Date of Award

12-14-2015

Document Type

Open Access Thesis

Department

Biological Sciences

First Advisor

Maria Marjorette O. Pena

Abstract

In the United States, colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer deaths. In 2015, approximately 143,000 new cases will be diagnosed and 50,000 deaths are predicted. Liver metastasis is the major cause of death. To understand the molecular and cellular mechanisms of liver metastasis, we used an orthotopic mouse model of CRC liver metastasis that recapitulated all stages of tumor growth and metastasis to perform whole genome microarray analysis to identify genetic changes in the liver microenvironment in response to primary tumor growth in the cecum. We identified lipocalin 2 (Lcn2) as the most highly expressed gene in pre-metastatic liver. LCN2 is a 25 kD secreted glycoprotein that plays a key role in the innate immune response. LCN2 has been associated with various types of cancers including thyroid, cervical, breast, and renal. However, its role in the tumor microenvironment has not been fully elucidated and there is conflicting data on its role in tumor growth and liver metastasis of CRC. To determine the effect of elevated serum levels of LCN2 on liver metastasis of CRC, Lcn2 was cloned into the pV1J plasmid and electroporated in vivo into syngeneic mice while control mice were electroporated with pV1J empty vector. MC38 CRC cells were then injected into the spleen of electroporated mice and the extent of liver metastases was determined after three weeks. The results showed that mice injected with Lcn2 expressing plasmid had elevated serum levels of LCN2 and showed a significantly higher rate of liver metastasis as compared to mice electroporated with empty vector. The results suggest that elevated LCN2 expression in the microenvironment is sufficient to enhance liver metastasis of CRC, underscoring its potential as a therapeutic target.

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