Molecular basis of colorectal cancer - role of gastrin and cyclooxygenase-2.
BACKGROUND
Tumors arising in the colorectal area have worldwide distribution and concern mostly older population being attributed to genetic, dietary and hormonal factors but most recently also to infection with Helicobacter pylori (HP). Both, HP discovery and molecular biology of colorectal cancer have been recently considered as two of ten greatest advances of gastroenterology at the dawn of 3rd millenium but little information is available regarding the relationship between the HP and colorectal cancer. Since HP infection is usually accompanied by an increase in plasma level of gastrin, which is also recognized as a trophic hormone for the colonic epithelium and a potent mitogen capable to induce cyclooxygenase-2 (COX-2), we decided 1) to compare the seroprevalence of HP, its cytotoxic protein, CagA, and cytokines (TNFalpha, IL-1beta and IL-8) in colorectal cancer patients, before and after removal of cancer, with those in age- and gender-matched controls; 2) to determine the gene expression of gastrin and gastrin receptors (CCK(B)-R) in colorectal cancer tissue, 3) to assess the plasma levels and tumor tissue contents of gastrin, 4) to examine the mRNA expression of cyclooxygenase COX-1 and COX-2 cancer tissue and intact colonic mucosa.


METHODS
The trial material included 80 patients with colorectal cancers and 160 age- and gender-matched controls. Anti-HP IgG, anti-CagA IgG seroprevalence and cytokine levels were estimated by ELISA tests. Gene expressions of gastrin, CCK(B)-R, COX-1, COX-2 and Bax and Bcl2 was examined using RT-PCR, while gastrin was measured by RIA.


RESULTS
The HP IgG seroprevalence, especially that expressing CagA, was significantly higher in colorectal cancer patients than in controls and did not change one week after tumor resection while plasma cytokines were significantly reduced after this operation. Gastrin and CCK(B)-R mRNA were detected in the cancer tissue and the resection margin and similarly COX-2 mRNA was expressed in most of cancers and their resection margin but not in intact colonic mucosa where only COX-1 was detected. The colorectal cancer tissue contained several folds more immunoreactive gastrin than cancer resection margin and many folds more than the intact colonic mucosa.


CONCLUSIONS
1) Colorectal carcinoma and its resection margin overexpress gastrin and receptors for gastrin (CCK(B)-R), and COX-2; 2) here, we propose that an increased plasma level of gastrin should be considered as suitable biomarker of colorectal cancer, 3) HP infection may contribute to colonic cancerogenesis by enhancing expression of gastrin and COX-2, they may account for stimulation of the tumor growth, angiogenesis and reduction in apoptosis as evidenced an increased ratio of mRNA expression for anti-apoptotic Bcl2 over proapoptotic Bax proteins and 4) HP positive patients who develop colorectal cancer should be subjected to the HP eradication; this is expected to reduce hypergastrinemia and to attenuate COX-2 expression. Our final conclusion would be: treatment of patients with colorectal cancer with COX-2 selective inhibitors now gained a strong support as a preventive measure.
Hartwich
J
J
Department of Surgery, District Hospital, Cracow, Poland.
Konturek
S J
SJ
Pierzchalski
P
P
Zuchowicz
M
M
Konturek
P C
PC
Bielański
W
W
Marlicz
K
K
Starzyńska
T
T
Ławniczak
M
M
D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002766:Cholecystokinin / Q000235:genetics; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism* / Q000382:microbiology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000097:blood; D017931:DNA Primers; D005260:Female; D005755:Gastrins / Q000235:genetics / Q000378:metabolism*; D016480:Helicobacter pylori / Q000302:isolation & purification; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; D017931:DNA Primers; D005755:Gastrins; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D002766:Cholecystokinin; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases