Targeted cancer therapy, for the most part, focuses on restricting the uncontrolled growth of a tumor. While these treatment strategies have been successful during the early stages of cancer, there is a constant need to identify treatment options for tumors that have undergone metastasis i.e. the tumor cells have dispersed from their primary site and localized to other organs of the body. In a recent study published by Nature, Pascual et al have shed some major insights into the process of metastasis and identified a fatty acid receptor, CD36 as a potential target to impair metastasis.
The researchers generated tumors in mice by injecting them with oral carcinoma cell lines and patient-derived cells. These cells were stained with a fluorescent label dye, which diminishes with every dividing cancer cell. They were able to identify slow dividing dye-retaining cells as well as rapidly dividing dye-negative cells in the tumors that developed. A transcriptome analysis, to identify differences in the gene signature of these two populations, showed an enhancement of genes involved in metastasis and lipid metabolism in the slow dividing dye-retaining cells. CD36, a cell surface receptor and a crucial component for lipid uptake and metabolism, was one of the top implicated genes in their data analysis. Cell surface receptors communicate with specific molecules in the extracellular environment and transmit signals within the cell, which consequently dictates cellular processes.
How does CD36 affect metastasis? Interestingly, loss of CD36 in mice reduced the ability of tumors to penetrate to other organs by 80-100% while it did not affect primary tumor formation. Consistent with its requirement for metastasis, antibodies that block the CD36 receptor significantly inhibited metastasis in mice without affecting the size of the tumor. Furthermore, the expression of the cell surface receptor, CD36 was greatly increased when mice were fed with a high-fat diet. In a series of subsequent experiments, the authors concluded that the metastatic potential of tumors is increased with a high fat diet in a CD36 dependent manner.
There are several aspects of this study that are interesting.
This work shifts the paradigm of cancer metastasis theories where tumor cells are believed to undergo a transition from an adhering epithelial cell to a migratory mesenchymal cell (EMT) to invade distant sites. These CD36 expressing cells did not exhibit a mesenchymal gene signature. While further experimentation is required to link CD36 and EMT, it is conceivable that these processes are independent of each other to facilitate metastasis. A detailed mechanism of how CD36 initiates and regulates metastasis remains to be determined.
A high fat diet, which included palmitic acid (an essential component of palm oil) enhanced metastasis in a CD36-dependent manner in these mice. Palm oil is a key ingredient in several food products including Nutella. A press release early last year claimed that the breakdown products of palm oil are potentially carcinogenic, therefore correlating Nutella consumption with cancer risk. While these correlative studies require further scrutiny, validation, and support by causation studies in humans, it is imperative to understand the impact of an EXCLUSIVE high-fat diet on health.
The constantly evolving landscape of cancer research has witnessed the discovery of promising molecules to combat the most aggressive forms of the disease. A majority of these molecules are immuno-oncological targets that enhance the anti-tumor immune response and prevent tumor spreading. In 2016, the FDA approved two drugs, Bristol Myers-Squibb’s Opdivo for metastatic head and neck squamous carcinoma and Genentech’s Tecentriq for metastatic non-small cell lung carcinoma. Both these drugs regulate the immune checkpoint PD-1 and PDL-1 respectively. Some other drugs in the pipeline include Bristol-Myers Squibb and ASLAN pharmaceuticals’ ASLAN002, an inhibitor of the receptor tyrosine kinase, RON. RON regulates immune surveillance and its activation enhances tumor metastasis. Innate Pharma‘s, anti-CD73 blocks the enzyme, CD73 whose function contributes to the generation of an immunosuppressed and pro-angiogenic tumor microenvironment. What makes the fatty acid receptor CD36 unique, so far, is that it exclusively affects metastasis without affecting primary tumor formation. While its cross talk with the immune system remains to be investigated, CD36 represents a novel class of potential anti-metastatic targets that requires further validation. Targeting CD36 by itself, or perhaps in combination with the other aforementioned drugs, might have the potential to treat some of the most aggressive forms of tumor and subsequently have a positive impact on patient lives.
Journal article:
http://www.nature.com/nature/journal/
Additional newsfeed :
http://www.nature.com/nature/journal/
https://www.worldwidecancerresearch.org/blog-post/
new-research-links-major-component-of-palm-oil-to-cancer-spread/
https://www.sciencedaily.com/releases/
http://healthmedicinet.com/i/preventing-cancer-spread-
https://www.centerwatch.com/drug-information/fda-approved-drugs/
http://www.aslanpharma.com/drug/aslan002/
http://www.innate-pharma.com/en/pipeline/
first-class-anti-cd73-checkpoint-inhibitor-program
Photo source: Shutterstock
Edited by Abhinav Dey.
About the author
Radhika completed her PhD from Cornell University and is currently a Postdoctoral fellow at the Brigham and Women’s Hospital. Her research interests have centered around oncology and neuroimmunology. Among other things, she is striving to effectively communicate scientific discoveries to the community.
