Role Of Calreticulin In The Spontaneous Development Of Lung Adenocarcinoma: Evidence From A Novel Transgenic Mouse Model

Lung cancer is the most common cause of cancer related deaths in both men and women worldiwide. The overall 5 year survival rate of lung cancer ranges between 5-15% (depending on the subtype). Based on histopathological criteria, lung cancer is subdivided into two main subtypes: small cell lung cancer (15%) and non-small cell lung cancer (NSCLC 85%). Adenocarcinoma a subtype of NSCLC is the most common type in both sexes, and it has a poor response to chemotherapy. We recently developed a transgenic mouse model of lung adenocarcinoma by overexpressing calreticulin (CRT) under the control of Tie2-promotor. The main phenotype of these mice is high incidence of metastatic lung adenocarcinoma similar to human patients. Immunohistological analysis showed these tumors to be SP-C+ve and CC10-ve phenotype. At the initial stages most of cells in the hyperplegic area and adenoma stained positive for exogenous CRT and HSCs markers, and as the tumor differentiated to carcinoma there were a significant loss of exogenous CRT and HSCs markers and increased expression of SP-C. The aim of our current project was therefore to identify the mechanism of development of metastatic lung adenocarcinoma in this mouse model. To address this objective we carried out microarray and quantitative proteomic analysis of tissue and cell lines isolated from lungs of this transgenic mouse model. Microarray analysis showed activation of cluster of genes involved in cellular development, growth and proliferation. Some of these pathways include genes invlved in VEGF signal transduction pathways and Epherin receptor signaling, at the same time there were decreased expression of cell-cell interaction and communication (needed for metastasis). At the protein level we observed a significant increase in proteins involved in tumor progression, invasion and metastasis. In addition we observed a significant change in the expression of genes invloved in lipid metabolism (both at protein and RNA level) in the lung of these mice. The change in the expression of lipid metabolizing genes suggest the metabolic shift needed during tumor progression. In conclusion, our data suggests that CRT as an endoplasmic reticulum chaperone and a regulator of intracellular calcium homeostasis affects multiple genes invivo resulting in the development of tumor. This research was funded by Qatar National Research Fund (NPRP4-043-3-016). Citation Format: Nasrin Mesaeli, Hamid Massaeli, Divya Viswanathan, Dhanya Pillai, Mercy Anna Thomas. Role of calreticulin in the spontaneous development of lung adenocarcinoma: Evidence from a novel transgenic mouse model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4166.