Date of Award

2017

Document Type

Open Access Dissertation

Department

Biological Sciences

Sub-Department

College of Arts and Sciences

First Advisor

Maria Marjorette O. Peña

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. The major cause of death is metastasis and the frequent target organ is the liver. When diagnosed early at a localized stage, the five year survival rate after resection is 90%. However, after metastasis has occurred, this drops to less than 12%. Metastasis is often asymptomatic and diagnosed at the final stage when therapeutic options are limited. Because of this, the genetic and cellular mechanisms regulating 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 (BMDCs) to create a pre-metastatic niche where cancer cells can attach and develop into a metastatic lesion. Identifying and understanding these signals can lead to the development of methods for early diagnosis or identifying targets for intervention.

Using an orthotopic mouse 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 in the liver. We found that Lipocalin-2 (Lcn2) was highly expressed in the liver and sera of mice bearing highly metastatic cells. Its expression is upregulated in tumors of epithelial origin, but has contrasting roles in metastasis. In the clinic, elevated LCN2 is associated with poor prognosis. The role of LCN2 in the tumor microenvironment has not thoroughly been studied. Our studies show overexpression of Lcn2 in mouse colon cancer cells had little impact on tumor growth or invasiveness; however, invasion assays show that Lcn2 from some stromal cells increases the invasiveness of colon tumor cells. These studies will allow us to better elucidate the role of Lcn2 in tumor and stromal cells in the early stages of CRC metastasis and in anticancer therapy.

Rights

© 2017, Daniel Titus Hughes

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