Abstract 1153: Stromal FoxM1 and p53 in lung cancer as mediators of tumor progression, metastatic spread and chemo-resistance

Abstract

Abstract Introduction: Insight into the processes of tumor initiation and progression as well as metastatic spread and response to therapies requires studies that take into consideration the stromal and epithelial components of tumors. Both FoxM1 and p53 have a major role in the progression, metastasis and chemo-resistance of non-small cell lung cancer (NSCLC). p53 is a well-recognized tumor-suppressor gene, commonly mutated in NSCLC and correlated with tumor aggressiveness. An anti-tumor role of p53 in the stroma has been demonstrated by us and others. p53 is reported to suppress FoxM1 transcription. FoxM1 is an oncogene, contributing to lung cancer progression and metastatic spread. Little is known about the role of FoxM1 in cancer's micro-environment. We hypothesized that tumor-induced-downregulation of p53 and upregulation of FoxM1 in the stromal compartments promotes lung cancer progression, metastatic spread and chemo-resistance. Materials and Methods: Cancer associated fibroblasts (CAFs) and normal fibroblasts (NFs) were produced from fresh lung tumor specimens. Cell lines and primary cells were grown in standard tissue culture conditions. Co-cultures were performed using transwell culture systems. DNA damage was induced by cisplatin treatment. Expression levels of mRNA and proteins were tested by real-time RT-PCR and western blots. Results: We have found FoxM1 levels to be higher in primary lung CAFs compared to NFs. In addition, CAFs that were treated with conditioned media of transformed epithelial cells showed down-regulation of stromal-p53 and up-regulation of FoxM1, in DNA damage conditions. mRNA levels of FoxM1 remain stable. While cancer-cells-CM up-regulate FoxM1 in CAFs, it was found to down-regulates it in NFs, suggesting both cancer and CAFs have evolved a unique mechanism of FoxM1 induction in stroma. In order to examine a possible paracrine effect between p53 levels in the stroma, and FoxM1 levels in tumor cells, we co-cultivated fibroblasts knocked-down for p53 with lung cancer cells and found up-regulation of FoxM1 the tumor cells. Summary: We demonstrate up-regulation of stromal FoxM1 by cancer-secreted-factors as well as by stable CAFs modifications, concomitantly to stromal p53 down-regulation. High stromal FoxM1 may promote tumor cells aggressiveness, similarly to low stromal p53, possibly being downstream to p53. Elaboration of these pathways will deepen our understanding of lung cancer and suggest novel therapeutic targets. Citation Format: Iris Kamer, Inbal Daniel, Gili Perry, Amir Onn, Jair Bar. Stromal FoxM1 and p53 in lung cancer as mediators of tumor progression, metastatic spread and chemo-resistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1153. doi:10.1158/1538-7445.AM2014-1153