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Guanylyl cyclase C signaling axis and colon cancer prevention

View Article: PubMed Central - PubMed

ABSTRACT

Colorectal cancer (CRC) is a major cause of cancer-related mortality and morbidity worldwide. While improved treatments have enhanced overall patient outcome, disease burden encompassing quality of life, cost of care, and patient survival has seen little benefit. Consequently, additional advances in CRC treatments remain important, with an emphasis on preventative measures. Guanylyl cyclase C (GUCY2C), a transmembrane receptor expressed on intestinal epithelial cells, plays an important role in orchestrating intestinal homeostatic mechanisms. These effects are mediated by the endogenous hormones guanylin (GUCA2A) and uroguanylin (GUCA2B), which bind and activate GUCY2C to regulate proliferation, metabolism and barrier function in intestine. Recent studies have demonstrated a link between GUCY2C silencing and intestinal dysfunction, including tumorigenesis. Indeed, GUCY2C silencing by the near universal loss of its paracrine hormone ligands increases colon cancer susceptibility in animals and humans. GUCY2C’s role as a tumor suppressor has opened the door to a new paradigm for CRC prevention by hormone replacement therapy using synthetic hormone analogs, such as the FDA-approved oral GUCY2C ligand linaclotide (Linzess™). Here we review the known contributions of the GUCY2C signaling axis to CRC, and relate them to a novel clinical strategy targeting tumor chemoprevention.

No MeSH data available.


Related in: MedlinePlus

Guanylyl cyclase C receptor signaling, silencing, and reactivation. Ligand-mediated (guanylin and uroguanylin) activation of GUCY2C in the intestinal epithelial cell leads to accumulation of cGMP. This results in the maintenance of homeostatic mechanism, including regulated proliferation, barrier integrity, and proper cellular metabolism. Silencing of GUCY2C signaling by loss of hormone ligands leads to changes including increased glycolysis, increased proliferation, and a leaky intestinal barrier, all associated with colorectal tumorigenesis. These tumorigenic pathways potentially can be regulated with hormone replacement by oral supplementation with the analog linaclotide which restores GUCY2C signaling to re-establish homeostasis. GUCY2C: Guanylyl cyclase C; cGMP: Cyclic guanosine monophosphate.
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Figure 1: Guanylyl cyclase C receptor signaling, silencing, and reactivation. Ligand-mediated (guanylin and uroguanylin) activation of GUCY2C in the intestinal epithelial cell leads to accumulation of cGMP. This results in the maintenance of homeostatic mechanism, including regulated proliferation, barrier integrity, and proper cellular metabolism. Silencing of GUCY2C signaling by loss of hormone ligands leads to changes including increased glycolysis, increased proliferation, and a leaky intestinal barrier, all associated with colorectal tumorigenesis. These tumorigenic pathways potentially can be regulated with hormone replacement by oral supplementation with the analog linaclotide which restores GUCY2C signaling to re-establish homeostasis. GUCY2C: Guanylyl cyclase C; cGMP: Cyclic guanosine monophosphate.

Mentions: Hormone deficiencies underlie a number of debilitating human diseases, including diabetes, thyroid disorders, and more recently CRC[13]: Guanylin is significantly decreased (100- to 1000 fold) in nearly 90% of all CRC tumors colorectal tumors when compared to adjacent normal mucosa[43]. The observation of a loss of guanylin expression in human colorectal tumors coupled with the potentiation of tumorigenesis observed in GUCY2C knockout mice supports a hypothesis suggesting that CRC initiates as a disease of hormone insufficiency and offers the possibility of a new paradigm for CRC treatment[13,44,59]. Importantly, although loss of the GUCY2C ligands guanylin and uroguanylin occur early in tumor development, GUCY2C receptor expression persists in CRC[60-62]. This suggests that the receptor is latent and that signaling can be reconstituted by ligand supplementation similar to other diseases of hormone deficiency in which reactivation of signaling using synthetic ligand analogs have been therapeutic (Figure 1).


