Colorectal cancer is a paracrine deficiency syndrome amenable to oral hormone replacement therapy

Area of Science:

• Molecular biology
• Gastroenterology
• Oncology

Background:

• Guanylin and uroguanylin, ligands for guanylyl cyclase C (GCC), are frequently lost in colorectal carcinogenesis.
• GCC-cGMP signaling regulates proliferation, genetic integrity, and metabolism in intestinal cells.
• GCC's role as a tumor suppressor in the intestine is increasingly recognized.

Purpose of the Study:

• To investigate the role of GCC signaling in intestinal homeostasis and colorectal tumorigenesis.
• To explore the potential of GCC ligand replacement therapy for colorectal cancer.

Main Methods:

• Studied GCC-deficient mice to assess effects on intestinal proliferation and metabolism.
• Examined GCC's role in mouse models of colorectal cancer (Apc(Min)(/+) and azoxymethane-induced).
• Analyzed GCC expression in human colorectal tumors.

Main Results:

• GCC elimination in mice led to hyperplasia, increased progenitor cells, and metabolic reprogramming (glycolysis shift).
• Loss of GCC exacerbated tumor initiation and promotion by compromising genomic integrity and cell cycle control.
• GCC is over-expressed in human colorectal tumors, contrasting with ligand loss in early carcinogenesis.

Conclusions:

• GCC is a critical regulator of intestinal homeostasis and acts as an intestinal tumor suppressor.
• Dysregulation of GCC signaling due to paracrine hormone insufficiency is an early event in colorectal cancer.
• Targeted oral replacement with GCC ligands shows promise for colorectal cancer prevention and therapy.