Guanylyl Cyclase C Suppresses Intestinal Tumorigenesis by Restricting Proliferation and Maintaining Genomic Integrity

Background & Aims: The most commonly lost gene products in colorectal carcinogenesis include guanylin and uroguanylin, endogenous ligands for guanylyl cyclase C (GCC). Beyond intestinal fluid balance, GCC mediates diarrhea induced by bacterial enterotoxins, and an inverse relationship exists between enterotoxigenic Escherichia coli infections producing the exogenous GCC ligand ST and colorectal cancer worldwide. However, the role of GCC in neoplasia remains obscure. Methods: Intestinal tumorigenesis was examined in wild-type (Gcc+/+) and GCC-deficient (Gcc−/−) mice carrying mutations in Apc (ApcMin/+) or exposed to the carcinogen azoxymethane. Markers of DNA damage, loss of Apc heterozygosity, and β-catenin mutations were used to assess genomic integrity. Hyperproliferation was explored using Ki67 and cell cycle markers. Apoptosis was quantified by transferase biotin-dUTP nick end labeling analysis. Results: In colons of ApcMin/+ mice, deletion of Gcc increased tumor incidence and multiplicity, reflecting uncoupling of loss of genomic integrity and compensatory apoptosis. Conversely, in the small intestine, elimination of Gcc increased tumorigenesis by enhancing proliferation without altering genomic integrity. Moreover, these distinct but mutually reinforcing mechanisms collaborate in azoxymethane-exposed mice, and deletion of Gcc increased tumor initiation and growth associated with hypermutation and hyperproliferation, respectively, in conjunction with attenuated apoptosis. Conclusions: GCC suppresses tumor initiation and growth by maintaining genomic integrity and restricting proliferation. This previously unrecognized role of GCC in inhibiting tumorigenesis, together with the invariant disruption in guanylin and uroguanylin expression early in carcinogenesis, and the uniform over-expression of GCC by tumors, underscores the potential of oral administration of GCC ligands for targeted prevention and therapy of colorectal cancer. Background & Aims: The most commonly lost gene products in colorectal carcinogenesis include guanylin and uroguanylin, endogenous ligands for guanylyl cyclase C (GCC). Beyond intestinal fluid balance, GCC mediates diarrhea induced by bacterial enterotoxins, and an inverse relationship exists between enterotoxigenic Escherichia coli infections producing the exogenous GCC ligand ST and colorectal cancer worldwide. However, the role of GCC in neoplasia remains obscure. Methods: Intestinal tumorigenesis was examined in wild-type (Gcc+/+) and GCC-deficient (Gcc−/−) mice carrying mutations in Apc (ApcMin/+) or exposed to the carcinogen azoxymethane. Markers of DNA damage, loss of Apc heterozygosity, and β-catenin mutations were used to assess genomic integrity. Hyperproliferation was explored using Ki67 and cell cycle markers. Apoptosis was quantified by transferase biotin-dUTP nick end labeling analysis. Results: In colons of ApcMin/+ mice, deletion of Gcc increased tumor incidence and multiplicity, reflecting uncoupling of loss of genomic integrity and compensatory apoptosis. Conversely, in the small intestine, elimination of Gcc increased tumorigenesis by enhancing proliferation without altering genomic integrity. Moreover, these distinct but mutually reinforcing mechanisms collaborate in azoxymethane-exposed mice, and deletion of Gcc increased tumor initiation and growth associated with hypermutation and hyperproliferation, respectively, in conjunction with attenuated apoptosis. Conclusions: GCC suppresses tumor initiation and growth by maintaining genomic integrity and restricting proliferation. This previously unrecognized role of GCC in inhibiting tumorigenesis, together with the invariant disruption in guanylin and uroguanylin expression early in carcinogenesis, and the uniform over-expression of GCC by tumors, underscores the potential of oral administration of GCC ligands for targeted prevention and therapy of colorectal cancer. Guanylyl cyclase C (GCC) is the only defined receptor for bacterial heat-stable enterotoxins (STs), which