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Appetite Control in C. elegans
Published in Ruth B.S. Harris, Appetite and Food Intake, 2017
Kristen Davis, Mi Cheong Cheong, Ji Su Park, Young-Jai You
The cGMP signaling pathway is involved in many essential functions; it regulates phototransduction in the eyes, hypertension, reproduction, attention and hyperactive behavior, vasodilation, circadian rhythms, intestinal homeostasis, and cancer progression (Januszewicz 1995, Oster et al. 2003, Yau and Hardie 2009, Francis et al. 2010, Zhang et al. 2010, Gong et al. 2011, Arshad and Visweswariah 2012, Kim et al. 2013). In addition, it regulates body size, exploratory behavior, stress-induced development, sleep, and feeding in invertebrates (Fujiwara et al. 2002, Raizen et al. 2008, You et al. 2008). Its role in appetite control and obesity was first discovered in C. elegans and later in mammals (Valentino et al. 2011). In mammals, a gut peptide, uroguanylin, is released upon feeding and binds to GUCY2C, its receptor in the hypothalamus, to suppress feeding (Valentino et al. 2011). GUCY2C is a membrane guanylyl cyclase (GCY) that produces cGMP upon its activation. Interestingly, there are several previous studies that suggest cGMP functions in obesity. For instance, sildenafil, a medicine that inhibits degradation of cGMP to treat erectile dysfunction, has protective effects in weight gain on a high-fat diet (Ayala et al. 2007, Mitschke et al. 2013). NPs that bind to NP receptors (also GCYs) to produce cGMP are not only important to control blood pressure and heart function (Takei 2001) but also play an important role in lipolysis in adipose tissue via phosphorylation of hormone sensitive lipase by cGMP-dependent protein kinase (PKG) (Sengenes et al. 2000). Furthermore, epidemiological studies show that a certain allele of the NP receptor type C gene is associated with a lean phenotype (Sarzani et al. 2004), suggesting a critical role of NP in fat metabolism.
The shifting paradigm of colorectal cancer treatment: a look into emerging cancer stem cell-directed therapeutics to lead the charge toward complete remission
Published in Expert Opinion on Biological Therapy, 2021
Jessica Kopenhaver, Madison Crutcher, Scott A. Waldman, Adam E. Snook
As previously stated, GUCY2C is a tumor suppressor densely expressed in the apical brush border of intestinal epithelium and is a receptor for the peptides guanylin and uroguanylin [76]. In the healthy colorectum, GUCY2C signaling helps modulate luminal secretion, epithelial renewal along the crypt-villus axis, gastrointestinal barrier integrity, and injury response [77]. GUCY2C activation can regulate colon cell proliferation by inducing cell cycle arrest, while GUCY2C knockout mice display increased cell proliferation in colonic crypts [78]. GUCY2C is silenced by the loss of guanylin in CRC, which is thought to be mediated by mutant APC-β-catenin-Tcf signaling [48]. GUCY2C may also be used as a prognostic indicator; in one study, 87% of colorectal patients considered stage II were found to harbor occult metastases by GUCY2C molecular staging, which correlated with a more rapid recurrence [79]. It is plausible, therefore, that the upregulation of GUCY2C occurs not only in differentiated tumor cells, but in CSCs and/or MCSCs as well. Again, although the receptor alone is likely insufficient to isolate colorectal CSCs, GUCY2C could be used in conjunction with other markers to specifically identify intestinal CSCs, given that the CSC markers described above are not exclusive to colorectal CSCs.
Guanylyl cyclase 2C (GUCY2C) in gastrointestinal cancers: recent innovations and therapeutic potential
Published in Expert Opinion on Therapeutic Targets, 2021
Ariana A. Entezari, Adam E. Snook, Scott A. Waldman
GUCY2C, a transmembrane receptor that regulates fluid and electrolyte secretion in the intestine, is a novel target for GI cancers [55]. The loss of its activating hormones guanylin and uroguanylin early in colorectal tumorigenesis suggests that colorectal cancer, in part, may be a disease of paracrine hormone loss silencing the receptor, and may be reversible by ligand replacement therapy [18,56,63,71]. Furthermore, the restricted expression of GUCY2C to healthy intestinal cells and a subset of neurons, but widespread expression in primary and metastatic GI cancers, makes it an ideal diagnostic to improve the sensitivity and specificity of staging patients with GI cancers. This restricted expression also makes it a useful target for immunotherapies such as cancer vaccines and CAR-T cell therapy. In that context, there is an ongoing phase II clinical trial for the GUCY2C-targeted AD5.F35-GUCY2C-PADRE vaccine in patients with a history of GI malignancies (NCT04111172). Moreover, preclinical studies have revealed that GUCY2C targeted CAR-T cells are highly effective in eliminating colorectal cancer metastases in mice [118,119]. The potential impact of GUCY2C-targeted diagnostics and therapeutics can be appreciated by considering that, beyond colorectal cancer that has a 5 year survival of >60%, current therapies for GI cancers such as gastric, esophageal, and pancreatic cancer only provide 5-year relative survival rates of 32%, 21%, and 10%, respectively [15]. These considerations highlight the considerable unmet clinical need in those diseases that might be satisfied with GUCY2C-targeted strategies.
An update on guanylyl cyclase C in the diagnosis, chemoprevention, and treatment of colorectal cancer
Published in Expert Review of Clinical Pharmacology, 2020
Jeffrey A. Rappaport, Scott A. Waldman
The unique anatomic characteristics of GUCY2C make it an ideal antigenic target for cancer immunotherapies. As described above, GUCY2C is expressed primarily by the intestinal mucosa. The extracellular domain is distinct from other guanylyl cyclases and faces the lumen of the intestine, an ‘immune privileged’ site inaccessible by the systemic immune system. These key features limit the potential for autoimmune toxicity from GUCY2C-targeted agents in systemic circulation [93–95]. Furthermore, GUCY2C expression is retained throughout tumorigenesis, in the majority of molecular subtypes, and carried by metastatic cells to distal sites, making it a tumor-selective target antigen for recognition by the immune system [18–21]. These features serve to maximize the potential targetability of metastatic cells, while minimizing autoimmunity against normal tissue. Approaches to targeting GUCY2C fall into three major strategies: vaccines, adoptive T cell therapies, and immunotoxins.