PACAP mediates the neural proliferative pathway of Mastomys enterochromaffin-like cell transformation.
OBJECTIVE
Pituitary adenylate-cyclase activating peptide (PACAP) is a more potent proliferative agent than gastrin for rat enterochromaffin-like (ECL) cell proliferation in vitro. The role of this neurotransmitter during gastrin-mediated ECL cell tumor formation and gastrin-autonomous ECL cell neoplasia is unknown.


RESULTS
ECL cell transformation was induced in the Mastomys using 16 wk H2 receptor blockade of acid inhibition. Examination of the epithelial fundic mucosa demonstrated that PACAP-immunoreactivity significantly increased in the tumor mucosa compared to the naïve stomach, and was associated with ECL cells. Naïve and tumor ECL cells were then purified (approximately 95%) from Mastomys and the presence of all three PACAP/VPAC receptor subtypes was demonstrated by polymerase chain-reaction amplification. Thereafter, cells were maintained in short-term (48 h) primary cultures. PACAP significantly (p<0.05) increased 24 h bromo-deoxyuridine uptake (approximately 4-fold) in both cell types with estimated EC(50) values of approximately 4x10(-16) M and approximately 2x10(-16) M, respectively. Specific receptor antagonists (PAC1/VPAC1) of PACAP competitively inhibited these proliferative effects in naïve cells. Oligonucleotide antisense directed against PAC1 significantly inhibited PACAP-stimulated DNA synthesis by approximately 85% (p<0.05) in tumor cells.


CONCLUSIONS
PACAP is a potent and effective modulator of ECL cell proliferation. The expression of this neuropeptide and its receptors, particularly PAC1, suggest the existence of a neural regulatory pathway of ECL cell proliferation and transformation.
Läuffer
J M
JM
Surgical Gastric Pathobiology Research Group, Yale University School of Medicine, and West Haven Veterans Administration Medical Center, New Haven, CT 06520-8062, USA.
Tang
L H
LH
Zhang
T
T
Hinoue
T
T
Rahbar
S
S
Odo
M
M
Modlin
I M
IM
Kidd
M
M
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D019861:Enterochromaffin-like Cells / Q000378:metabolism* / Q000473:pathology*; D005753:Gastric Mucosa / Q000187:drug effects / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008856:Microscopy, Fluorescence; D009115:Muridae; D009434:Neural Pathways / Q000187:drug effects*; D009479:Neuropeptides / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
C495401:ADCYAP1 protein, human; C495503:ADCYAP1R1 protein, human; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C495506:VIPR1 protein, human; D004247:DNA