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Systematic Characterization of the Disruption of Intestine during Liver Tumor Progression in the xmrk Oncogene
Yan Li1, Ai Qi Lee1, Zhiyuan Lu1,2
1Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
Abstract:
The crosstalk between tumors and their local microenvironment has been well studied, whereas the effect of tumors on distant tissues remains understudied. Studying how tumors affect other tissues is important for understanding the systemic effect of tumors and for improving the overall health of cancer patients. In this study, we focused on the changes in the intestine during liver tumor progression, using a previously established liver tumor model through inducible expression of the oncogene xmrk in zebrafish. Progressive disruption of intestinal structure was found in the tumor fish, displaying villus damage, thinning of bowel wall, increase in goblet cell number, decrease in goblet cell size and infiltration of eosinophils, most of which were observed phenotypes of an inflammatory intestine. Intestinal epithelial cell renewal was also disrupted, with decreased cell proliferation and increased cell death. Analysis of intestinal gene expression through RNA-seq suggested deregulation of genes related to intestinal function, epithelial barrier and homeostasis and activation of pathways in inflammation, epithelial mesenchymal transition, extracellular matrix organization, as well as hemostasis. Gene set enrichment analysis showed common gene signatures between the intestine of liver tumor fish and human inflammatory bowel disease, the association of which with cancer has been recently noticed. Overall, this study represented the first systematic characterization of the disruption of intestine under the liver tumor condition and suggested targeting intestinal inflammation as a potential approach for managing cancer cachexia.
Insights
Liver tumors disrupt intestinal structure and function, causing inflammation. Targeting this intestinal inflammation may help manage cancer cachexia.
Area of Science:
- Oncology
- Gastroenterology
- Zebrafish models
Background:
- Tumor-microenvironment interactions are known, but systemic effects on distant organs are less understood.
- Investigating distant tissue changes is crucial for understanding cancer's systemic impact and patient care.
- The intestine's response to liver tumors is a key area for systemic cancer research.
Purpose of the Study:
- To systematically characterize intestinal changes during liver tumor progression.
- To explore the molecular mechanisms underlying tumor-induced intestinal alterations.
- To identify potential therapeutic targets for cancer-related complications.
Main Methods:
- Utilized a zebrafish liver tumor model with inducible oncogene expression (xmrk).
- Assessed intestinal structure and cellular phenotypes through histological analysis.
- Performed RNA sequencing (RNA-seq) for comprehensive gene expression profiling of the intestine.
- Conducted gene set enrichment analysis to compare intestinal signatures with human diseases.
Main Results:
- Liver tumors caused progressive intestinal damage, including villus atrophy, bowel wall thinning, and goblet cell changes.
- Intestinal inflammation was evident, characterized by eosinophil infiltration and disrupted epithelial cell renewal (decreased proliferation, increased death).
- RNA-seq revealed deregulation of genes involved in intestinal function, barrier integrity, and homeostasis, with activation of inflammation and epithelial-mesenchymal transition pathways.
- Common gene signatures were found between the intestine of tumor-bearing fish and human inflammatory bowel disease.
Conclusions:
- Liver tumors induce significant structural and functional disruption in the distant intestine, primarily through inflammation.
- The observed intestinal changes share molecular signatures with inflammatory bowel disease, suggesting a link between gut inflammation and cancer.
- Targeting intestinal inflammation presents a potential therapeutic strategy for managing cancer cachexia.
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