cause secretory diarrhea in endemic populations, travelers, agriculturally important animal herds, and the endogenous ligands guanylin and uroguanylin.1Lucas K.A. Pitari G.M. Kazerounian S. Ruiz-Stewart I. Park J. Schulz S. Chepenik K.P. Waldman S.A. Guanylyl cyclases and signaling by cyclic GMP.Pharmacol Rev. 2000; 52: 375-414PubMed Google Scholar Beyond fluid and electrolyte secretion, GCC and its ligands regulate epithelial cell dynamics and the homeostatic balance of proliferation and differentiation that organizes the crypt-villus axis.2Li P, Lin JE, Chervoneva I, Schulz S, Waldman SA, Pitari GM. Homeostatic control of the crypt-villus axis by guanylyl cyclase C restricts the proliferating compartment in intestine. Submitted 2007.Google Scholar, 3Steinbrecher K.A. Wowk S.A. Rudolph J.A. Witte D.P. Cohen M.B. Targeted inactivation of the mouse guanylin gene results in altered dynamics of colonic epithelial proliferation.Am J Pathol. 2002; 161: 2169-2178Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Activation of GCC controls enterocyte progression through the cell cycle without imposing arrest.2Li P, Lin JE, Chervoneva I, Schulz S, Waldman SA, Pitari GM. Homeostatic control of the crypt-villus axis by guanylyl cyclase C restricts the proliferating compartment in intestine. Submitted 2007.Google Scholar This proliferative regulation by GCC coincides with the expression of guanylin and uroguanylin in the differentiated, but not proliferating, compartment along the crypt-villus axis.4Steinbrecher K.A. Tuohy T.M. Heppner Goss K. Scott M.C. Witte D.P. Groden J. Cohen M.B. Expression of guanylin is downregulated in mouse and human intestinal adenomas.Biochem Biophys Res Commun. 2000; 273: 225-230Crossref PubMed Scopus (67) Google Scholar Elimination of endogenous ligand3Steinbrecher K.A. Wowk S.A. Rudolph J.A. Witte D.P. Cohen M.B. Targeted inactivation of the mouse guanylin gene results in altered dynamics of colonic epithelial proliferation.Am J Pathol. 2002; 161: 2169-2178Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar or Gcc2Li P, Lin JE, Chervoneva I, Schulz S, Waldman SA, Pitari GM. Homeostatic control of the crypt-villus axis by guanylyl cyclase C restricts the proliferating compartment in intestine. Submitted 2007.Google Scholar expands the proliferating compartment, increasing the number of dividing crypt cells and their cell cycle rate, in part reflecting acceleration through G1-S, in the absence of spontaneous tumor formation. In the absence of GCC signaling, hyperplasia of crypt-villus units is prevented by compensatory increases in the migration of cells to the lumenal surface and apoptosis.2Li P, Lin JE, Chervoneva I, Schulz S, Waldman SA, Pitari GM. Homeostatic control of the crypt-villus axis by guanylyl cyclase C restricts the proliferating compartment in intestine. Submitted 2007.Google Scholar, 3Steinbrecher K.A. Wowk S.A. Rudolph J.A. Witte D.P. Cohen M.B. Targeted inactivation of the mouse guanylin gene results in altered dynamics of colonic epithelial proliferation.Am J Pathol. 2002; 161: 2169-2178Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 5Mann E.A. Steinbrecher K.A. Stroup C. Witte D.P. Cohen M.B. Giannella R.A. Lack of guanylyl cyclase C, the receptor for Escherichia coli heat-stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model.Int J Cancer. 2005; 116: 500-505Crossref PubMed Scopus (14) Google Scholar There is an underappreciated inverse relationship between the worldwide incidence of colorectal cancer and infections by ST-producing enterotoxigenic bacteria, with the incidence of colorectal cancer lowest in underdeveloped countries where enterotoxigenesis is greatest.6Shailubhai K. Yu H.H. Karunanandaa K. Wang J.Y. Eber S.L. Wang Y. Joo N.S. Kim H.D. Miedema B.W. Abbas S.Z. Boddupalli S.S. Currie M.G. Forte L.R. Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse and induces apoptosis in human colon adenocarcinoma cells via cyclic GMP.Cancer Res. 2000; 60: 5151-5157PubMed Google Scholar, 7Pitari G.M. Zingman L.V. Hodgson D.M. Alekseev A.E. Kazerounian S. Bienengraeber M. Hajnoczky G. Terzic A. Waldman S.A. Bacterial enterotoxins are associated with resistance to colon cancer.Proc Natl Acad Sci U S A. 2003; 100: 2695-2699Crossref PubMed Scopus (131) Google Scholar Like enterocytes, GCC signaling restricts colon cancer cell progression through the cell cycle.7Pitari G.M. Zingman L.V. Hodgson D.M. Alekseev A.E. Kazerounian S. Bienengraeber M. Hajnoczky G. Terzic A. Waldman S.A. Bacterial enterotoxins are associated with resistance to colon cancer.Proc Natl Acad Sci U S A. 2003; 100: 2695-2699Crossref PubMed Scopus (131) Google Scholar, 8Pitari G.M. Di Guglielmo M.D. Park J. Schulz S. Waldman S.A. Guanylyl cyclase C agonists regulate progression through the cell cycle of human colon carcinoma cells.Proc Natl Acad Sci U S A. 2001; 98: 7846-7851Crossref PubMed Scopus (139) Google Scholar Furthermore, expression of guanylin and uroguanylin is invariably lost early along the adenoma-carcinoma continuum in animals and humans.4Steinbrecher K.A. Tuohy T.M. Heppner Goss K. Scott M.C. Witte D.P. Groden J. Cohen M.B. Expression of guanylin is downregulated in mouse and human intestinal adenomas.Biochem Biophys Res Commun. 2000; 273: 225-230Crossref PubMed Scopus (67) Google Scholar, 9Notterman D.A. Alon U. Sierk A.J. Levine A.J. Transcriptional gene expression profiles of colorectal adenoma, adenocarcinoma, and normal tissue examined by oligonucleotide arrays.Cancer Res. 2001; 61: 3124-3130PubMed Google Scholar, 10Zhang L. Zhou W. Velculescu expression profiles in normal and cancer PubMed Scopus Google Scholar Moreover, oral administration of uroguanylin suppresses intestinal polyp formation and growth in ApcMin/+ K. Yu H.H. Karunanandaa K. Wang J.Y. Eber S.L. Wang Y. Joo N.S. Kim H.D. Miedema B.W. Abbas S.Z. Boddupalli S.S. Currie M.G. Forte L.R. Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse and induces apoptosis in human colon adenocarcinoma cells via cyclic GMP.Cancer Res. 2000; 60: 5151-5157PubMed Google Scholar tumor initiation and in the colon of GCC signaling and proliferative reflecting loss of ligand K.A. Tuohy T.M. Heppner Goss K. Scott M.C. Witte D.P. Groden J. Cohen M.B. Expression of guanylin is downregulated in mouse and human intestinal adenomas.Biochem Biophys Res Commun. 2000; 273: 225-230Crossref PubMed Scopus (67) Google Scholar, K. Yu H.H. Karunanandaa K. Wang J.Y. Eber S.L. Wang Y. Joo N.S. Kim H.D. Miedema B.W. Abbas S.Z. Boddupalli S.S. Currie M.G. Forte L.R. Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse and induces apoptosis in human colon adenocarcinoma cells via cyclic GMP.Cancer Res. 2000; 60: 5151-5157PubMed Google Scholar, 7Pitari G.M. Zingman L.V. Hodgson D.M. Alekseev A.E. Kazerounian S. Bienengraeber M. Hajnoczky G. Terzic A. Waldman S.A. Bacterial enterotoxins are associated with resistance to colon cancer.Proc Natl Acad Sci U S A. 2003; 100: 2695-2699Crossref PubMed Scopus (131) Google Scholar, 8Pitari G.M. Di Guglielmo M.D. Park J. Schulz S. Waldman S.A. Guanylyl cyclase C agonists regulate progression through the cell cycle of human colon carcinoma cells.Proc Natl Acad Sci U S A. 2001; 98: 7846-7851Crossref PubMed Scopus (139) Google Scholar In role for GCC tumor to the inverse between colorectal cancer and enterotoxigenesis in in underdeveloped countries to ST-producing K. Yu H.H. Karunanandaa K. Wang J.Y. Eber S.L. Wang Y. Joo N.S. Kim H.D. Miedema B.W. Abbas S.Z. Boddupalli S.S. Currie M.G. Forte L.R. Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse and induces apoptosis in human colon adenocarcinoma cells via cyclic GMP.Cancer Res. 2000; 60: 5151-5157PubMed Google Scholar, 7Pitari G.M. Zingman L.V. Hodgson D.M. Alekseev A.E. Kazerounian S. Bienengraeber M. Hajnoczky G. Terzic A. Waldman S.A. Bacterial enterotoxins are associated with resistance to colon cancer.Proc Natl Acad Sci U S A. 2003; 100: 2695-2699Crossref PubMed Scopus (131) Google Scholar these are role for GCC in intestinal tumorigenesis not E.A. Steinbrecher K.A. Stroup C. Witte D.P. Cohen M.B. Giannella R.A. Lack of guanylyl cyclase C, the receptor for Escherichia coli heat-stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model.Int J Cancer. 