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TLR2 controls the development of hepatocellular carcinoma by reducing interleukin-18-mediated immunosuppression

Inﬂammation is thought to be related to tumor development, but the immune mechanisms underlying hepatocellular carcinoma (HCC) are still not well understood. In our study, we found that Toll-like receptor 2 (TLR2) inhibited production of the inflammatory cytokine interleukin-18 (IL-18) and protected mice from diethylnitrosamine (DEN)-induced HCC. Tlr2-/- mice showed a signiﬁcant increase in HCC progression after DEN treatment along with impaired CD8+ T cell function. Meanwhile, hepatic Ly6Chigh myeloid-derived suppressor cells (MDSCs) were significantly increased in Tlr2-/- mice after 5 months of DEN treatment. Furthermore, MDSCs exhibited higher iNOS expression levels, which could inhibit IFN-γ production and CD8+ T cell proliferation in vitro. Hepatocytes from Tlr2-/- mice produced more mature IL-18 after DEN treatment, which caused accumulation of Ly6ChighIL-18Rα+ MDSCs in the liver. Recombinant IL-18 induced accumulation of Ly6Chigh MDSCs, and hepatocyte-specific silencing of IL-18 in Tlr2-/- mice decreased the proportion of MDSCs, increased the proportion of functional CD8+ T cells, and alleviated HCC progression. Caspase-8 was responsible for IL-18 production in Tlr2-/- mice since Tlr2-/- mice treated with caspase-8 shRNA exhibited decreased IL-18 production. Furthermore, the TLR2 agonist Pam3CSK4 inhibited both caspase-8 and IL-18 expression, decreased Ly6Chigh MDSCs, increased CD8+ T cell function, and promoted HCC regression. Our findings indicate that TLR2 deficiency accelerates IL-18-mediated immunosuppression in hepatocarcinogenesis, and TLR2 activation may alleviate HCC progression by inhibiting IL-18 production. Thus, these findings provide new insights that may be helpful in designing tumor immunotherapy.

Does caffeine fight cancer?

Epidemiological studies have shown that caffeinated drinks may help prevent skin cancer by inhibiting a DNA repair pathway, thus killing potentially precancerous cells. In English, it means that drinking drinks containing caffeine will reduce one’s chances of developing some types of cancer, including UV-associated skin cancer. That just proves that caffeine fight cancer. The results, published in the Proceedings of the National Academy of Sciences, lend support to the idea that caffeine could be added to sunblock to increase its protective effects. At the cellular level, they’re showing that caffeine is working in this way of inducing an apoptotic mechanism. This statement was then made by cancer epidemiologist Joanne Kotsopoulos of the University of Toronto.

In the 2007, a study stated that woman who drank caffeinated coffee on a daily basis had a 10 percent lower risk of nonmelanoma skin cancer. Six or more cups of coffee a day translated to a 30 percent reduction in risk. Mouse studies have also confirmed the link, with both ingested and topically-applied caffeine lowering skin cancer rates in the animals. But exactly how the stimulant protected against cancer remained mysterious. One possibility is the drug’s inhibition of ataxia telangiectasia and Rad3-related (ATR), a large protein kinase that senses incomplete DNA replication often a result of DNA damage and signals the cell to not divide. By inhibiting ATR activity, caffeine could make cells more likely to die in response to UV damage, preventing damaged cells from ever becoming cancerous.

Studies have shown that the caffeine molecule acts as a sunscreen. It therefore blocks the penetration of UV rays. And that is why today we see many sunblocks with a good amount of caffeine in them.

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Can sugar consumption cause breast cancer?

A recent study stated that drinking three sugar sweetened drinks a week would increase the risk of having breast cancer. The study had 776 pre-menopausal women and 779 post-menopausal women. Each women’s breast density was assessed by examining their mammograms. The women were told to make a note of sweet they consumed such as chocolates, cakes, ice cream or any sweet drinks. Also they were asked to make a note of how much of spoonful of sugar they add to the drinks.

It was then found out that post-menopausal women who consumed more of sugar, an increase in the density of breast. While the pre-menopausal women observed an increase in breast density when they consumed sugar food. These women, in a week were just consuming three sugar sweetened drinks. The study then further stated that sugar tends to increase the migration of breast cells together. This explains the fact that the premenopausal women who consumed sugar-sweetened drinks were 3 percent more likely to have dense breasts than those who didn’t consume the drinks. And having dense breasts increases your risk of breast cancer by making it difficult to see tumors on mammograms.

However, there is more to be studied on this matter. But until then there is still a link between the sugar consumption and breast density. About 40% of women in the US have dense breast and they are totally unaware of it. Doctors say that women with a dense breast are five time more likely to have a breast cancer and 10 times more likely to miss the tumor in the mammogram test.

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