Identifying the Culprit: Who Started It?

It is so commonly observed that every individual knows at least one person with cancer. Since every cancer is unique, the treatments must be tailored to each cancer patient, hence, maintaining awareness of new, groundbreaking cancer therapies is so critical for clinicians and researchers. In the Nature article entitled “Targeting metastasis – initiating cells through the fatty acid receptor CD36”, the authors discover a potential interesting therapy for multiple forms of cancer.

The authors observe that a major blockade for progression in cancer research is that scientists have yet to identify the cells that are responsible for the initiation of metastasis, the spread of cancer cells to other parts of the body from the primary tumor. To study this issue, the authors injected a fluorescent lipophilic (“fat-liking”) dye into human oral carcinoma cells which were subsequently injected into the mouths of mice. It is critical to note that the researchers studied a population of cells that contain the CD44 gene, which, when expressed, often plays a role in tumor metastasis. More specifically, a subset of these cells express the CD36 gene, and this protein, which is a fatty acid receptor, plays a major role in metastasis via lipid metabolism according to this study. The authors wanted to isolate the label-retaining cells from the carcinoma, defined by their slow-cycling nature, as these cells have the potential to transition to mesenchymal cells which are stem cells in connective tissue. These cells were of interest because they play a role in cancer development. To the authors’ surprise, these slowly proliferating cells were indeed those that were expressing CD36 and CD44. Fatty acid metabolism genes were also being expressed in these cells, and this is what leads to some interesting findings.

Working our way through the details of metastasis initiation, the first finding was that CD36 does increases metastatic potential of cancer cells. The authors describe that the overexpression of CD36 not only leads to large increases in metastatic potential but also increases in size of the metastatic tumors. CD36 doesn’t seem to have an effect on the size of primary tumors, but it is certainly directly correlated with the size of tumors that resulted from the migration of cells from the original cancer site.

This begs the question: what is the mechanism by which CD36+ cells cause large increases in metastasis? It turns out that dietary lipids are deeply involved in this process. The label-retaining cells express genes that code for enzymes required for fatty acid oxidation. The largest metastases were found in mice that were fed diets with high fat content. The authors suspect that the expression of CD36 is related to the concentration of fatty acids, specifically palmitic acid. They note that the only observed effects were on metastasis levels and metastases sizes – not primary tumor growth. They further solidify this idea by pointing out that their data show that while CD36+ cells result in a high level of metastasis, CD36+ and CD36 cells yield primary tumors of the same size.

This research has some very obvious clinical implications related to thwarting metastasis of malignant tumor cells. Thus, the authors used antibodies that inhibit all discovered functions of CD36 and inoculated the mice. The mice received an injection every three days and the result was the prevention of metastasis initiation. Daily injections resulted in 80-90% size reduction of lymph node metastases. The ultimate idea is that targeting cells that are CD36+ and inhibiting its known functions may be a very effective therapy and prophylactic treatment of the spread of cancer. Such high impact results can have a major influence on new medicines and treatments of such a widespread disease. Clearly this work also relates to our recent discussions about lipids, and it is useful for us to see the impacts lipid metabolism has in areas we might not expect, like metastasis. Since – as already pointed out – most, if not all, of us know someone with cancer, it is possible for us to see this work materialize into treatments that effectively crash the spread of such a deadly disease first hand.

Pascual, G. et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541, 41-45 (2017).

This picture shows the high impact results of the paper. On the left, it is shown that the CD36 antibody has no significant effect on the primary tumor growth. On the right, however, the size of the metastases is reduced due to treatment with the antibody.

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