Cyclic-GMP-elevating agents suppress polyposis in Apc Min mice by targeting the preneoplastic epithelium

Sarah K. Sharman, Bianca N. Islam, Yali Hou, Nagendra Singh, Franklin G. Berger, Subbaramiah Sridhar, Wonsuk Yoo, Darren D Browning

Research output: Contribution to journalArticle

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Abstract

The cGMP signaling axis has been implicated in the suppression of intestinal cancers, but the inhibitory mechanism and the extent to which this pathway can be targeted remains poorly understood. This study has tested the effect of cGMP-elevating agents on tumorigenesis in the Apc Min/+ mouse model of intestinal cancer. Treatment of Apc Min/+ mice with the receptor guanylylcyclase C (GCC) agonist linaclotide, or the phosphodiesterase- 5 (PDE5) inhibitor sildenafil, significantly reduced the number of polyps per mouse (67% and 50%, respectively). Neither of the drugs affectedmean polyp size, or the rates of apoptosis and proliferation. This was possibly due to increased PDE10 expression, as endogenous GCC ligands were not deficient in established polyps. These results indicated that the ability of these drugs to reduce polyp multiplicity was primarily due to an effect on nonneoplastic tissues. In support of this idea, Apc Min/+ mice exhibited reduced levels of endogenous GCC agonists in the nonneoplastic intestinal mucosa compared with wildtype animals, and this was associated with crypt hyperplasia and a loss of goblet cells. Administration of either sildenafil or linaclotide suppressed proliferation, and increased both goblet cell numbers and luminal apoptosis in the intestinal mucosa. Taken together, the results demonstrate that targeting cGMP with either PDE5 inhibitors or GCC agonists alters epithelial homeostasis in a manner that reduces neoplasia, and suggests that this could be a viable chemoprevention strategy for patients at high risk of developing colorectal cancer. Cancer Prev Res; 11(2); 81-92.

Original languageEnglish (US)
Pages (from-to)81-91
Number of pages11
JournalCancer Prevention Research
Volume11
Issue number2
DOIs
StatePublished - Feb 1 2018

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Cyclic GMP
Polyps
Epithelium
Intestinal Neoplasms
Phosphodiesterase 5 Inhibitors
Goblet Cells
Intestinal Mucosa
Apoptosis
Chemoprevention
Pharmaceutical Preparations
Hyperplasia
Colorectal Neoplasms
Neoplasms
Carcinogenesis
Homeostasis
Cell Count
Ligands
Sildenafil Citrate
linaclotide
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cyclic-GMP-elevating agents suppress polyposis in Apc Min mice by targeting the preneoplastic epithelium . / Sharman, Sarah K.; Islam, Bianca N.; Hou, Yali; Singh, Nagendra; Berger, Franklin G.; Sridhar, Subbaramiah; Yoo, Wonsuk; Browning, Darren D.

In: Cancer Prevention Research, Vol. 11, No. 2, 01.02.2018, p. 81-91.

Research output: Contribution to journalArticle

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