of SHH pathway members (SHH, PTCH1, SMO, GLI1, GLI2, GLI3, and SUFU) and SMO, GLI1, GLI3, SUFU, β-catenin, and Ki67 proteins were evaluated by quantitative real-time PCR and immunohistochemistry respectively. Anterior normal pituitaries were used as controls. Associations between molecular findings and clinical data were analyzed. RESULTS: The aCPs presented higher mRNA expression of SHH (+400-fold change (FC); P<0.01), GLI1 (+102-FC; P<0.001), and GLI3 (+5.1-FC; P<0.01) than normal anterior pituitaries. Longer disease-free survival was associated with low SMO and SUFU mRNA expression (P<0.01 and P=0.02 respectively). CTNNB1/β-catenin mutations were found in 47% of the samples. aCPs with identified mutations presented with higher mRNA expression of SMO and GLI1 (+4.3-FC; P=0.02 and +10.2-FC; P=0.03 respectively). SMO, GLI1, GLI3, and SUFU staining was found in 85, 67, 93, and 64% of the samples respectively. Strong GLI1 and GLI3 staining was detected in palisade cells, which also labeled Ki67, a marker of cell proliferation. CONCLUSIONS: The upregulation of SHH signaling occurs in aCPs. Thus, activation of Wnt/β-catenin and SHH pathways, both of which are important in pituitary embryogenesis, appears to contribute to the pathogenesis of aCP.
Authors: Jacob M Gump; Andrew M Donson; Diane K Birks; Vladimir M Amani; Karun K Rao; Andrea M Griesinger; B K Kleinschmidt-DeMasters; James M Johnston; Richard C E Anderson; Amy Rosenfeld; Michael Handler; Lia Gore; Nicholas Foreman; Todd C Hankinson Journal: Acta Neuropathol Commun Date: 2015-05-21 Impact factor: 7.801
Authors: John R Apps; Gabriela Carreno; Jose Mario Gonzalez-Meljem; Scott Haston; Romain Guiho; Julie E Cooper; Saba Manshaei; Nital Jani; Annett Hölsken; Benedetta Pettorini; Robert J Beynon; Deborah M Simpson; Helen C Fraser; Ying Hong; Shirleen Hallang; Thomas J Stone; Alex Virasami; Andrew M Donson; David Jones; Kristian Aquilina; Helen Spoudeas; Abhijit R Joshi; Richard Grundy; Lisa C D Storer; Márta Korbonits; David A Hilton; Kyoko Tossell; Selvam Thavaraj; Mark A Ungless; Jesus Gil; Rolf Buslei; Todd Hankinson; Darren Hargrave; Colin Goding; Cynthia L Andoniadou; Paul Brogan; Thomas S Jacques; Hywel J Williams; Juan Pedro Martinez-Barbera Journal: Acta Neuropathol Date: 2018-03-14 Impact factor: 17.088