Why does the high-fat diet promote colorectal cancer?

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Why does the high-fat diet “covering” cancer cells and promote colorectal cancer?

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Why does the high-fat diet promote colorectal cancer?  It turns out that they are “covering” cancer cells.

Colorectal cancer (CRC) is a general term for cancers that initially develop in the tissues of the colon or rectum. It is the third most common malignant tumor after breast cancer and lung cancer. The proportion of patients is as high as 9.4%.

Among them, colorectal cancer patients in China account for 31% of the world. Not only that, but in many other countries, the incidence of early-onset colorectal cancer (people younger than 50 years old) has been rising year after year.

As we all know, illness comes from the mouth. Diet is an important factor that directly affects health and disease status.

More and more important epidemiological and preclinical studies have linked long-term diet patterns (such as high-fat diets) to several types of cancer, including colorectal cancer.

However, how the adaptation of intestinal epithelial cells to a high-fat diet alters cancer risk is still unknown.

The intestinal epithelium is maintained by Lgr5+ intestinal stem cells (ISC) located at the base of the crypt, and produces a variety of special cell types in the inner wall of the intestine.

These rapidly renewing ISCs coordinate the intestinal adaptation by balancing the self-renewal and differentiation of stem cells in response to changes in diet.

Intestinal stem cells are also the origin cells of many early intestinal tumors, and are related to dietary nutrients, symbiotic microorganisms and immune cells.

Therefore, understanding how diet induces changes in intestinal stem cells and their surrounding components will help clarify the early steps in the onset of colorectal cancer.

Recently, a research team from Cold Spring Harbor Laboratory, Harvard Medical School, and Massachusetts Institute of Technology published a research paper titled: Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis in Cell Stem Cell, a sub-Journal of Cell.

The study showed that a high-fat diet disrupted the interaction between the gut microbiome, intestinal stem cells and the immune system, causing immune cells to “turn a blind eye” to cancer-like cells, thereby providing a breeding ground for tumor growth. It is expected to enhance cancer immunotherapy through diet, drugs or changing the composition of the gut microbiome.

Although several strategies that cancer uses to evade the immune system have been well studied, however, scientists know very little about how diet affects tumor immune recognition by intestinal stem cells.

Under normal circumstances, immune cells patrol the tissues to find and eliminate health hazards. Some immune cells look for labels that distinguish normal cells from abnormal cells. One of them is Major Histocompatibility Complex Type II, or MHC Type II.

T cells recognize antigens through the antigen presentation pathway is the main mechanism for triggering anti-tumor immunity. Although the activation of cytotoxic CD8+ T cells mediated by the major histocompatibility complex class I (MHC-I) antigen presentation pathway plays a major role in the anti-tumor immune response, CD4+T mediated by MHC class II Cell activation is also the key to tumor immunity. MHC-II on the cell surface can activate the immune system to destroy all kinds of abnormal cells including cancer cells.

To explore how a high-fat diet interferes with the expression of immunomodulatory genes in intestinal stem cells, the researchers examined the mRNA sequencing data of Lgr5+ intestinal stem cells isolated from control and high-fat diet-fed mice.

They found that a high-fat diet reduced the expression of MHC class II genes in intestinal epithelial cells (including ISC), and the decrease in epithelial MHC class II expression was associated with a decrease in the diversity of the gut microbiome.

This means that these tags will not be recognized by the immune system, so abnormal cells can evade the immune system and quietly develop into tumor cells.

In order to gain insight into the members of the microbiome that can induce the expression of MHC class II in the epithelium, the researchers sequenced and compared fecal DNA isolated from high-fat-fed mice and a control group.

Consistent with the previous results, obesity induced by a high-fat diet led to a disorder of the gut microbiome and reduced bacterial diversity in feces. Bacteria that are significantly reduced under high-fat diets include Helicobacter.

In order to determine whether the colonization of Helicobacter in mice is related to the expression of MHC class II in the intestinal epithelium, the researchers conducted a “dirty roommate” experiment. They kept mice without these bacteria together with normal mice. As a result, “clean” mice were infected with Helicobacter pylori and produced more MHC-II tags.

Then, the researchers performed fecal transplantation on sterile mice, again confirming that Helicobacter colonization is related to the expression level of MHC class II in intestinal epithelial tissue.

These results indicate that the expression of MHC class II in epithelial tissue is regulated by intestinal commensal bacteria (including Helicobacter) and is inhibited in response to a high-fat diet.

This research also proposes a new method to promote current cancer immunotherapy, which is to increase the production of MHC-II labels through diet, drugs or changing the composition of the intestinal microbiome, thereby helping the immune system to recognize and eliminate cancer cells.

Paper link:
https://doi.org/10.1016/j.stem.2021.08.007

Why does the high-fat diet promote colorectal cancer?

(source:internet, reference only)

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