- Colon cancer screening looks for the presence of polyps, some of which can become cancerous.
- One type, serrated adenoma, is considered pre-cancerous, can come back after it is removed and can lead to particularly invasive colon cancers.
- Researchers have discovered a mechanism that drives these cancers, which involves dysregulation of cholesterol metabolism, in a preclinical trial.
- This means there is the possibility this cholesterol dysregulation could be targeted by statins, and trials are planned to investigate this further.
Colon cancer is the
Screening for colon cancer is done either through a fecal immunochemical test, which looks for blood in the stool that can come from polyps, or through a colonoscopy, to visualize the polyps.
There are
- hyperplastic polyps that are typically benign
- adenomatous polyps (adenomas), which may turn into cancer.
Treatment generally involves removal of these polyps.
One particular type of polyp, known as a serrated adenoma, is considered precancerous, and needs to be removed completely.
This poses a challenge as the polyps are flat, rather than growing on stalks like other polyps, and are harder to visualize due to this and the part of the colon they appear in.
Cancers from this type of polyp make up
So far, it has been unclear exactly why this particular type of polyp was more likely to result in cancer than other types of polyps, but now, a metabolic mechanism has been proposed by a group of scientists from Weill Cornell Medicine, NY.
The results of their study appeared in in Nature Communications on December 13, 2023.
Previous research by some members of the team had shown that serrated adenoma polyps had lower levels of a protein kinase C (PKC) enzyme, which is responsible for regulating a number of genes involved in cell proliferation, among other cell metabolic pathways. The cells also evaded the body’s immune system, allowing the cancerous tumor to grow.’
In their latest study, the researchers used a previously developed mouse model that developed these serrated lesions in the colon.
The researchers started by analyzing the genes transcribed in these tumor cells, and found that cholesterol synthesis remained high in these cells, despite the high level of cholesterol present in them. This suggested cholesterol synthesis had become dysregulated in these tumor cells.
Further analysis of mouse tumor cells showed that loss of the protein kinases led to an activation of a transcription factor called SREBP2, which switches on cholesterol production.
Cholesterol is a driver of many metabolic processes, and the study authors showed that cholesterol drove cancer in these cells, initiating the growth of tumors.
Lead author Prof. Jorge Moscat, professor of pathology and laboratory medicine at Weill Cornell Medical College, explained to Medical News Today:
“It gets activated normally when cholesterol is low, that happens in all cells in the body, cholesterol is low SREBP2 is activated, right, and then when cholesterol is high, SREBP2 is reduced. In the case of this tumor cell, the pathway is totally screwed up in a way that our cells know how to turn it on, but not to turn it off. So SREBP2 is constantly being activated, cholesterol is constantly made, and cholesterol is constantly being imported.“
“So that that gives this particular type of cancer cells a competitive advantage,” he added.
Researchers then looked at how applicable these results were in human cells using existing cell atlases. They used these to examine the gene activity in serrated adenomas in humans and found only serrated-type tumors, rather than other types of colorectal tumor, had low levels of PKC enzymes, and accumulation of the transcription factor SREBP2.
Dr. Misagh Karimi, a medical oncologist specializing in gastrointestinal cancers at City of Hope Orange County Lennar Foundation Cancer Center, Irvine, CA, who was not involved in the research, told MNT that “[t]he connection between cholesterol and cancer is an evolving area of research, in which previous studies have indicated that high cholesterol can trigger malignant cell activity and slow down the immune response to cancer cells.“
“Studies have also shown that alterations in blood cholesterol level are common in many cancers, but researchers are still determining if these alterations cause the cancer or are the result of the cancer,” he noted.
The scientists who conducted the research also created organoids from cancer patients’ tumors, to examine the levels of these metabolites. These were used to test the effectiveness of a commonly prescribed statin, atorvastatin, at inhibiting growth of cells with low levels of PKC.
Statins are one of the most commonly prescribed drugs in the United States, and many other countries and have been shown to reduce the risk of major cardiac events by reducing the amount of cholesterol in the blood.
Prof. Moscat and co-lead author Prof. Maria T. Diaz-Meco, professor of oncology in pathology at Weill Cornell Medical College, told MNT they were planning on developing a clinical trial to determine if statins could lower the risk of cancer in patients with serrated adenoma.
Designing a trial to examine whether statins could help people who have polyps removed would be a long-term investigation, as it takes around 5 years for the polyps to come back, if they do at all.
“I think this will be a beautiful chemo prevention protocol or strategy. Just using a statin. It’s such a simple thing. Like we’re looking for very sophisticated molecules and then we have something very easy,” said Prof. Moscat.
Dr. Kamiri said evidence was growing that statins could help reduce the risk of several types of cancer. He said: “A 2020 study found evidence that statins may “starve” cancer cells to death.
In 2019, researchers in China found a link between taking a statin before diagnosis and
“Currently, statins are not generally prescribed to reduce cancer risk,“ Dr. Kamiri cautioned. “There are millions of patients in the U.S. on statins for their high cholesterol, and the cancer-protective benefits they may gain from taking them have not been fully proven. The best way to prevent colorectal cancer is to make healthy lifestyle choices and understand your individual genetic risk of the disease.”