2005; 116: 500-505Crossref PubMed Scopus (14) Google Scholar mice using S. 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Homeostatic control of the crypt-villus axis by guanylyl cyclase C restricts the proliferating compartment in intestine. Submitted 2007.Google Scholar, 3Steinbrecher K.A. Wowk S.A. Rudolph J.A. Witte D.P. Cohen M.B. Targeted inactivation of the mouse guanylin gene results in altered dynamics of colonic epithelial proliferation.Am J Pathol. 2002; 161: 2169-2178Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar that increased tumorigenesis in mice in tumor initiation and However, increased multiplicity, but not of of to tumorigenesis in colons of Apc mutations are associated with over-expression of β-catenin in with normal in ApcMin/+ mice in proliferation of was in and mice and to and mice were in the expression of cell cycle in normal colonic tissue and mice elimination of Gcc increased DNA in of mice and that in of ApcMin/+ mice, quantified using of DNA reflecting disruption of DNA integrity and of PubMed Scopus Google Scholar of the Apc C. S. of in intestinal Res. Google Scholar, C. K.A. W. of multiple intestinal neoplasia (Min) to of the PubMed Scopus Google Scholar in of mice but in only of mice associated with deletion of Gcc genomic or induced by DNA M. Intestinal with and Natl Acad Sci U S A. 2002; PubMed Scopus Google Scholar Moreover, increased DNA induced by deletion of Gcc was compensatory cell induced in mice by loss of GCC P, Lin JE, Chervoneva I, Schulz S, Waldman SA, Pitari GM. Homeostatic control of the crypt-villus axis by guanylyl cyclase C restricts the proliferating compartment in intestine. Submitted 2007.Google Scholar and were in in ApcMin/+ mice tumorigenesis in colons of mice the of genomic by in the of apoptosis associated with mutations in Apoptosis and in colorectal Natl Acad Sci U S A. 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Targeted inactivation of the mouse guanylin gene results in altered dynamics of colonic epithelial proliferation.Am J Pathol. 2002; 161: 2169-2178Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar and by Apoptosis and in colorectal Natl Acad Sci U S A. PubMed Scopus Google Scholar, that to the cell of colon Res. 2001; 61: Google Scholar without an in tumor initiation associated with DNA in colons of mice with increased tumor and of and DNA to Hyperproliferation in and was in mice, by the over-expression of cell cycle Furthermore, is by DNA in and not in and mice and induces mutations in β-catenin which its M. S. K. mutations of the gene in mouse colon induced by 2000; PubMed Google Scholar induced β-catenin in in to normal elimination of Gcc increased the of mutations in in that Furthermore, cell in and in compensatory apoptosis induced by loss of GCC P, Lin JE, Chervoneva I, Schulz S, Waldman SA, Pitari GM. Homeostatic control of the crypt-villus axis by guanylyl cyclase C restricts the proliferating compartment in intestine. Submitted 2007.Google Scholar tumor initiation and in mice mutually reinforcing of and apoptosis in the absence of the ligands for GCC are lost early in K.A. Tuohy T.M. Heppner Goss K. Scott M.C. Witte D.P. Groden J. Cohen M.B. Expression of guanylin is downregulated in mouse and human intestinal adenomas.Biochem Biophys Res Commun. 2000; 273: 225-230Crossref PubMed Scopus (67) Google Scholar, 9Notterman D.A. Alon U. Sierk A.J. Levine A.J. Transcriptional gene expression profiles of colorectal adenoma, adenocarcinoma, and normal tissue examined by oligonucleotide arrays.Cancer Res. 2001; 61: 3124-3130PubMed Google Scholar, 10Zhang L. Zhou W. Velculescu expression profiles in normal and cancer PubMed Scopus Google Scholar the of the in GCC signaling to colorectal carcinogenesis remains E.A. Steinbrecher K.A. Stroup C. Witte D.P. Cohen M.B. Giannella R.A. Lack of guanylyl cyclase C, the receptor for Escherichia coli heat-stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model.Int J Cancer. 