【Gut Microbes】The Fudan team found that the characteristics of the tumor microbiota of liver cancer showed anti-tumor activity

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Author: Mia

Intrahepatic cholangiocarcinoma (ICC) is the second largest primary liver cancer, accounting for 10-15%
of primary liver cancers.
Recently, a research team analyzed the bacterial metagenomic characteristics of ICC tissues and explored their anti-cancer potential
.

Recently, Fan Jia of Fudan University and others published a research paper
entitled "Intratumor microbiome features reveal antitumor potentials of intrahepatic cholangiocarcinoma" in Gut Microbes.
The intratumor flora of intrahepatic cholangiocarcinoma was characterized and found that the content of fungal Parkholderia paraborkholderia in the adjacent tissues of ICC was significantly higher and had anti-tumor potential
.

https://doi.
org/10.
1080/19490976.
2022.
2156255

Microorganisms and cholangiocarcinoma

 01 

Cholangicarcinoma (CHOL) is a malignancy that originates from the extrahepatic bile ducts, including the portal region of the liver to the lower end of the common bile duct, and has a lower incidence than hepatocellular carcinoma (HCC).

Intrahepatic cholangiocarcinoma (ICC) is a common type of CHOL with a high incidence, high degree of malignancy and poor prognosis in China and Southeast Asia
.

Studies in recent years have found that human symbiotic microorganisms are closely related
to complex diseases such as mental disorders, cardiovascular diseases, and tumors.
Studies have shown that intestinal flora is of great significance
in maintaining the intestinal mucosal barrier and promoting the development and maturation of the immune system.
In addition, microbial communities have been shown to parasitize the human liver and bile ducts, which can affect liver metabolism, immune environment, and disease status
.
Clinical studies have found that intestinal flora imbalance is associated with the progression of nonalcoholic steatohepatitis (NASH) and cirrhosis; Another study reported that the gut microbiota and functional toll-like receptor 4 (TLR4) are required for liver fibrogenesis; Both clinical and animal studies have shown that microbial communities can stimulate the inflammatory response and liver fibrosis of the liver and induce the production of IL-6, thereby promoting the development of
liver tumors.

However, the relationship between microbes and cholangiocarcinoma has been
relatively poorly studied.
Epidemiological studies have shown that Helicobacter pylori in bile is a risk factor for an increased risk
of cholangiocarcinoma.
Helicobacter pylori located in the biliary tract activates the NFKB signaling pathway, increases the transcriptional expression of vascular endothelial growth factor, and promotes tumor angiogenesis
.
Therefore, a good understanding of how the intrahepatic microbiota affects the occurrence, progression and treatment of liver and bile duct diseases deserves further study
.

Research process

 02 

In this study, the researchers performed 16S rRNA sequencing on 99 tissues to characterize the microbiota within the tumor, followed by single-cell RNA sequencing (scRNA-seq) and multi-level validation
.
The presence of
microbial DNA in tissues was detected using staining, fluorescence in situ hybridization (FISH), and transmission electron microscopy (TEM).

The results of the study showed that intrahepatic cholangiocarcinoma (ICC) tumor tissue contains a greater variety of microbiota and higher
α diversity than adjacent tissue.
The researchers also cultured gram-positive aerobic bacteria from fresh tissue and identified them as staphylococcus cephalicus
.
At the same time, scRNA-seq showed that intratumoral bacteria can be present in
a variety of cell types.

Using 16S rRNA sequencing, the most abundant bacterial orders include Burkholderiales, Pseudomonadales, Xanthomonadales, Bacillales, and Clostridiales
。 In addition, the content of Paraburkholderia fungorum was significantly higher in adjacent tissues than in adjacent tissues and was negatively correlated
with CA199 (carbohydrate antigen 199) levels.
In vitro and in vivo experimental results showed that P.
fungorum has certain antitumor activity
against tumors.
Metabolomics and transcriptomics suggest that P.
fungorum can inhibit tumor growth
through alanine, aspartate, and glutamate metabolism.

Analysis of bacterial flora composition in ICC tissues

Research significance

 03 

In summary, the results suggest that bacteria in ICC may exert important anti-tumor effects, and the number of bacteria in tumors is correlated
with clinical factors.
Therefore, bacterial microbiota DNA can be used as a diagnostic or prognostic marker for tumors, and even as a target for clinical drug treatment
.
However, the molecular mechanisms by which they interact with cancer cells remain to be thoroughly studied
.
The researchers say they also need to clearly understand the molecular mechanisms by which microbiota enter and reside in tumor tissue, and study how they can be used as targets for tumor prevention
.

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.