Researchers Find How Key Cancer Switch May Hide from Therapy
Madison, Wisconsin - Medical researchers in the University of Wisconsin School of Medicine and Public Health (UWSMPH) have discovered a previously unknown mechanism within human cells that may explain how many cancers develop a resistance to common cancer therapies.
Published online April 18 and in the April 29 edition of Developmental Cell, the research paper authored by several UW School of Medicine and Public Health scientists examines the relationships between epidermal growth factor, its receptors and the biological process for regulating cellular growth.
Cells rely on numerous receptor mechanisms, like signaling switches, outside of the cell wall to communicate with their surroundings and respond to their environment in very specific ways.
One intensively studied communication method is the epidermal growth factor receptor (EGFR), which is a major contributor in breast, colon, lung, head and neck, pancreatic, brain, and many other cancers.
Under normal conditions, the EGFR switch is turned on by molecules outside the cell and begins signaling to the cell to grow and multiply. But once that receptor is activated, the cell encapsulates it in an internal structure called an endosome.
While in the endosome, the receptor - still active and signaling to the cell - is transported to another cellular structure, the lysosome, where it stops the receptor from communicating and ultimately recycles the endosome and its receptor. This process is highly regulated to prevent abnormal growth like cancer.
A common therapeutic approach for many cancers is treatment with antibodies that seek out tumors with high levels of these receptors. The antibodies attach themselves to the receptors and stop them from signaling.
But, when the endosome isn’t transported correctly, the receptor continues to signal within the cell. This is important because once receptors are taken inside the cell, antibody therapies cannot reach them and become ineffective, allowing the unchecked growth to continue.
“What we’ve discovered is a mechanism for how the EGF receptor is sorted from the endosome to the lysosome within cells,” said Dr. Richard Anderson, professor of molecular and cellular pharmacology at the UW School of Medicine and Public Health. According to the paper, an enzyme on endosomes, which synthesizes the messenger known as phosphatidylinositol-4,5-bisphosphate (PtdIns4,5P2), is necessary for ultimately deactivating the EGFR.
Without the enzyme, the endosomal EGFR becomes lost within the cell and continues to signal. “What is very significant is that this pathway involves a key signaling enzyme and protein partners that are known to be disrupted in cancers,” said Anderson.
“In the research literature, it’s been dogma in the field that endosome to lysosome transport is regulated by phosphatidylinositol-3 phosphate. What we discovered is that EGFR sorting to the lysosome actually requires a signaling enzyme that generates the messenger PtdIns4,5P2 as well,” said Anderson.
“There are roughly more than 100 different growth factors in our bodies. One of the real questions that keeps popping up is, are these receptors down regulated in the same way? The answer is they’re not. The pathway that we have discovered is selective for the EGFR and a subset of receptors. What this indicates is that there are different pathways selective for other receptors,” said Anderson.
“That’s important in understanding how to therapeutically treat cancers that are driven specifically by EGFR versus another growth factor receptor. That’s the key to defining effective therapies.”
When radiation is used to treat cancer, the EGFR is stimulated, so therapy has developed into duel treatments with radiation and antibodies, which can be very effective if there is limited resistance.
Drs. Yue Sun, Andrew C. Hedman, and Nicholas J. Schill, with graduate student Xiaojun Tan, compose the scientific team in Dr. Anderson’s laboratory. The National Cancer Institute of the National Institutes of Health, the American Heart Association and the Howard Hughes Medical Institute supported this research.
“We’ve discovered multiple other components that modulate this pathway of EGFR down regulation, and it’s interesting that each of these new components have clear roles in cancer progression and in turning on or shutting off the EGF signal. It looks more and more like this could be a major therapeutic target,” said Anderson.
Date Published: 05/07/2013