Between a passing episode of traveler's diarrhea and a fatal case ofcolon carcinoma extends a litany of assaults on the delicate mucousmembrane that lines and shields the stomach and intestines.
Harsh acids, alkalis and enzymes may punish the mucosa, bacterialinfections inflame it, radiation and chemotherapy damage it,ulcerative colitis and Crohn's disease devastate it. Even ethanol andnon-steroidal anti-inflammatory agents such as indomethacin andibuprofen can harm the mucosal barrier. But the human gut doesn'ttake these insults and injuries lying down.
In recent years, scientists have identified a trio of "trefoil peptides"that protect and repair lesions in the gastrointestinal wall. One of thethree even shows signs of acting as a tumor suppressor.
The genes that encode these peptides cluster as a compact triad onthe long arm of human chromosome 21. "Trefoil," meaning "three-leaf," and a.k.a. "P-Domain Peptide," describes each peptide'sunusual triple-loop molecular structure. How they do their gut-mending jobs is the current subject of intensive and extensiveresearch.
Some 60 "trefoilologists" from 10 countries on five continentscongregated last week in the French hot spring resort of Aix-les-Bains for a first international symposium on the theme: "Trefoil/P-Domain Peptide: From basic research to molecular medicine." Theyheard reports on the trefoils' structural biology, gene expression androle in gastrointestinal ulceration.
Can Trefoil pS2 Curb Colon Cancer?
France's national institute of health and medical research, INSERM,sponsored the event, and one of INSERM's leading trefoilinvestigators, molecular biologist Marie-Christine Rio, presented twopapers: One reported on "pS2 and cancer;" the other, "Search for apS2 receptor, using double-hybrid techniques."
Rio discovered and cloned the human and murine pS2 trefoil peptidesin the early 1990s. She also is senior author of an article in today'sScience titled: "Gastric mucosa abnormalities and tumorigenesis inmice lacking the pS2 trefoil protein."
She and her co-authors at INSERM's institute of genetics andmolecular biology in Strasbourg, France, raised a colony of knockoutmice lacking the 4.1-kilobase murine pS2 gene. Abnormal forms ofthe gene's peptide product occur in ulcerative gastrointestinal diseaseand in various cancers.
While otherwise normal and healthy, 10 pS2-minus mice at fivemonths of age had developed adenomatous (benign) tumorsencircling the pylorus of their stomachs. And three of those animals(30 percent) showed early progression to malignant carcinoma.
"In 50 percent of human gastric carcinomas," Rio told BioWorldToday, "there is a decrease in pS2 expression. We are now trying tounderstand how this could happen."
The INSERM team she directs is testing genomic DNA frombiopsied tumor tissue "to see if there could be some modification ofthe pS2 gene." This work is hampered, she explained, "by the factthat in France there is not a lot of gastric carcinoma."
Although her line of investigation may have long-term therapeuticpotential, Rio said, "for the time being we have no industrialpartner."
A separate project, on which she reported at the meeting last week,"is trying to check for pS2 receptors. We have made new cDNAclones of putative protein, which could interact with the trefoilpeptide, and are beginning to sequence them," she said.
The pS2 trefoil peptide hangs out mainly in the lower stomach, asdoes the second of the triad, SP. The third, intestinal trefoil factor(ITF), was discovered by gastroenterologist Daniel Podolsky ofMassachusetts General Hospital in Boston. (See BioWorld Today,Dec. 4, 1995, p. 1.)
"ITF," he told BioWorld Today, "is normally expressed throughoutthe small and large intestine. But in pathological conditions thoserules of regional localization get overridden, and you can get any ofthe three trefoil peptides in any area."
Can Trefoil ITF Cure Bowel Disease?
At the meeting in Aix-les-Bains, Podolsky reported on "ITF'sfunction in vitro and in vivo." The substance of his presentation, hesaid, appears in today's Science, titled: "Impaired defense ofintestinal mucosa in mice lacking intestinal trefoil factor." Podolsky,who heads the inflammatory bowel disease unit at MassachusettsGeneral Hospital, is the paper's corresponding author.
He and his colleagues constructed knockout mice lacking the gene forITF. These, like Rio's pS2 knockouts, grew up sound in body. Butwhen fed a chemical, dextran sulfate sodium, which reliably inflictsmild colonic epithelial injury on wild type mice, half of 20 knockoutsdeveloped bloody diarrhea and died of acute colitis. Most of the wildtype controls had no ill effects.
To confirm that lack of ITF was responsible for healing failure, theteam produced gut injury in their knockouts with acetic acid, thenfollowed up with direct instillation of recombinant ITF. It evoked themigration of healing epithelial cells to the sites of damage, with"marked attenuation of gross injury."
Trefoil factors, Podolsky observed, "have potential as oral therapyfor various forms of gastrointestinal tract injury."
He added: "We're very actively exploring the molecular regulation ofthe trefoil genes' expression, and have identified some regulatoryelements in ITF that we think make it a peptide important in a non-specific way against many different types of potential damage to themucosa."
Podolsky also mentioned "data presented at the meeting in Francesuggesting some central nervous system effects of these trefoilpeptides, which may be expressed in the brain." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.