Hard-to-detect colorectal pre-cancerous lesions known as serrated polyps, and the aggressive tumors that develop from them, depend heavily on the ramped-up production of cholesterol, according to a preclinical study from researchers at Weill Cornell Medicine. The finding points to the possibility of using cholesterol-lowering drugs to prevent or treat such tumors.
In the study, published in Nature Communications, the researchers analyzed mice that develop serrated polyps and tumors, detailing the chain of molecular events in these tissues that leads to increased cholesterol production.
They confirmed their findings in analyses of human serrated polyps and tumors, and showed in mouse models that replicate the human cancer that blocking cholesterol production prevented the progression of these types of intestinal tumors.
Cholesterol is generally considered a pro-growth molecule, being a building block for cell membranes and having other growth-supporting functions. Prior studies have linked high blood cholesterol levels to various cancers, including colorectal cancers.
However, it hasn’t been clear that lowering cholesterol, for example with common statin drugs, can prevent colorectal cancers.
Serrated polyps are so-called because of their sawtooth appearance under a microscope. They are flatter than ordinary colorectal polyps and can often be missed during colonoscopies.
Yet the tumors into which they develop, which account for roughly 15 to 30 percent of colorectal cancers, contain many “metaplastic” cells that are particularly invasive and resistant to treatments.
Several years ago, the Moscat/Diaz-Meco team linked serrated polyps and tumors to low levels of two enzymes known as aPKCs.
In the new study, the scientists found that in serrated-type tumors in these mice, and even in intestinal tissue poised to develop these types of cancerous lesions, cholesterol synthesis was strikingly upregulated, suggesting that cholesterol may be an early driver of tumor development.
The researchers revealed how the absence of aPKC enzymes, especially in metaplastic tumor cells, unleashes the activation of a transcription factor called SREBP2, which switches on cholesterol production.
Lastly, the researchers tested a combination of two cholesterol synthesis-blocking drugs, including the widely used atorvastatin.
The treatment, delivered when the low-aPKC mice were still quite young, significantly lowered the rate at which both serrated polyps and tumors later formed — and the serrated-type tumors that did form were less aggressive than those normally arising in the untreated mice.
The results indicate that targeting cholesterol could be a viable strategy for treating and preventing serrated-type colorectal tumors.
The Moscat and Diaz-Meco labs are now hoping to set up an initial clinical trial of a cholesterol-lowering intervention in patients from whom serrated colorectal polyps have been removed.
Yu Muta, Juan F. Linares, Anxo Martinez-Ordoñez, Angeles Duran, Tania Cid-Diaz, Hiroto Kinoshita, Xiao Zhang, Qixiu Han, Yuki Nakanishi, Naoko Nakanishi, Thekla Cordes, Gurpreet K. Arora, Marc Ruiz-Martinez, Miguel Reina-Campos, Hiroaki Kasashima, Masakazu Yashiro, Kiyoshi Maeda, Ana Albaladejo-Gonzalez, Daniel Torres-Moreno, José García-Solano, Pablo Conesa-Zamora, Giorgio Inghirami, Christian M. Metallo, Timothy F. Osborne, Maria T. Diaz-Meco, Jorge Moscat. Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis. Nature Communications, 2023; 14 (1) DOI: 10.1038/s41467-023-43690-5
Weill Cornell Medicine. (2023, December 13). Cholesterol-lowering therapy may hinder aggressive type of colorectal tumor. ScienceDaily. Retrieved December 13, 2023 from www.sciencedaily.com/releases/2023/12/231213112537.htm
Photo by Pixabay from Pexels: https://www.pexels.com/photo/close-up-photo-of-a-stethoscope-40568/