ErbB and Nrg: potential molecular targets for vestibular schwannoma pharmacotherapy.
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.


METHODS
Molecular analyses, retrospective clinical correlation.


METHODS
Tertiary referral center.


METHODS
Thirty-eight specimens from patients operated for sporadic (n=21) and neurofibromatosis (NF) 2-related (n=17) VS.


METHODS
VS analyses via real-time polymerase chain reaction, immunohistochemistry, and correlation with patient clinical data.


METHODS
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).


CONCLUSIONS
These findings implicate the ErbB pathway in VS growth and as potential molecular targets for VS pharmacotherapy.
Doherty
Joni K
JK
Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of California, San Diego, USA. jkdoherty@ucsd.edu
Ongkeko
Weg
W
Crawley
Brianna
B
Andalibi
Ali
A
Ryan
Allen F
AF
D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D018815:Genes, erbB / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008297:Male; D008875:Middle Aged; D020880:Neuregulins / Q000187:drug effects* / Q000235:genetics; D016518:Neurofibromatosis 2 / Q000235:genetics / Q000473:pathology; D009464:Neuroma, Acoustic / Q000188:drug therapy* / Q000473:pathology; D010524:Peripheral Nervous System Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012189:Retrospective Studies; D014015:Tissue Banks; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D008024:Ligands; D020880:Neuregulins; D012333:RNA, Messenger; D012313:RNA; D004247:DNA