For Some Tumor Cells, Fat Greases the Skids for Metastasis

    Tumor cells that promote metastasis can be distinguished from tumor cells that do not, report scientists at the Institute for Research in Biomedicine (IRB Barcelona). According to these scientists, metastasis-inducing tumor cells have a particular taste for fat—very particular, in that they express high levels of the fatty acid receptor CD36 and lipid metabolism genes. These distinguishing features could, the scientists suggest, help predict metastasis and guide the development of new antimetastatic cancer therapies. They also help substantiate the observed link between high-fat diets and the heightened risk of certain kinds of cancer.

    IRB Barcelona researchers led by Salvador Aznar Benitah, Ph.D., discovered the metastatic CD36⁺ cells in samples from patients with oral cancer with different degrees of aggressiveness. In the mouth tumors analyzed, very few cells were found to have metastasis-initiating capacity. The addition of CD36 expression to tumors that had been free of metastasis made them become metastatic.

    Furthermore, the researchers demonstrated that the effect exerted by CD36 on metastasis is the same for melanoma cells and luminal breast cancer cells. Likewise, statistical analyses of samples from patients revealed that the metastasis of ovarian, bladder, and lung cancer are also dependent on CD36.

    Detailed findings appeared December 7 in the journal Nature, in an article entitled “Targeting Metastasis-Initiating Cells through the Fatty Acid Receptor CD36.” The article not only explored the role of the CD36 receptor, it also suggested that metastasis-initiating cells particularly rely on dietary lipids to promote metastasis.

    “Palmitic acid or a high-fat diet specifically boosts the metastatic potential of CD36⁺ metastasis-initiating cells in a CD36-dependent manner,” wrote the article’s authors. “The use of neutralizing antibodies to block CD36 causes almost complete inhibition of metastasis in immunodeficient or immunocompetent orthotopic mouse models of human oral cancer, with no side effects.”

    Commenting on the clinical implications of their findings, the authors noted that the presence of CD36⁺ metastasis-initiating cells correlates with a poor prognosis for numerous types of carcinomas. They added that inhibition of CD36 also impairs metastasis, at least in human melanoma- and breast cancer-derived tumors.

    “Although we have not yet tested this in all tumor types, we can state that CD36 is a general marker of metastatic cells, the first marker I know of that is generally specific to metastasis,” said Dr. Benitah. “We expect this study to have a big impact on the scientific community and to further advances in metastasis research, and we hope to be able to validate the potential of CD36 as an antimetastasis treatment. Things like this don’t happen every day.”

    The study demonstrated the antimetastatic effect of blocking the CD36 protein, both in immunodepressed mice and in mice with intact immune systems. Figures were similar for all tests. Inhibition of CD36 when the animals were inoculated with the tumor cells eliminated their metastatic potential. In addition, the administration of CD36-blocking antibodies to mice with already established metastases led to total removal of the metastases in 20% of the animals, whereas for the others it brought about a dramatic reduction of 80–90% in the number of metastatic foci and their size.

    “In mice inoculated with human tumor cells, there appears to be a direct link between fat intake and an increase in metastatic potential through CD36,” noted Dr. Benitah. “More studies are needed to unravel this intriguing relationship between diet and metastasis, above all because industrialized countries are registering an alarming increase in the consumption of saturated fats and sugar.”

    IRB Barcelona has applied for intellectual property protection of the results, and the researchers are working with MRC Technology in the U.K. to co-develop new antibody-based therapeutics against CD36 that are suitable for treatment of patients in a range of cancers.

    “We can now obtain metastatic cells in the laboratory,” remarked IRB Barcelona’s Gloria Pascual, Ph.D., the first author of the Nature paper. “This will allow us to trace them and to study, for example, their distribution in the tumor, where they anchor when they leave it, or why they are so sensitive to fat, among other questions.”