Mahlon D Johnson1, Mary J O'Connell, Webster Pilcher, Jay E Reeder. 1. Department of Pathology and Laboratory Medicine, Division of Neuropathology, University of Rochester Medical Center, Rochester, New York 14623, USA. mahlon_johnson@urmc.rochester.edu
Abstract
OBJECT: Fibroblast growth factor receptors (FGFRs)-1, -2, and -3 are expressed in the developing brain and may participate in CNS neoplasia. Fibroblast growth receptor-3 has not been demonstrated in the human CNS or its tumors. Nonetheless, it has been implicated in the pathogenesis of several other forms of neoplasia. METHODS: Twenty-four human meningiomas were evaluated using Western blot analysis for expression of FGFR3, its ligand acidic FGF, and concomitant phosphorylation/activation of p44/42 mitogen-activated protein kinase (MAPK), Akt, and STAT3. Mutations in exons 7 and 10 of the FGFR3 gene were analyzed by polymerase chain reaction in 10 meningiomas. Primary meningioma cells cultured from 10 human meningiomas were also treated with acidic FGF and evaluated for cell proliferation or activation/phosphorylation of p44/42 MAPK, Akt, and STAT3. RESULTS: Immunoblotting demonstrated the presence of FGFR3 in 12 (71%) of 17 primarily fibroblastic and transitional WHO Grade I meningiomas. The FGFR3 was detected in 4 (80%) of 5 WHO Grade II, and 2 of 2 Grade III tumors. Acidic FGF was detected in 3 (18%) of 17 Grade I, 1 (20%) of 5 Grade II, and 1 (50%) of 2 Grade III meningiomas. In WHO Grade I meningiomas, 3 of 6 tumors with no detectable FGFR3 had no detectable p-STAT3. In WHO Grades II and III meningiomas, FGFR3 expression was associated with p-STAT3, p-Akt, and p-p44/42 MAPK expression. No mutations were demonstrated in exons 7 or 10 by polymerase chain reaction in any meningioma. Treatment with acidic FGF, a ligand for FGFR3, stimulated meningioma cell proliferation and activation of Akt and STAT3 in primary meningioma cell cultures. CONCLUSIONS: These findings suggest that FGFR3 and acidic FGF are expressed in adult human leptomeninges as well as WHO Grades I and II meningiomas. Fibroblast growth factor receptor-3 activation stimulates meningioma cell proliferation by activation of the phosphoinositide 3 kinase-Akt-PRAS40-mTOR and STAT3 pathways.
OBJECT: Fibroblast growth factor receptors (FGFRs)-1, -2, and -3 are expressed in the developing brain and may participate in CNS neoplasia. Fibroblast growth receptor-3 has not been demonstrated in the human CNS or its tumors. Nonetheless, it has been implicated in the pathogenesis of several other forms of neoplasia. METHODS: Twenty-four humanmeningiomas were evaluated using Western blot analysis for expression of FGFR3, its ligand acidic FGF, and concomitant phosphorylation/activation of p44/42 mitogen-activated protein kinase (MAPK), Akt, and STAT3. Mutations in exons 7 and 10 of the FGFR3 gene were analyzed by polymerase chain reaction in 10 meningiomas. Primary meningioma cells cultured from 10 humanmeningiomas were also treated with acidic FGF and evaluated for cell proliferation or activation/phosphorylation of p44/42 MAPK, Akt, and STAT3. RESULTS: Immunoblotting demonstrated the presence of FGFR3 in 12 (71%) of 17 primarily fibroblastic and transitional WHO Grade I meningiomas. The FGFR3 was detected in 4 (80%) of 5 WHO Grade II, and 2 of 2 Grade III tumors. Acidic FGF was detected in 3 (18%) of 17 Grade I, 1 (20%) of 5 Grade II, and 1 (50%) of 2 Grade III meningiomas. In WHO Grade I meningiomas, 3 of 6 tumors with no detectable FGFR3 had no detectable p-STAT3. In WHO Grades II and III meningiomas, FGFR3 expression was associated with p-STAT3, p-Akt, and p-p44/42 MAPK expression. No mutations were demonstrated in exons 7 or 10 by polymerase chain reaction in any meningioma. Treatment with acidic FGF, a ligand for FGFR3, stimulated meningioma cell proliferation and activation of Akt and STAT3 in primary meningioma cell cultures. CONCLUSIONS: These findings suggest that FGFR3 and acidic FGF are expressed in adult human leptomeninges as well as WHO Grades I and II meningiomas. Fibroblast growth factor receptor-3 activation stimulates meningioma cell proliferation by activation of the phosphoinositide 3 kinase-Akt-PRAS40-mTOR and STAT3 pathways.
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