Guanylyl cyclase C signaling axis and colon cancer prevention
Guanylyl cyclase C receptor signaling, silencing, and reactivation. Ligand-mediated (guanylin and uroguanylin) activation of GUCY2C in the intestinal epithelial cell leads to accumulation of cGMP. This results in the maintenance of homeostatic mechanism, including regulated proliferation, barrier integrity, and proper cellular metabolism. Silencing of GUCY2C signaling by loss of hormone ligands leads to changes including increased glycolysis, increased proliferation, and a leaky intestinal barrier, all associated with colorectal tumorigenesis. These tumorigenic pathways potentially can be regulated with hormone replacement by oral supplementation with the analog linaclotide which restores GUCY2C signaling to re-establish homeostasis. GUCY2C: Guanylyl cyclase C; cGMP: Cyclic guanosine monophosphate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037076&req=5

Figure 1: Guanylyl cyclase C receptor signaling, silencing, and reactivation. Ligand-mediated (guanylin and uroguanylin) activation of GUCY2C in the intestinal epithelial cell leads to accumulation of cGMP. This results in the maintenance of homeostatic mechanism, including regulated proliferation, barrier integrity, and proper cellular metabolism. Silencing of GUCY2C signaling by loss of hormone ligands leads to changes including increased glycolysis, increased proliferation, and a leaky intestinal barrier, all associated with colorectal tumorigenesis. These tumorigenic pathways potentially can be regulated with hormone replacement by oral supplementation with the analog linaclotide which restores GUCY2C signaling to re-establish homeostasis. GUCY2C: Guanylyl cyclase C; cGMP: Cyclic guanosine monophosphate.
Mentions: Hormone deficiencies underlie a number of debilitating human diseases, including diabetes, thyroid disorders, and more recently CRC[13]: Guanylin is significantly decreased (100- to 1000 fold) in nearly 90% of all CRC tumors colorectal tumors when compared to adjacent normal mucosa[43]. The observation of a loss of guanylin expression in human colorectal tumors coupled with the potentiation of tumorigenesis observed in GUCY2C knockout mice supports a hypothesis suggesting that CRC initiates as a disease of hormone insufficiency and offers the possibility of a new paradigm for CRC treatment[13,44,59]. Importantly, although loss of the GUCY2C ligands guanylin and uroguanylin occur early in tumor development, GUCY2C receptor expression persists in CRC[60-62]. This suggests that the receptor is latent and that signaling can be reconstituted by ligand supplementation similar to other diseases of hormone deficiency in which reactivation of signaling using synthetic ligand analogs have been therapeutic (Figure 1).

View Article: PubMed Central - PubMed

ABSTRACT

Colorectal cancer (CRC) is a major cause of cancer-related mortality and morbidity worldwide. While improved treatments have enhanced overall patient outcome, disease burden encompassing quality of life, cost of care, and patient survival has seen little benefit. Consequently, additional advances in CRC treatments remain important, with an emphasis on preventative measures. Guanylyl cyclase C (GUCY2C), a transmembrane receptor expressed on intestinal epithelial cells, plays an important role in orchestrating intestinal homeostatic mechanisms. These effects are mediated by the endogenous hormones guanylin (GUCA2A) and uroguanylin (GUCA2B), which bind and activate GUCY2C to regulate proliferation, metabolism and barrier function in intestine. Recent studies have demonstrated a link between GUCY2C silencing and intestinal dysfunction, including tumorigenesis. Indeed, GUCY2C silencing by the near universal loss of its paracrine hormone ligands increases colon cancer susceptibility in animals and humans. GUCY2C’s role as a tumor suppressor has opened the door to a new paradigm for CRC prevention by hormone replacement therapy using synthetic hormone analogs, such as the FDA-approved oral GUCY2C ligand linaclotide (Linzess™). Here we review the known contributions of the GUCY2C signaling axis to CRC, and relate them to a novel clinical strategy targeting tumor chemoprevention.

No MeSH data available.


Related in: MedlinePlus