Sub theme 4.1
Neoplastic lesions and chronic inflammation of the gastrointestinal tract

Goals of research: general outline
Scientific achievements
Future plans: special goals and approach
Running projects
Associated staff

Goals of research: general outline

Cancer of the gastrointestinal tract, i.e. esophageal, gastric, and colorectal cancer, comprises one of the most common forms of cancer in the Western world, and is a prominent cause of cancer-related death. The vast majority of GI cancer patients die as the result of the formation of distant tumor metastases. One of the main goals of our research is to acquire a better understanding of the molecular basis of colorectal tumor invasion and metastasis. Tumor cells largely depend on the surrounding stroma to establish a permissive and supportive growth environment, and to acquire metastatic potential. They adapt their microenvironment by recruiting endothelial, inflammatory, and fibroblast-like cells. In turn, the newly formed stromal compartment strongly affects tumor cell behaviour by producing growth factors, chemokines, hormones and extracellular matrix components. In fact, one could even postulate that epithelial tumor growth is impossible without the support of the stromal compartment. Therefore, one of our main research focus points will be to gain a better understanding of the interactions between tumor cells and the stromal tissue.

In the last decade it has also become clear that chronic inflammation strongly contributes to the formation and progression of various forms of cancer, including those of the gastrointestinal tract. Patients suffering from chronic forms of inflammatory bowel disease show an increased risk of tumor formation, while reflux-induced chronic inflammation is thought to be the initiating factor for the development of Barrett's esophagus, a precursor of adenocarcinoma of the gastro-esophageal junction. We will establish new research lines aimed at obtaining a better understanding of inflammation-inducing factors in the gastrointestinal tract, as well as investigate immunological aspects of colorectal cancer-related neoplastic progression.

Scientific achievements

Generation of transgenic pre-clinical in vivo models for intestinal carcinogenesis

In association with Prof. Dr. R. Fodde of the Dept. of Pathology, we have generated and analyzed various mouse models for the analysis of intestinal cancer, including models carrying specific mutations at the adenomatous polyposis coli (Apc) gene. One of the main conclusions obtained from these analyses is that tumor formation requires a tissue specific level of ß-catenin signaling which is optimal for tumor growth to be initiated, a concept that we termed “the just-right signaling” hypothesis. More recently, we have generated the Villin-rtTA transgenic model allowing temporally controlled expression of transgenes throughout the intestinal tract. This model is currently being used worldwide for various intestinal research purposes, and also for the identification of normal intestinal stem cells in the laboratory of Prof. Dr. Fodde.

The in vivo role of ß-catenin tyrosine phosphorylation for colorectal cancer

A large number of cancers, including colorectal cancer, are characterized by increased growth factor signalling caused by overexpression or mutational activation of receptor tyrosine kinases (RTK) or upstream components. At various cellular levels, ß-catenin and RTK signalling pathways show extensive cross-regulation. One aspect of this cross-regulation is the RTK-mediated tyrosine phosphorylation of ß-catenin, assumed to result in its release from adherens junctions and in the increase of its signalling pool. We have generated a mouse model carrying an activating knock-in mutation at tyrosine residue 654 of ß-catenin, providing in vivo evidence that phosphorylation at this site significantly contributes to tumor formation.

Markers for tumor development in chronic inflammatory conditions of the GI tract

The past years have yielded much insight into progression rates of premalignant lesions of esophagus, stomach, small bowel and colon, as well as predictors of progression risks. For this purpose, we performed multiple clinical-epidemiological and translational studies, involving the endoscopy unit, external databases, the lab, and population-based screening programs.

Future plans: special goals and approach

Further studies on the selection and early treatment of high-risk cases

We will continue the above-mentioned research line looking into the yield, benefits and side effects of early selection and surveillance plus targeted treatment of patients with high risk lesions of the GI tract. This involves screening and surveillance studies for Barrett’s esophagus and gastric premalignant lesions, as well as studies into colorectal adenomas, both in high-risk as well as sporadic cases.