2005; 116: 500-505Crossref PubMed Scopus (14) Google Scholar GCC intestinal tumorigenesis associated with carcinogen and mutations through distinct mechanisms proliferation and genomic integrity. of these in the of tumor initiation in the colon and growth in the small of ApcMin/+ mice with the proliferation and genomic integrity and to K. Y. S. M. by in 2003; PubMed Scopus Google Scholar In the the role of GCC and its ligands in the crypt-villus restricting the of the crypt compartment, the number of cells proliferating, and the of the cell cycle through the P, Lin JE, Chervoneva I, Schulz S, Waldman SA, Pitari GM. Homeostatic control of the crypt-villus axis by guanylyl cyclase C restricts the proliferating compartment in intestine. Submitted 2007.Google Scholar, 3Steinbrecher K.A. Wowk S.A. Rudolph J.A. Witte D.P. Cohen M.B. Targeted inactivation of the mouse guanylin gene results in altered dynamics of colonic epithelial proliferation.Am J Pathol. 2002; 161: 2169-2178Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Beyond the potential for progression through and S is associated with of K. Y. S. M. by in 2003; PubMed Scopus Google Scholar, K.A. induces PubMed Scopus Google Scholar In to role for GCC in maintaining genomic integrity was previously tumorigenesis of of reinforcing in loss of genomic and the of homeostatic proliferation and K. Y. S. M. by in 2003; PubMed Scopus Google Scholar, K.A. induces PubMed Scopus Google Scholar, M.B. J. and PubMed Scopus Google Scholar, J. control and PubMed Scopus Google Scholar The of GCC signaling to of the and and the associated of remains to M.B. 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Steinbrecher K.A. Stroup C. Witte D.P. Cohen M.B. Giannella R.A. Lack of guanylyl cyclase C, the receptor for Escherichia coli heat-stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model.Int J Cancer. 2005; 116: 500-505Crossref PubMed Scopus (14) Google Scholar were in in the the small and colon were mechanisms tumorigenesis in these K. Y. S. M. by in 2003; PubMed Scopus Google Scholar The of these distinct in the the of colon tumorigenesis in the absence of the of are by the small in ApcMin/+ the of the loss of guanylin and uroguanylin expression early in progression to colorectal cancer in animals and humans.4Steinbrecher K.A. Tuohy T.M. Heppner Goss K. Scott M.C. Witte D.P. Groden J. Cohen M.B. Expression of guanylin is downregulated in mouse and human intestinal adenomas.Biochem Biophys Res Commun. 2000; 273: 225-230Crossref PubMed Scopus (67) Google Scholar, 9Notterman D.A. Alon U. Sierk A.J. Levine A.J. Transcriptional gene expression profiles of colorectal adenoma, adenocarcinoma, and normal tissue examined by oligonucleotide arrays.Cancer Res. 2001; 61: 3124-3130PubMed Google Scholar, 10Zhang L. Zhou W. Velculescu expression profiles in normal and cancer PubMed Scopus Google Scholar that loss of ligand expression and of GCC signaling is initiation and progression of intestinal In guanylin and uroguanylin are in and their loss early in Zhou W. C. that an early of colorectal Res. 2001; 61: Google Scholar, K. M. A. the of and expression of the gene in cell carcinoma of the oral J 2002; Google Scholar or K. K. K. M. Y. M. S. M. for by in colorectal for J 2005; Google Scholar In that the of early in its role in K. Y. S. M. by in 2003; PubMed Scopus Google Scholar K. Y. S. M. by in 2003; PubMed Scopus Google Scholar, J. C. M. C. C. J. in the gene cause 2001; PubMed Scopus Google Scholar and Apoptosis and in colorectal Natl Acad Sci U S A. 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Waldman S.A. to by of guanylyl cyclase C in with colorectal Res. PubMed Scopus Google Scholar, K. J. Schulz S. Waldman S.A. The tumor is by human colorectal Res. 2005; PubMed Scopus Google Scholar, Schulz S. Waldman S.A. Guanylyl cyclase C is of intestinal and adenocarcinoma of the 2005; Full Text Full Text PDF PubMed Scopus Google Scholar these previously in which initiation of colorectal cancer of in receptor (GCC) In the of the of in which are by these the potential of oral of GCC ligands for targeted prevention and therapy of colorectal K. Yu H.H. Karunanandaa K. Wang J.Y. Eber S.L. Wang Y. Joo N.S. Kim H.D. Miedema B.W. Abbas S.Z. Boddupalli S.S. Currie M.G. Forte L.R. 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