Advancing the Understanding of Lymphatic Metastasis in Colorectal and Gastric Cancers
Abstract
This project is focused on the topic areas of gastric and colorectal cancers and is designed to address the focus area of gaps in prognosis or treatment. Patients with metastatic cancer have few options for therapy, and most of those options have limited efficacy. While the recent development of immunotherapy approaches, such as checkpoint inhibitors, has profoundly changed the outlook for some patients with different cancers, widespread benefit in gastric or colorectal cancers has not yet been seen. Understanding more about the biology of metastatic disease, including how the immune system interacts with tumor cells in lymph nodes, is likely to enable more effective use of these types of exciting therapeutic approaches. In the clinic, disease aggressiveness is defined by several factors including the size of the primary tumor, the number of lymph nodes showing evidence of tumor, and whether the tumor has spread to other organs. Exactly how lymph node metastasis affects further progression to secondary organ metastasis is not well understood. Moreover, despite lymph nodes being immune organs where anti-tumor immune cells can be “educated,” the impact on anti-tumor immunity of tumor cells in the lymphatics or lymph nodes has been little explored. One reason is that most mouse models of metastatic disease concentrate on the blood-borne or hematogenous route of cancer spread and ignore lymphatic spread. In this proposal, our aim is to develop a robust model of lymphatic metastasis and use it to profile effects of having tumor cells present in lymph nodes on immune signals. We will also test if the presence of tumor cells in the lymphatics increases the likelihood that metastases in distant organs such as lung or liver will establish and grow. Finally, we will test if being in the lymphatics allows tumor cells to survive despite treatment with current standard-of-care chemotherapy. Of course, this is an early-stage investigation in mice; however, we believe that it could lead to a new way of thinking about treating human patients with metastatic gastric and colon cancer by paying attention to the signals from the lymph. We also envision that this model would be especially useful for testing new therapeutic approaches going forward. Drugs that work on primary cancers may not be so effective on cancers that have spread to the lymphatics, but currently this may not be known because of the lack of relevant models. Since both gastric and colorectal cancer have poor survival rates when they have progressed to metastatic disease, developing models to understand would might work to treat later disease would be valuable military personnel deployed overseas have a risk of developing gastric cancer due to H. pylori infection, while colorectal cancer is the fourth most common cancer in the U.S. Thus, improving care of these diseases could have a significant impact on the long-term health of Service members, Veterans, and beneficiaries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810234
Entities
People
- Barbara Mary Fingleton
Organizations
- United States Army
- Vanderbilt University