Journal
HUMAN PATHOLOGY
Volume 87, Issue -, Pages 103-114Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1016/j.humpath.2018.11.032
Keywords
Serrated adenoma; Tubular adenoma; Colorectal cancer; Guanylin; Guanylate cyclase C; CDX2
Categories
Funding
- National Institutes of Health (NIH) [R01 CA204881, R01 CA206026, P30 CA56036]
- Targeted Diagnostics and Therapeutics, Inc
- PhRMA Foundations
- Margaret Q. Landenberg Foundation
- NIH [T32 GM008562]
- PhRMA Predoctoral Fellowship Award in Pharmacology/Toxicology
- NIH Ruth Kirschstein Individual Predoctoral MD/PhD Fellowship [F3ODK 103492, F30CA 232469]
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Colorectal cancers (CRCs) initiate through distinct mutations, including in APC pathway components leading to tubular adenomas (TAs); in BRAF, with epigenetic silencing of CDX2, leading to serrated adenomas (SAs); and in the DNA mismatch repair machinery driving microsatellite instability (MSI). Transformation through the APC pathway involves loss of the hormone GUCA2A that silences the tumor-suppressing receptor GUCY2C. Indeed, oral hormone replacement is an emerging strategy to reactivate GUCY2C and prevent CRC initiation and progression. Moreover, retained expression by tumors arising from TAs has established GUCY2C as a diagnostic and therapeutic target to prevent and treat metastatic CRC. Here, we defined the potential role of the GUCA2A-GUCY2C axis and its suitability as a target in tumors arising through the SA and MSI pathways. GUCA2A hormone expression was eliminated in TAs, SAs, and MSI tumors compared to their corresponding normal adjacent tissues. In contrast to the hormone, the tumor-suppressing receptor GUCY2C was retained in TA and MSI tumors. Surprisingly, GUCY2C expression was nearly eliminated in SAs, reflecting loss of the transcription factor CDX2. Changes in the GUCA2A-GUCY2C axis in human SAs and MSI tumors were precisely recapitulated in genetic mouse models. These data reveal the possibility of GUCA2A loss silencing GUCY2C in the pathophysiology of, and oral hormone replacement to restore GUCY2C signaling to prevent, MSI tumors. Also, they highlight the potential for targeting GUCY2C to prevent and treat metastases arising from TA and MSI tumors. In contrast, loss of GUCY2C excludes patients with SAs as candidates for GUCY2C-based prevention and therapy. (C) 2019 Elsevier Inc. All rights reserved.
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