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Review
. 2022 Sep;19(5):457-472.
doi: 10.2217/pme-2022-0026. Epub 2022 Aug 3.

Guanylyl cyclase C as a diagnostic and therapeutic target in colorectal cancer

Adi Caspi  1 , Ariana A Entezari  1 , Madison Crutcher  1   2 , Adam E Snook  1 , Scott A Waldman  1
Affiliations
Review

Guanylyl cyclase C as a diagnostic and therapeutic target in colorectal cancer

Adi Caspi et al. Per Med. 2022 Sep.

Abstract

Colorectal cancer remains a major cause of mortality in the USA, despite advances in prevention and screening. Existing therapies focus primarily on generic treatment such as surgical intervention and chemotherapy, depending on disease severity. As personalized medicine and targeted molecular oncology continue to develop as promising treatment avenues, there has emerged a need for effective targets and biomarkers of colorectal cancer. The transmembrane receptor guanylyl cyclase C (GUCY2C) regulates intestinal homeostasis and has emerged as a tumor suppressor. Further, it is universally expressed in advanced metastatic colorectal tumors, as well as other cancer types that arise through intestinal metaplasia. In this context, GUCY2C satisfies many characteristics of a compelling target and biomarker for gastrointestinal malignancies.

Keywords: GUCY2C; biomarker; cancer prevention; colorectal cancer; guanylin; guanylyl cyclase C; hormone replacement; linaclotide; plecanatide; uroguanylin.

Plain language summary

Colorectal cancer is a leading cause of death in the USA. In recent years, there has been a shift in the field of oncology from generic treatments, such as surgery and chemotherapy, to personalized molecular therapies, which focus on targeting specific attributes of each patient's unique cancer. Guanylyl cyclase C is a receptor expressed in the intestinal tract, where it regulates fluid secretion and prevents tumor formation. Beyond its function in the healthy intestine, it is expressed in colorectal tumors, and other types of cancer, where it regulates transformation. Therefore, guanylyl cyclase C can serve as a useful target in cancer for prevention and therapy, as well as a marker for tumor cell detection.

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Figures

Figure 1.
Figure 1.. Guanylyl cyclase C signaling cascade in the intestinal epithelium.
Epithelial cells along the intestinal tract express GUCY2C on their apical surface, where it is activated by its endogenous ligands guanylin and uroguanylin, or the super agonist enterotoxigenic peptide ST. Activation of GUCY2C produces intracellular cGMP, which, by activating PKGII, creates an electrolyte gradient via CFTR activation and NHE3 inactivation. This signaling cascade promotes fluid secretion into the intestinal lumen, as well as regulates critical cellular processes such as metabolic activity, barrier integrity and genomic stability.
Figure 2.
Figure 2.. Frequency of colorectal cancer gene mutations.
Analysis of TCGA-COAD cohort indicates frequency of simple somatic mutations in five commonly mutated colorectal cancer genes, APC, TP53, KRAS, PIK3CA, SMAD4 as well as GUCY2C, GUCA2B, and GUCA2A. The total TCGA-COAD cohort assessed consists of n = 400 cases. The data were compiled directly from the TCGA Research Network: www.cancer.gov/tcga. TCGA-COAD: The Cancer Genome Atlas colorectal adenocarcinoma.
Figure 3.
Figure 3.. GUCY2C-targeted therapies along the colorectal cancer disease continuum.
As a chemopreventative approach, ligand replacement by GUCY2C agonists could reconstitute cGMP signaling in the intestinal environment, restoring homeostasis and preventing hyperproliferation. Existing polyps may be removed surgically, and a GUCY2C-targeted vaccine can serve as a secondary preventative of recurring disease. In case of advanced or metastatic disease, T-cell therapy may be used as advanced treatment.
See this image and copyright information in PMC

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