If we are unfortunate enough to suffer from cancer, in addition to active treatment, doctors recommend that we eat lightly, avoid big oil and meat, achieve balanced nutrition, and delay the metastasis or recurrence of cancer from living habits. The popularity of this view is also due to the fact that cancer is caused by multiple factors, including not only genetic mutations but also the environment and even bad living habits. Scientific research also supports this view, such as high-fat diets (see BioArt report: Cell Stem Cell | A new mechanism for promoting tumorigenesis by a high-fat diet - inhibition of intestinal stem cell MHCII expression), obesity (see BioArt report: Cell Meta | The mechanism by which obesity drives the development of breast cancer) is a high risk factor for cancer. Among them, fatty acids and their transporter CD36 have been linked to the occurrence, development and drug resistance of cancer (see BioArt report: Nature | A low-sugar diet not only lowers sugar but also inhibits cancer, depending on lipid metabolism). So which fatty acids are associated with cancer development and what are their mechanisms in our daily diets?
On November 10, 2021, Salvador Aznar Benitah and Gloria Pascual of the Institute of Science and Technology in Barcelona, Spain, in collaboration with Ali Shilatifard of Northwestern University in the United States, published an article in Nature. It was revealed that palmitic acid instead of oleic or linoleic acid could promote metastasis of oral cancer and melanoma in mice.
The researchers selected palmitic acid (palmitic acid, PA, the main saturated fatty acid in palm oil), oleic acid (OA, oleic acid) and linoleic acid (LA), which are common in edible oils, as research subjects, and used these three fatty acids to treat human oral squamous cell carcinoma cells (OSCC) for 4 days (palmitic acid 300uM, within the physiological concentration of human blood; oleic acid and linoleic acid are both 50uM, avoiding lipotoxicity), Later, the treated cell xenotransplanted to mice found that none of the three fatty acids could affect tumor formation, but palmitic acid alone could significantly promote the metastasis of tumors and the size of metastases, and could induce the expression of the fatty acid transporter CD36.
Is this transfer-promoting capacity of palmitic acid due to sustained stimulation? The researchers first stimulated oral cancer cells with different fatty acids for 4 days, then removed fatty acids for 14 days, and then transplanted them into mice, and found that the palmitic acid treated cancer cells still showed a strong ability to promote metastasis, oleic acid and linoleic acid were even reduced, and palmitic acid also showed metastatic ability at 50uM. This result suggests that palmitic acid can even allow cancer cells to produce "metastatic memories."
So, how effective is the daily use of palm oil? The researchers transplanted OSCC to mice, then fed palm oil, olive oil and standard diet for 10 days, and then all switched to standard diets until death, killed the mice and purified cancer cells (CD36bright) for secondary transplantation and standard diet, the results showed that only mice fed palm oil still had strong metastasizing ability, not only oral cancer cells, but also melanoma cells. If CD36 is knocked out or cd36 is neutralized, tumor metastasis is suppressed.
Cellular memory has a lot to do with epigenetics. So is the memory of tumor metastasis caused by palmitic acid also related to epigenetics? The researchers treated oral cancer cells with palmitic acid or oleic acid in vitro for 4 days, followed by 14 days of removal of palmitic acid cultures for ChIP-Seq (including H3K4me3, H3K4me1, H3K27ac, H3K27me3, H3K9me3). Although the distribution of H3K4me1, H3K27me3 and H3K27ac was altered after 4 days of palmitic acid treatment, most of them subsided after 14 days of palmitic acid removal, and only H3K4me3 formed stable changes. GO analysis showed that these H3K4me3 altered genes are associated with neurogenesis and neural remodeling, and not only that, the researchers used 6-hydroxydopamine to effectively inhibit the metastasis of cancer cells. Promoter transcription factor binding experiments revealed that the EGR2 binding region is rich, and knocking out EGR2 can change the distribution of H3K4me3 and inhibit the "metastatic memory" of cancer cells in vivo.
H3K4me3 is associated with the methyltransferase MLL/COMPASS family, including MLL1, MLL2, Set1A, and Set1B. The next step is to determine which methyltransferase is specifically related to the "metastatic memory" of cancer cells. After knocking out Set1B, the "metastatic memory" of cancer cells caused by palmitic acid was suppressed.
As mentioned earlier, the genes that cause epigenetic alterations in tumor cells by palmitic acid are enriched in genes related to nerves, so will this "neural signature" affect the tumor matrix, especially the nerve-related cells in it? The researchers performed bulg RNA-seq on stromal cells and found that differential genes were enriched in genes related to extracellular matrix tissue, neural production, nerve distribution, glial production, etc., and the prediction analysis of nodal pathway interaction revealed pathways related to neural mapping and Schwann cell development. So the researchers performed a single-cell transcriptome analysis and found that the tumor-associated Schwann cells and lymphangial endothelial progenitor cells were the most pronounced. Spatial transcriptome analysis also revealed that Schwann cells were infested in palm oil-fed mice with cancer foci, and the use of cholinesterase ABC to digest Schwann cell-specific extracellular matrix components prevented palmitic acid's pro-metastasis ability.
In conclusion, the study not only revealed that palmitic acid in palm oil can promote the metastasis of oral cancer and melanoma cells in mice, but also caused these cancer cells to form "metastatic memory" through epigenetics, but also suggested a high risk factor for long-term consumption of palm oil or cancer metastasis.
Original link:
https://doi.org/10.1038/s41586-021-04075-0