oa Identification of molecular pathways implicated in the metastasis process in a mouse model of lung adenocarcinoma

A global survey of cancer has shown that lung cancer is the most common cause of the new cancer cases and cancer deaths in both men and women worldiwide. In Qatar a recent retrospective study based on a cohort of patient registry of Al Amal Cancer Hospital from 1991-2006, showed that lung cancer and lumph node cancer are the major cancers in men (5.9%, incident rate per 100,000) while in women breast cancer had the highest incidence. To study the mechanisms of lung cancer development we recently developed a transgenic mouse model overexpressing CRT under the control of Tie2-promotor. The main phenotype of these mice is the development of metastatic lung adenocarcinoma similar to human patients. The objectives of the current study was to identify the molecular pathways involved in the metastatic behavior of lung adenocarcinoma. To examine our objectives we used anchorage independent and adherent culture of lung adenocarcinoma cells isolated from mouse and human cell lines. Using microarray and bioinformatic analysis we have identified several pathways and genes that are altered in mouse cells. The microarray analysis demonstrates that 90 genes are up-regulated and 66 genes are down regulated under anchorage-independent condition compared to adherent conditions. The bioinformatic analyses demonstrate that the up-regulated genes are implicated in cellular development, cellular growth and proliferation pathways. These pathways include: VEGF signaling, bladder cancer signaling, VEGF family ligand-receptor interaction and Ephrin-receptor signaling. The bioinformatic analyses also demonstrate that the downregulated genes were implicated in cell cycle regulation and cell-to-cell signaling and interaction. The analysis of these genes by canonical pathawy demonstrate that these genes are involved in the regulation of very relevant pathaway implicated in cancer essentially : Hematopoeisis from multipotent stem cells, TGF-β signaling and tight junction signaling. We are currently examining these pathways in human adenocarcinoma cell line. In conclusion, our data illustrate that although calreticulin is an endoplasmic reticulum calcium binding chaperone, it is involved in the process of tumor development and metastasis. Further work is needed to decipher the molecular mechanism of involvement of calreticulin in tumor development. This research was funded by QNRF grants UREP09-084-3-016 and NPRP4-043-3-016.