MODELING ESTROGEN DRIVEN FIBROBLAST-IMMUNE CELL INTERACTIONS IN THE HUMAN PROSTATE CANCER MICROENVIRONMENT

Presentation Number: OR07-6
Date of Presentation: June 15th, 2013

Gail P Risbridger*1, Ashlee K Clark1, Anna V Taubenberger2, Zhen Chea1, John Pedersen3, Mark Frydenberg1, Mitchell G Lawrence1, Dietmar W Hutmacher2, Renea A Taylor1 and Stuart J Ellem1
1Monash University, Melbourne, Australia, 2Queensland University of Technology, Australia, 3Tissupath Pathology Services, Melbourne, Australia

Abstract

The stromal microenvironment is a heterogeneous mix of cells that regulates the differentiation and function of prostate cancer cells. It comprises cancer-associated fibroblasts (CAFs) and immune cells, with the latter including mast cells, a resident population that is expanded in the peri-tumoral microenvironment. There is a current need for human models to study stromal cell interactions, especially immune cells, and their impact on cancer development and progression. Although tissue recombination is commonly used to study the functional effects of CAFs, the method is not quantitative, is lengthy, technically challenging, and the xenografts are grown in immune suppressed hosts thereby excluding the immune contribution. Therefore, we have developed a novel bioengineered cellularized matrix co-culture model, to investigate and quantify multiple cellular interactions between human tumour stromal fibroblasts and mast cells on epithelial cell morphology and motility. Patient-matched CAFs and non-malignant prostatic fibroblasts (NPFs) from moderate grade (Gleason Score 7) or more aggressive tumors (Gleason Score 8-9 or CRCP) were cultured with epithelia in the cellularised matrix and quantitative cell morphometric analyses of epithelial cell shape factor, spread area or orientation were measured. Surprisingly, CAFs induce morphological changes in epithelial cells independent of the Gleason grade of the tumor of origin; all CAFs regardless of grade induced epithelial changes of the same magnitude. However, when human mast cells were included in the co-culture system, there was further and significant potentiation of the effects of CAFs on epithelial cells features. Further mechanistic studies also revealed that estrogen (via ERalpha) mediates the synergism of CAFs and mast cells. These data, using a quantitative method to study the tumourigenic properties of human prostate cancer stroma, show a complex interplay between CAFs and mast cells orchestrated by estrogen action at the tumour interface.

 

Nothing to Disclose: GPR, AKC, AVT, ZC, JP, MF, MGL, DWH, RAT, SJE