Helicobacter pylori, gastrin and cyclooxygenases in gastric cancer.
BACKGROUND
Tumors arising in the stomach have worldwide distribution and the infection with Helicobacter pylori (HP) has been implicated in causation of this disease. The HP discovery, which is considered as the greatest advance of gastroenterology at the dawn of 3rd millennium, is accompanied by hypergastrinemia, which seems to play a key role in gastric cancerogenesis but no study was undertaken to assess the relationship between the HP infection and coexpression of gastrin and cyclooxygenases (COX), the rate limiting enzymes in the eicosanoids production.


OBJECTIVE
Since gastrin is recognized as a effective gastric mitogen, it could be capable to induce COX-2, a potent tumor growth promoting and angiogenic factor, we decided 1) to compare the seroprevalence of HP and its cytotoxic protein, CagA, in gastric cancer patients with those in age- and gender-matched controls; 2) to determine the gene expression of gastrin and its receptors (CCK(B)-R) in gastric cancer, 3) to assess the plasma levels, gastric lumen and tumor tissue contents of gastrin and 4) to examine the mRNA and enzyme protein expression of COX-1 and COX-2 in cancer tissue and intact gastric mucosa before and after HP eradication.


METHODS
The trial material included 20 patients with gastric cancers and 100 age- and gender-matched controls. Anti-HP and anti-CagA IgG seroprevalence was estimated by specific antisera using ELISA tests. Gene expressions of gastrin, CCK(B)-R, COX-1 and COX-2 was examined using RT-PCR with GAPDH as a reference and employing Western blot for COX-2 expression, while gastrin was measured by RIA.


RESULTS
The seroprevalence of HP, especially that expressing CagA, was significantly higher in gastric cancers than in controls. Both gastrin and CCK(B)-R mRNA were detected by RT-PCR in the cancer tissue and similarly COX-2 mRNA and protein were found in most of cancers and in the HP infected antral mucosa but not in HP eradicated patients in whom only cancer tissue but not gastric mucosa expressed COX-2. The gastric cancer tissue contained 20 times more of immunoreactive gastrin than the HP infected antral gastric mucosa and following HP eradication the gastrin content in the tumor and antrum showed a marked and significant reduction. No significant change in CCK(B)-R expression was noticed before and after HP eradication in the tumor and the corpus mucosa.


CONCLUSIONS
1). Gastric carcinoma coexpresses gastrin, its receptors (CCK(B)-R), and COX-2; 2) HP infection may contribute to gastric cancerogenesis via gastrin andCOX-2 that may account for the stimulation of tumor growth, angiogenesis, and reduction in apoptosis 3) HP positive patients developing gastric cancer should be considered for HP eradication to reduce the HP provoked hypergastrinemia and COX-2 overexpression in the tumor tissue.
Konturek
P C
PC
Department of Medicine, Erlangen-Nuremberg University, Germany.
Hartwich
A
A
Zuchowicz
M
M
Labza
H
H
Pierzchalski
P
P
Karczewska
E
E
Bielanski
W
W
Hahn
E G
EG
Konturek
S J
SJ
D000368:Aged; D000369:Aged, 80 and over; D000942:Antigens, Bacterial; D001426:Bacterial Proteins / Q000378:metabolism*; D001706:Biopsy; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D005755:Gastrins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D016480:Helicobacter pylori / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011949:Receptors, Cholecystokinin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016036:Seroepidemiologic Studies; D013274:Stomach Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000382:microbiology*
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D005755:Gastrins; D012333:RNA, Messenger; D011949:Receptors, Cholecystokinin; C080866:cagA protein, Helicobacter pylori; D011451:Prostaglandin-Endoperoxide Synthases