CD73 promotes colitis-associated tumorigenesis in mice.

Area of Science:

• Immunology
• Oncology
• Gastroenterology

Background:

• Patients with inflammatory bowel disease (IBD) face an elevated risk of colitis-associated colorectal cancer (CRC).
• CD73 plays a potential role in IBD-associated tumorigenesis, necessitating further investigation.

Purpose of the Study:

• To investigate the role of CD73 in the development of colitis-associated tumorigenesis (CAT) in a mouse model.
• To evaluate the therapeutic potential of CD73 inhibition and adenosine receptor activation in CAT.

Main Methods:

• A mouse model of CAT was induced using azoxymethane and dextran sulfate sodium.
• Mice were treated with a CD73 inhibitor (APCP) or an adenosine receptor agonist (NECA).
• Macroscopic assessments (colon length, body weight, tumor formation), histological analysis, inflammatory cytokine measurements, and RNA sequencing were performed.

Main Results:

• CD73 inhibition (APCP) significantly suppressed CAT, reducing weight loss, tumor number, and tumor size, while increasing colon length.
• Adenosine receptor activation (NECA) exacerbated CAT, worsening histological damage and increasing pro-inflammatory cytokines (TNF-α, IL-6).
• RNA sequencing revealed downregulation of oncogenes (ALOX15, Bcl2l15, Nat8l) with APCP and upregulation with NECA.

Conclusions:

• CD73 inhibition attenuates IBD-associated tumorigenesis in a mouse model.
• Adenosine receptor activation exacerbates IBD-associated tumorigenesis.
• These effects are linked to modulation of pro-inflammatory cytokines and key oncogenes (ALOX15, Bcl2l15, Nat8l).