Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology · 2008
ErbB and Nrg: potential molecular targets for vestibular schwannoma pharmacotherapy.
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Doherty Joni K, Ongkeko Weg, Crawley Brianna, Andalibi Ali, Ryan Allen F
Аннотация
OBJECTIVE: Identify molecular targets for development of tumor-specific pharmacotherapeutics aimed at treating vestibular schwannomas (VSs). Activated epidermal growth factor receptor B (ErbB) 2 and ErbB3 are abundantly expressed in VS. ErbB2 signaling is essential for Schwann cell differentiation, survival, and proliferation. VS arise after loss of functional merlin, a putative tumor suppressor. Merlin internalizes ErbB2 receptors in rodent Schwann cells. Unregulated ErbB signaling may contribute to VS tumorigenesis.
STUDY DESIGN: Molecular analyses, retrospective clinical correlation.
SETTING: Tertiary referral center.
PATIENTS: Thirty-eight specimens from patients operated for sporadic (n=21) and neurofibromatosis (NF) 2-related (n=17) VS.
INTERVENTION(S): VS analyses via real-time polymerase chain reaction, immunohistochemistry, and correlation with patient clinical data.
MAIN OUTCOME MEASURE(S): ErbB signaling molecule expression, tumor size, age, and NF2 status.
RESULTS: VS upregulated epidermal growth factor (EGF) receptor in 68% (62% sporadic and 75% NF2-associated VS) and ErbB2 in 84% (76% sporadic and 94% NF2-related VS). ErbB3 was upregulated in 34%, and ErbB4 is downregulated in NF2-related VS. Of EGF receptor (EGFR) ligands, EGF was upregulated in all NF2-related VS, but none of the sporadic VS (p<0.01), and transforming growth factor alpha and beta-cellulin showed upregulation in 67% of NF2-related VS but not sporadic VS (p=0.02 and p=0.01, respectively). Neuregulin (Nrg) was upregulated in 86% of sporadic VS versus 19% of NF2-related VS (p<0.01). EGFR expression levels correlated directly with VS tumor size and inversely with patient age, whereas Nrg expression correlated directly with age (p=0.0005). EGF expression predicts NF2 status, whereas Nrg predicts non-NF2 status (p<0.01).
CONCLUSION: These findings implicate the ErbB pathway in VS growth and as potential molecular targets for VS pharmacotherapy.
STUDY DESIGN: Molecular analyses, retrospective clinical correlation.
SETTING: Tertiary referral center.
PATIENTS: Thirty-eight specimens from patients operated for sporadic (n=21) and neurofibromatosis (NF) 2-related (n=17) VS.
INTERVENTION(S): VS analyses via real-time polymerase chain reaction, immunohistochemistry, and correlation with patient clinical data.
MAIN OUTCOME MEASURE(S): ErbB signaling molecule expression, tumor size, age, and NF2 status.
RESULTS: VS upregulated epidermal growth factor (EGF) receptor in 68% (62% sporadic and 75% NF2-associated VS) and ErbB2 in 84% (76% sporadic and 94% NF2-related VS). ErbB3 was upregulated in 34%, and ErbB4 is downregulated in NF2-related VS. Of EGF receptor (EGFR) ligands, EGF was upregulated in all NF2-related VS, but none of the sporadic VS (p<0.01), and transforming growth factor alpha and beta-cellulin showed upregulation in 67% of NF2-related VS but not sporadic VS (p=0.02 and p=0.01, respectively). Neuregulin (Nrg) was upregulated in 86% of sporadic VS versus 19% of NF2-related VS (p<0.01). EGFR expression levels correlated directly with VS tumor size and inversely with patient age, whereas Nrg expression correlated directly with age (p=0.0005). EGF expression predicts NF2 status, whereas Nrg predicts non-NF2 status (p<0.01).
CONCLUSION: These findings implicate the ErbB pathway in VS growth and as potential molecular targets for VS pharmacotherapy.
Предметные рубрики MeSH
AdultAgedAgingAntineoplastic AgentsDNAEnzyme-Linked Immunosorbent AssayFemaleGene Expression RegulationGenes, erbBHumansImmunohistochemistryLigandsMaleMiddle AgedNeuregulinsNeurofibromatosis 2Neuroma, AcousticPeripheral Nervous System NeoplasmsRNARNA, MessengerRetrospective StudiesTissue BanksUp-Regulation