Identification and characterization of stromal-derived factors involved in tumor growth

As mentioned above, the interaction between tumor cells and non-tumorigenic stromal cells is of great importance to acquire malignant growth potential. Using primary stromal cultures obtained from intestinal tumors and their analysis in various “omics” assays, we plan to identify stromal-derived factors that might contribute to tumor growth. Their relevance will be tested in various in vitro co-culture systems, and by generating mouse models for the most promising targets.

Development of mouse models truly recapitulating metastatic colorectal disease

Metastases originating from the primary tumor are the ultimate threat to the patient. Although the mouse models developed for spontaneous intestinal cancer formation have proven to be good models for studying processes linked to tumor initiation and local invasion, the scientific community has not yet succeeded in developing a model showing clear metastasis to other organs. This shows that we still lack some fundamental insight in the mechanisms contributing to metastatic spread and outgrowth. Using educated guesses we hope to develop such a model in the future. We will also study the role of inflammation in contributing to the metastatic potential of tumor cells.

Most recent publications

1.      Gaspar C, Franken P, Molenaar L, Breukel C, van der Valk M, Smits R, Fodde R. A targeted constitutive mutation in the APC tumor suppressor gene underlies mammary but not intestinal tumorigenesis. PloS Genet (2009) Jul;5(7):e1000547 IF 8.9

2.      Sikkema M, Kerkhof M, Steyerberg EW, Kusters JG, van Strien PM, Looman CW, van Dekken H, Siersema PD, Kuipers EJ. Aneuploidy and Overexpression of Ki67 and p53 as Markers for Neoplastic Progression in Barrett's Esophagus: A Case-Control Study. Am J. Gastroenterol (2009) IF 6.4

3.      Roth S, Franken P, Van Veelen W, Blonden L, Raghoebir L, Beverloo B, van Drunen E, Kuipers EJ, Rottier R, Fodde R, Smits R. Generation of a tightly regulated doxycycline-inducible model for studying mouse intestinal biology. Genesis (2009) 47:7-13. IF 2.2

4.      de Vries AC, van Grieken NC, Looman CW, Casparie MK, de Vries E, Meijer GA, Kuipers EJ. Gastric cancer risk in patients with premalignant gastric lesions: a nationwide cohort study in the Netherlands. Gastroenterology (2008) 134:945-952 IF 12.6

5.      Korsisaari N, Kasman IM, Forrest WF, Pal N, Bai W, Fuh G, Peale FV, Smits R, Ferrara N. Inhibition of VEGF-A prevents the angiogenic switch and results in increased survival of Apc+/min mice. Proc Natl Acad Sci USA (2007) 104:10625-10630 IF 9.6

6.      Janssen KP, Alberici P, Fsihi H, Gaspar C, Breukel C, Franken P, Rosty C, Abal M, El Marjou F, Smits R, Louvard D, Fodde R, Robine S. APC and oncogenic KRAS are synergistic in enhancing Wnt signalling in murine intestinal tumor formation and progression. Gastroenterology (2006) 131:1096-109.  IF 11.7

7.      Jubb AM, Chalasani S, Frantz GD, Smits R, Grabsch HI, Kavi V, Maughan NJ, Hillan KJ, Quirke P, Koeppen H. Achaete-scute like 2 (ascl2) is a target of Wnt signalling and is upregulated in intestinal neoplasia. Oncogene (2006) 25:3445-3457 IF 7.2

8.      Drabek K, van Ham M, Stepanova T, Draegestein K, van Horssen R, Akhmanova A, Laura Sayas C, ten Hagen T, Smits R, Fodde R, Grosveld F, Galjart N. Role of CLASP2 in Microtubule Stabilisation and the Regulation of Persistent Motility. Curr Biol (2006) 16:2259-64 IF 10.8

9.      van Dieren JM, van Vuuren AJ, Kusters JG, Nieuwenhuis EE, Kuipers EJ, van der Woude CJ. ITPA genotyping is not predictive for the development of side effects in AZA treated inflammatory bowel disease patients. Gut (2005) 54:1664 IF 9.7

10.  de Vries AC, Meijer GA, Looman CW, Casparie MK, Hansen BE, van Grieken NC, Kuipers EJ. Epidemiological trends of pre-malignant gastric lesions: a long-term nationwide study in the Netherlands. Gut (2007) 56:1665-70. IF 9.7