A three-dimensional “organoid” model derived from human tissue grown in the lab is designed to study how early stages of cancer develop at the gastroesophageal junction (GEJ)—the point where the digestive system’s esophagus meets the stomach.
Gastroesophageal Cancer: Facts and Figures
According to the American Cancer Society, esophageal cancer kills more than one million people worldwide each year, with GEJ cancer rates more than doubling in recent decades, from 500,000 to 1 million new cases annually. Acid reflux, smoking, and Helicobacter pylori bacterial infection of the stomach are well-established risk factors for esophageal and gastric tumors. But experts say it has been difficult to show how cancer starts at the gastroesophageal junction because there are no biologically relevant GEJ-specific early disease models for research.
Stomach organs
“Because we don’t have a unique pattern that differentiates GEJ tumors, esophageal cancers are often classified as either esophageal cancer or stomach cancer — not GEJ cancer,” says gastroenterologist Stephen Meltzer, MD, Harry and Betty Myerberg/Thomas R. Hendrix. and the American Cancer Society Clinical Research Professor of Medicine at the Johns Hopkins University School of Medicine and corresponding author of the study. “Our model not only helps identify important changes that occur at the GEJ during tumor growth, but also provides a strategy for future studies that will help us understand tumors in other organs.”
“The study reveals a possible biological target for the treatment of gastrojejunal junction (GEJ) cancers with a drug that researchers have already shown can slow or stop the growth of such tumors in mice.”
Meltzer and a team of experts in cell biology, epigenomics, lipid profiling and big data analysis created a GEJ disease model by taking normal human biopsy tissue from patients undergoing upper endoscopy. Organoids are three-dimensional collections of cells derived from stem cells that can replicate the characteristics of an organ or reproduce what an organ does, such as making specific types of cells.
The researchers then knocked out two key tumor suppressor genes (TP53 and CDKN2A) in the organelles, using a gene editing technology called clustered regularly spaced palindromic repeats (CRISPR/Cas9). Double knockout of these genes caused the cells to grow faster and become cancerous with microscopic features closer to malignancy. These modified organelles also formed tumors in immunodeficient mice.
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The team then discovered abnormalities in a class of molecules (lipids) that store energy but also perform several other functions, and identified platelet-activating factor as a key regulated lipid in GEJ organelles. Platelets circulate in the bloodstream and when they recognize damaged blood vessels, they stick together or clot and can cause clotting disorders in some people. The researchers used WEB2086, which stopped the growth of implanted GEJ organelle tumors. WEB2086, a Food and Drug Administration-approved compound used to treat platelet disorders, inhibits platelet-activating factor receptors in the enamel.
Meltzer said more preclinical studies may be needed before using the compound for human patients, but the organelles could help advance such studies.
Source: Eurekalert
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