Activation of Cholecystokinin-B Receptor-Positive Stem Cells Induces Hepatic Carcinogenesis
Abstract
Military Health Focus Area: Gaps in cancer prevention, early detection/diagnosis, prognosis, and/or treatment that may impact mission readiness and the health and well-being of military members, Veterans, their beneficiaries, and the general public Liver cancer – also called hepatocellular carcinoma (HCC) – is the second leading cause of cancer-related death worldwide. The most common risk factors for liver cancer include chronic virus infections like hepatitis B and hepatitis C, alcohol abuse, and most recently fatty liver disease. The best protection from HCC is vaccination for hepatitis B, but there is no vaccination available for hepatitis C. The prevalence of hepatitis C in Veterans born in the 1945-1965 birth cohort (most of the Vietnam Veterans) is almost three times higher than that of the general U.S. population. New treatments for hepatitis C in the past decade have helped with lowering the incidence of this infection; however, many still have residual scarring or cirrhosis from having had the disease. Ninety percent of liver cancers develop in injured and scarred livers – or in those with cirrhosis. When the liver is injured by viruses, alcohol, or fat, some of the liver cells die. Fortunately, the liver is amazing, in that it has the capacity to regenerate. There are two possible sources of the new regenerated cells that develop during liver injury: (1) stem cells – a population of cells that are quiescent in the adult liver but were responsible for liver cells’ specialization and growth during the fetus development; and (2) liver cells or hepatocytes are thought to perhaps divide and allow for regrowth. If the insult to the liver tissue is of short duration, usually the liver recovers without sequela, but with chronic inflammation from ongoing hepatitis or fat or alcohol, sometimes the regenerative processes of the liver becomes overwhelmed and does not “shut off,” leading to the development of cancer. In a pre-clinical study, we found that when we fed mice a diet containing chemicals that injured the liver, the liver cells expressed a surface protein (or receptor) call the CCK-B receptor. If the injury continued over time, the mice developed HCC, but in mice that were treated with a medication called proglumide that blocks the activity of the CCK-B receptor, no cancer occurred. Since this receptor protein is not found in the normal liver but appears with injury, we propose it may be a marker for liver stem cells. Since the liver stem cells that grow out of control are thought to lead to cancer and become cancer stem cells, we studied human liver cancer tissues and found the CCK-B receptor was highly increased. In this Idea Award proposal, we will use two different diets that induce liver injury in mice, then examine the livers over time for the cells that express the CCK-B receptors. In each liver injury experiment, we will have control mice on standard chow and another group of mice on the liver injury diet that will be treated with proglumide. In addition to helping us understand if this receptor is truly implemented in stem cells and liver cancer, we will breed mice that genetically are deficient of this receptor. There are several methods we will use in this proposal to determine if the CCK-BR is a stem cell marker. One is by using special known antibodies that bind to another marker on stem cells called CD133. Using the CD133 antibody we can identify stem cells from our mouse livers and then analyze those isolated stem cells to see if they also have the CCK-B receptor. The isolated stem cells from the mouse livers can be grown in tissue culture plates in special medium so that they form 3-dimensional mini-liver organs, called organoids. We can treat these organoids with the proteins that activate the CCK-B receptor (gastrin or CCK) and measure activation and growth. Also we will treat the organoids with proglumide to see if it dampens the activity of the stem cells. In the third aim of this i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110605
Entities
People
- Jill P Smith
Organizations
- Georgetown University
- United States Army