Abstract 4244: The role of hypoxia on the tumor-stromal interaction in pancreatic ductal adenocarcinoma

Abstract

Abstract INTRODUCTION: Pancreatic cancer is characterized by extraordinary fibrosis and pancreatic stellate cells (PSCs) are the major player in synthesizing extracellular matrix (ECM) upon activation. The interaction/communication between PSCs and pancreatic ductal adenocarcinoma (PDAC) cells is essential for inducing stroma/ECM production, pancreatic cancer progression and general therapy resistance. Compared to traditional 2D cell culture, cells in a three-dimensional context demonstrate different behavior and functions as reflected by building up a microenvironment that more closely mimics the one observed in the native tissue. This feature is especially critical for testing drug efficiency as cellular response to drugs is profoundly affected by environmental cues. AIMS & METHODS: Our aim was to build up a more reliable and predictive drug screening system. To this end we set up and compared 2D and 3D cell cultures containing either human PSC and PDAC cells alone or in combination. RESULTS: Among PDAC cells, panc-1 cells are the most commonly used which are also able to form spheres in vitro. We generated mono-spheres from panc-1 cells and compared them to conventional 2D culture. The efficiency of different drugs on viability of cells in panc-1 sphere resulted to be much lower than on viability in 2D cultures. Cells in 3D compared to the 2D culture show higher gene expression for ECM proteins as collagen and fibronectin, for growth factors as PDGF and VEGF, as well as for protein like Cox2, Glut1. We co-cultured panc-1 and PSCs, allowing them to interact and form hetero-spheres in which PSCs localized in the cortical area and were identified e.g. by expression of asma, a marker for PSCs activation. These avascular mini-tumors were further characterized at different levels. CONCLUSION: 3D cultures are more resistant to chemotherapy compared to their 2D counterpart offering a more predictive platform for drug screening before proceeding to more expensive in vivo models and clinical trials. The avascular mini-tumors can be considered as an alternative in vitro cell model for studying pancreatic cancer development and fibrosis from a more complete perspective. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4244. doi:1538-7445.AM2012-4244