Abstract
The fact that the identity of the cells that initiate metastasis in most human cancers is unknown hampers the development of antimetastatic therapies. Here we describe a subpopulation of CD44bright cells in human oral carcinomas that do not overexpress mesenchymal genes, are slow-cycling, express high levels of the fatty acid receptor CD36 and lipid metabolism genes, and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet specifically boosts the metastatic potential of CD36+ metastasis-initiating cells in a CD36-dependent manner. 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. Clinically, the presence of CD36+ metastasis-initiating cells correlates with a poor prognosis for numerous types of carcinomas, and inhibition of CD36 also impairs metastasis, at least in human melanoma- and breast cancer-derived tumours. Together, our results indicate that metastasis-initiating cells particularly rely on dietary lipids to promote metastasis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Neutralizing / immunology
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Antibodies, Neutralizing / pharmacology*
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Antibodies, Neutralizing / therapeutic use
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CD36 Antigens / antagonists & inhibitors*
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CD36 Antigens / genetics
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CD36 Antigens / immunology
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CD36 Antigens / metabolism
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Cell Proliferation
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Diet, High-Fat / adverse effects
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Disease Models, Animal
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Hyaluronan Receptors / metabolism
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Lipid Metabolism / genetics
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Lymphatic Metastasis / genetics
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Lymphatic Metastasis / pathology
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Male
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Mice
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Mouth Neoplasms / diagnosis
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Mouth Neoplasms / drug therapy
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Mouth Neoplasms / metabolism
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Mouth Neoplasms / pathology*
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Neoplasm Metastasis / drug therapy
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Neoplasm Metastasis / genetics
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Neoplasm Metastasis / pathology*
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Neoplasm Metastasis / prevention & control*
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology*
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Palmitic Acid / administration & dosage
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Palmitic Acid / metabolism
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Palmitic Acid / pharmacology
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Penetrance
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Prognosis
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Transcriptome
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Neutralizing
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CD36 Antigens
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Hyaluronan Receptors
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Palmitic Acid