Defining the Protective Role of the Innate Immune Molecule, NLRC5, in Stomach B-Cell Lymphomagenesis
Abstract
This research proposal addresses the Fiscal Year 2016 Peer Reviewed Cancer Research Program Topic Areas of “stomach cancer” and “lymphoma” and the Military Relevance Focus Areas of “critical health issues or gaps in biomedical knowledge that may affect the health and well-being of the military.” The project relates to a militarily relevant risk factor associated with cancer, i.e., infection by the bacterium, Helicobacter pylori. Half of the world’s population is infected with the bacterium H. pylori. This microorganism lives in the stomach where it causes inflammation. Most infected individuals have the bacterium throughout their lives, but without any symptoms. However, in approximately 1%-2% of cases, long-term infection causes stomach cancer. One type of stomach cancer, known as MALT lymphoma, is associated with the multiplication of large numbers of white blood cells within the lining of the stomach wall. It is known that H. pylori infection is the major cause of stomach MALT lymphoma and that if the disease is detected early enough, antibiotic treatment against the infection can result in regression of these tumors. Nevertheless, our understanding of the processes leading to formation of this type of tumor is still very poor. Using a novel animal model of stomach MALT lymphoma, we have identified a new host protein that we believe plays a role in formation of these types of cancers in H. pylori-infected subjects. This protein, called NLRC5, normally plays a role in defending the host against infection, but seems to be important in preventing excessive multiplication of white blood cells in the stomach in response to chronic H. pylori infection. We showed that mice lacking this protein in a specific family of white blood cells, known as myeloid cells, are more prone to develop an early form of stomach MALT lymphoma due to Helicobacter infection. We hypothesize that myeloid-specific NLRC5 plays a protective role against the formation of stomach MALT lymphoma. The overall objective of this study is to define the role of NLRC5 as a regulator of the white blood cells that lead to the formation of this tumor. H. pylori infection is very common among US military Veterans, in particular, those who are Asian, African-American, or Hispanic. It has been reported that these Veterans are also most likely to suffer from gastric cancer and to be hospitalized due to the complications arising from this cancer. Furthermore, there is evidence that H. pylori transmission is facilitated by certain environments, such as those encountered by military personnel. Therefore, it is likely that at some point Veterans and their families will come into contact with the infection and that a proportion will go on to develop severe disease later in life. Although antibiotic therapies are available to eliminate H. pylori infection, the rise in antibiotic resistance among H. pylori isolates means that many of these treatments are becoming less effective. Therefore, new approaches are needed to better manage the infection and particularly the diseases associated with it. The proposed research is basic in nature but is expected to lead, in the first instance, to the identification of NLRC5 as a prognostic marker for stomach MALT lymphoma. We will identify the molecular and cellular processes by which NLRC5 plays a protective role against this malignancy. It is possible that the findings of this research will also be relevant to other forms of lymphoma for which treatment options are limited. One potential clinical application of this work is the development of improved methods for identifying those H. pylori-infected individuals that are most likely to develop stomach MALT lymphoma. Early detection is important as diagnosis of stomach MALT lymphoma requires invasive techniques and this cancer is generally detected once the disease has progressed to a point at which it can no longer be treated easily. By detecting the diseas
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710606
Entities
People
- Richard L. Ferrero
Organizations
- Monash University
- United States Army