Abstract 2869: p53 response of cancer associated fibroblasts (CAFs) to cisplatin is closely correlated with the p53 response of tumor cells in lung cancer tissue cultures

Abstract

Abstract One of the major molecular players in cellular stress responses is the p53 tumor suppressor protein. The vast majority of the research of p53 activities upon DNA damage has focused on its cell autonomous functions, i.e. its ability to induce cell cycle arrest, DNA repair, apoptosis, autophagy, or senescence in a homogenous cell population. However, data on the impact of tumor cells on p53 activation in their neighboring cancer associated fibroblasts (CAFs) and also vice versa are still limited. We investigated p53 status and responses to the p53-activating drug cisplatin both in tumor cells and in their adjacent CAFs in intact tumor tissues derived from 28 individual lung cancer patients. For this, 200µm thick patient derived tissue slices were cultivated ex vivo in presence or absence of cisplatin for 72 hours. By comparing cultivated control slices with the corresponding tumor tissue material immediately fixed after surgery (pathological routine material) we could show that morphology and p53 staining pattern were highly preserved during cultivation. TP53 mutations were detected in 16 of the 28 cases (57.1%). Independent of their p53 mutation status, the tumor samples could be divided into 3 categories according to their p53 immunostaining characteristics in the tumor cell compartment: (I) tumor cells with constitutively low p53 protein which was accumulated upon cisplatin (12 cases, 7 with mutated p53); (II) tumor cells with constitutively high p53 and no further accumulation upon cisplatin (8 cases, 7 with mutated p53); (III) tumor cells with constitutively no detectable p53 and no accumulation upon cisplatin (8 cases, 2 with mutated p53). Importantly, regardless of the p53 mutation status of the tumor cell compartment we detected a CAF specific p53 accumulation and induction of the p53 target p21 selectively in category I tumors (i.e. tumor tissue samples characterized by p53 accumulation in the tumor cell compartment). In sharp contrast, tumor tissues with no detectable p53 accumulation in tumor cells (categories II and III) showed no p53 accumulation or p21 induction in their adjacent fibroblast compartment. Furthermore, a CAF specific induction of TUNEL positive cells in cisplatin treated samples (7 of 28 cases) was selectively observed in tumor tissues characterized by a parallel induction of tumor cell death. These data for the first time show a close correlation of p53 response in tumor cells and adjacent fibroblasts in intact lung tumor tissues from patient derived material indicating that tumor cells control molecular and functional responses of their neighborhood fibroblasts upon DNA damage. 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 2869. doi:1538-7445.AM2012-2869