The Lankenau Institute for Medical Research
Association: Resident Faculty
Dr. James Mullin uncovered that the connections (tight junctions) between the cells that make up the digestive tract become leaky in the early stage of gastrointestinal (GI) cancer and in inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. In association with clinicians at Lankenau Medical Center, Dr. Mullin's work is establishing the importance of GI leakiness in cancer, inflammatory diseases and drug delivery. One example of where the Mullin group has found GI leakiness to be important is in Barrett's esophagus. Barrett's esophagus affects about 1% of adults in the US and occurs in individuals with chronic heartburn known medically as gastroesophageal reflux disease (GERD). It is too often a precursor to cancer of the esophagus which has a very high fatality rate. Barrett's remains frequently unnoticed until cancer occurs, and Dr. Mullin is developing an inexpensive and simple test (based on leak across the Barrett's lining) to determine which GERD patients are most in need of upper endoscopy to detect the presence of Barrett's prior to the occurrence of cancer.
In a parallel project, Dr. Mullin is examining whether reducing the amount of the essential amino acid methionine helps the digestive tract to become less leaky at the cellular connections The findings of this work could improve GI barrier function in numerous patients and thereby alleviate GI inflammation in diseases such as Crohn's. Together with doctors at Lankenau Medical Center, Dr. Mullin is investigating whether a diet with reduced methionine can reduce pain and suffering in patients with Crohn's disease, known to involve compromised barrier function of the digestive tract.
Proton pump inhibitors (PPIs) such as Nexium, Prilosec and Zegerid are the second most widely prescribed drug type in the country, with over 90 million Rxs per year. They are used for the treatment of chronic heartburn and associated disorders. In a very interesting finding Dr. Mullin observed that PPIs cause a leak in the stomach. In a third project, Dr. Mullin's laboratory is looking to exploit PPI-induced gastric leak as a safe, effective means of delivering certain drugs orally rather than by injection. Oral drug delivery is a great improvement over other methods as it is painless and can be done at home rather than in medical offices.
Research in our group focuses on the breakdown of the epithelial barrier lining of the major organs of the GI tract in various disease states and as a result of various types of drugs and chemicals in general (1). We are particularly interested in the regulation of the tight junction, a gasket-like seal, which limits transit across the epithelium through the paracellular or ""between cell"" pathway. We have shown that phorbol esters, which are known tumor promoting chemicals ers, activate the signaling protein, PKC, in our renal and gastrointestinal epithelial cell culture models and increase tight junctional permeability [2-4]. We documented a similar phenomenon occurring with proinflammatory cytokines and with certain oncogene mutations (5,6). We have observed that specific tight junction proteins, such as occludin and various claudins, are targeted . The leak of tight junctions in precancerous epithelial tissues may allow growth factors like EGF to enter subepithelial tissue and enhance tumor development tumor microenvironments . Parallel studies from our group have demonstrated that the tight junctions between epithelia of normal human colon mucosa act as good barriers whereas the junctions between the epithelia of adenocarcinomas are all ""leaky"" . Such leakiness may associate with aberrant colon crypts as well. The tight junction proteins of metaplastic epithelium of Barrett's esophagus also have this leaky character [9, 10]. As an offshoot to our work with Barrett's esophagus, our group serendipitously made a pharmacological finding that proton pump inhibitor drugs cause a transepithelial, paracellular leak in the gastric epithelium (11). Our group is currenbtly exploring the potential compklications of such leak, but also exploring the possibility of utilizing the leak for delivery of peptide and oligonucleotide drugs orally (12).
Inflammatory bowel disease associated with increased colon cancer risk has been linked with increased tight junction permeability as well as increased levels of proinflammatory cytokines, among them TNF. The biological significance of these findings is that if tight junctions become ""leaky"" in the course of tumor promotion or inflammation, growth factors normally restricted to the GI Lumen may cross the epithelial barrier, access their receptors and stimulate cell growth and motility The leak itself may also be the cause of persistent inflammation in the tissue. [1,7].
In addition to determining the pathophysiological conditions and
mechanisms by which junctional seals (and epithelial barriers) become
leaky, our group has also found that junctional seals can be
strengthened – rendered less leaky – by nutritional means (13). The
dietary interventions of caloric restriction and methionine restriction
(both known to lengthen lifespan) may be achieving their benefits in
part by inducing tighter junctional seals. Our group is currently
investigating the mechanism of this effect, the characteristics of the
reduced leak, and the implications it may have for reduced risk of
cancer and inflammation in the enhanced tissue.
Due to the favorable environment at Lankenau, with its close interplay between basic research and clinical medicine, the above research programs are pursued using cell culture and animal models, but also small patient-based, clinical trials performed jointly with the Division of Gastroenterology of Lankenau Medical Center (10).
Dr. Mullin's Google Scholar page