1. INTERACTION BETWEEN TUMOR & ITS MICROENVIRONMENT AVNER FRIEDMAN Mathematical Biosciences Institute Ohio State University, Columbus, USA

4. ● Epithelial cells are transformed by gene mutations (TECs). ● TECs secrete TGF-ß (transforming growth factor beta). ● TGF-ß signals to fibroblasts which get transformed to myofibroblasts; both secrete EGF (epidermal growth factor). ● Fibroblasts/myofibroblasts form the microenvironment of the tumor ● We want to examine how they interact with the TECs at the very early stage of cancer. Thin slice of a breast tumor http://www.jamesline.com/images/frontiers/summer2005/PartnersInCrime1.jpg Background on Breast Cancer

5. EGF, RAS, MAPK TGF- , SMAD Complex pathways stimulating cell proliferation biocarta.com

6. TRANSFORMED EPITHELIAL CELLS (TECs)

7. X = 0 MEMBRANE EGF (E) TGF-  (G) fibroblasts ( f ) myofibroblasts ( m ) TEC ( n ) fibroblasts myofibroblasts EGF (E) TGF-  (G) EXPERIMENT & MODEL DOMAIN ● Place TECs in solution at bottom of well. ● Place semi-permeable membrane above the solution. ● Deposit fibroblasts/myofibroblasts above the membrane. ● Count the number of TECs in day 2, 4, 6, and 8. ● TGF-ß and EGF can cross the membrane, but cells cannot. ( TECs ) MEMBRANE -- ++

9. Diffusion of TECs

10. CHEMOTAXIS : n cells move towards increasing concentration of EGF

11. Cell proliferation : logistic growth enhanced by EGF via Hill-type kinetics

12. production of EGF by fibroblasts & myofibroblasts in  -

13. on the semi-permeable membrane

17. ● Having gained understanding of the early stage of breast cancer in vitro without ECM, the next step is to include ECM, using the value of  that was established.