Need another reason to think twice before ordering that extra serving of fries? It can lead to a higher risk of developing liver cancer. Cases of nonalcoholic steatohepatitis (NASH) — a type of fatty liver that can also lead to cancer — are on the rise and treatment remains elusive. A research group led by Osaka Metropolitan University took a possible step toward suppression and treatment of NASH-associated liver cancer with their study in obese mice that explains the importance of secreted proteins from cell membrane pores formed in cells near cancer cells in the tumor microenvironment for cancer development. Their findings were published in Science Immunology†
While cancer cells themselves are clearly harmful, neighboring cells, including cancer-associated fibroblasts in a so-called “tumor microenvironment”, may also play a role in cancer development. “In the Obesity-Associated Liver” tumor microenvironmentfibroblasts called ‘liver stellate cells’ age,” explains lead researcher Professor Naoko Ohtani. “This causes them to exhibit a senescence-associated secretory phenotype (SASP), releasing a series of proteins that promote cancer by suppressing anti-inflammatory tumor immunity.” The mechanism by which proteins such as SASP factors are released and accelerate tumor development remains unclear.
Professor Ohtani’s team tried to uncover this mechanism by using a high-fat diet to cancer-prone mice and studying the obesity-induced liver cancer. They first performed a comprehensive gene expression analysis to determine which SASP factors were produced by hepatic stellate cells and then examined how they were released.
The SASP factors IL-1β and IL-33 have been shown to be two of the major facilitators of liver cancer growth. Their release will take place in two main phases. “First, the high-fat diet weakens the function of the gut barrier, resulting in the migration and accumulation of lipoteichoic acid in the liver,” explains Professor Ohtani. “Second, the accumulated lipoteichoic acid stimulates the cleavage of gasdermin D protein. This in turn forms cell membrane pores where IL-1β and IL-33 are exported or released from hepatic stellate cells.”
These pores play a critical role because once IL-33 is released, it activates its receptor-positive regulatory T cells that act to immune response until cancer cells and possibly worsen the development of cancer.
Understanding this mechanism is an important step forward in humanity’s fight against cancer. “Our study revealed a very interesting mechanism by which the tumor-promoting SASP factors are released through the cell membrane pores formed by the stimulation of the microbial component in the gut,” concluded Professor Ohtani. “Inhibiting this pore formation may facilitate prevention and therapeutic strategies for NASH-associated.” liver cancer patients.”
Ryota Yamagishi et al, Gasdermin D-mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma, Science Immunology (2022). DOI: 10.1126/sciimmunol.abl7209† www.science.org/doi/10.1126/sciimmunol.abl7209
Provided by Osaka Metropolitan University
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