Cholesterol is an organic molecule that has a chequered history and is generally associated with an unhealthy diet. High levels of cholesterol in the blood stream were found to correlate with a greater risk of heart disease which led government healthcare officials to advise citizens to avoid foods such as red meat, eggs, and butter. It turns out the picture is more complex, with cholesterol playing a vital role in cell membranes and serving as a precursor to important hormones. Interestingly, elevated levels of the molecule have been linked to poor prognosis in breast cancer patients.
A recent study published in Molecular Therapy has shown that tumour cells are able to synthesise cholesterol and thereby stimulate metastatic growth. The researchers, who are based in Los Angeles and Beijing, focused on triple-negative beast cancer (TNBC) which occurs in about 15% of patients. TNBC, so called because it lacks three cell surface receptors, is an extremely difficult cancer to treat, with patients suffering a worse prognosis compared to other cancer subtypes. TNBC has a propensity to metastasise to other organs, especially the lungs and brain, and the researchers were keen to understand the molecular mechanisms.
Bingchen Han (seen left) and his co-authors discovered that metastatic growth was mediated by communication between TNBC cells and fibroblasts in the lungs and they were able to inhibit this signalling cascade by using statins, drugs which reduce cholesterol levels. Oncologist Kevin Nead from Houston, Texas commented: “This study provides a promising route through which cholesterol pathways could be targeted to treat TNBC, which agrees with epidemiological studies that show a potential benefit to statins in patients who have been diagnosed with TNBC.”
The key to understanding the process was the role played by a group of chemokines, a family of signalling proteins that are secreted by cells. To unravel the mechanisms by which the chemokines fuel metastasis, the researchers conducted a series of experiments in both human cell lines and in mice with TNBC. They discovered there was a positive feedback loop between tumour cells and lung cells, leading to synthesis of cholesterol which in turn induced the formation of new blood vessels in the lung that are critical to metastasis.
With this knowledge, Han used simvastatin to treat TNBC in a mouse model, with the drug being administered through the nose using nanoparticles that specifically target tumour cells. The treatment led to fewer metastatic nodules and reduced blood vessel density, and the results now need to be validated in humans. Han is optimistic but said “there is still a long way to go.”