Abstract A22: The effects of Lipocalin-2 in the early stages of colorectal cancer metastasis

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. When diagnosed at an early, localized stage, the five year survival rate is approximately 90%; however, when patients are diagnosed at the metastatic stage, this drops to 12%. Metastasis, the spread of cancer cells from the primary tumor to a distant organ, is the primary cause of death in cancer patients. In CRC, metastasis is typically found in the liver, asymptomatic, and often detected at the final stage when therapeutic options are few. The genetic and cellular mechanisms driving the early stages of metastasis are still poorly understood. Recent studies have shown that prior to the arrival of cancer cells at the secondary organ, molecular signals from the tumor direct the recruitment of bone marrow derived cells to create a pre-metastatic niche where cancer cells can attach and develop into a metastatic lesion. Identifying and understanding these molecules can lead to the development of methods for early diagnosis or targets for intervention. Using an orthotopic model of CRC liver metastasis, we performed microarray analyses of the liver microenvironment in tumor bearing mice before and after the arrival of metastatic cells. We found that Lipocalin-2 (LCN2, 24p3, NGAL) was highly expressed in the liver and in circulation of mice bearing highly metastatic cells. LCN2 is a 25 kD secreted glycoprotein that binds small lipophilic molecules. Its expression is upregulated in a number of primary tumors of epithelial origin, but its role in metastasis remains unclear. It has contrasting roles in metastasis in breast cancer models and has been associated with poor prognosis in CRC patients; however its role in the tumor microenvironment has not been studied. Our studies thus far show that overexpression of Lcn2 in mouse colon cancer cells either had little impact on tumor growth and invasiveness, or it enhanced invasion in the presence of macrophages; however, it resulted in an overall reduction of circulating iron levels in sera from tumor bearing mice. In-vitro, iron also seems to have an effect in conjunction with Lcn2 on the invasiveness of the tumor cells. The results from this study will allow us to better describe the role of LCN2 in tumor and stromal cells in the early stages of liver metastasis. Citation Format: Daniel Hughes, Celestia Davis, Yu Zhang, John Bonaparte, Maria Pena. The effects of Lipocalin-2 in the early stages of colorectal cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A22.