Gastrin-releasing peptide receptor-mediated autocrine growth in squamous cell carcinoma of the head and neck.
BACKGROUND
Gastrin-releasing peptide receptor (GRPR)-mediated autocrine growth appears to be an early marker of susceptibility to tobacco-related lung cancers. Because expression of GRPR, however, has not been reported in squamous cell carcinoma of the head and neck (SCCHN), we investigated its expression and that of its ligand GRP in normal mucosa and SCCHN tissues and the involvement of these proteins in the proliferation of SCCHN cells.


METHODS
We assessed GRPR messenger RNA (mRNA) expression in specimens from 25 patients with SCCHN, six control noncancer patients, and 14 SCCHN cell lines by use of quantitative reverse transcriptase-polymerase chain reaction. We used neutralizing GRP monoclonal antibody 2A11 to block the GRP-GRPR interaction in SCCHN cell lines and xenografts and assessed the antibody's effect on proliferation by counting cultured cells or measuring xenograft tumor volume in vivo. All statistical tests were two-sided.


RESULTS
Tumor and mucosa tissues, respectively, from SCCHN patients expressed sixfold and fourfold higher levels of GRPR mRNA than normal mucosa tissue from noncancer patients (P<.001). The levels of GRPR expression in the tumor and adjacent normal epithelium of individual patients with SCCHN were correlated (r =.652; P =.001), suggesting that increased GRPR expression is an early event in SCCHN formation. SCCHN cells expressed fivefold higher levels of GRPR mRNA than did cultured normal mucosal epithelial cells (P =.005). GRP stimulated proliferation of SCCHN cells in a dose-dependent fashion (P =.006). Neutralizing GRP monoclonal antibody 2A11 inhibited SCCHN cell proliferation in vitro and in vivo. Median survival was 54 months in patients with higher levels of GRPR mRNA and was not reached in those with lower levels.


CONCLUSIONS
GRP and GRPR appear to participate in an autocrine regulatory pathway in SCCHN. Thus, strategies that specifically target GRP and/or GRPR may be effective therapeutic approaches for this disease.
Lango
Miriam N
MN
Department of Otolaryngology, University of Pittsburgh School of Medicine, PA, USA.
Dyer
Kevin F
KF
Lui
Vivian Wai Yan
VW
Gooding
William E
WE
Gubish
Christopher
C
Siegfried
Jill M
JM
Grandis
Jennifer Rubin
JR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D019898:Autocrine Communication; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D019886:Gastrin-Releasing Peptide / Q000276:immunology / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D018004:Receptors, Bombesin / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D013997:Time Factors
D000911:Antibodies, Monoclonal; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018004:Receptors, Bombesin; D019886:Gastrin-Releasing Peptide