Abstract
The accumulation of genetic and epigenetic alterations mediates colorectal cancer (CRC) formation by deregulating key signaling pathways in cancer cells. In CRC, one of the most commonly inactivated signaling pathways is the transforming growth factor-beta (TGF-β) signaling pathway, which is often inactivated by mutations of TGF-β type II receptor (TGFBR2). Another commonly deregulated pathway in CRC is the phosphoinositide-3-kinase (PI3K)-AKT pathway. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is an important negative regulator of PI3K-AKT signaling and is silenced in ∼30% of CRC. The combination of TGFBR2 inactivation and loss of PTEN is particularly common in microsatellite-unstable CRCs. Consequently, we determined in vivo if deregulation of these two pathways cooperates to affect CRC formation by analyzing tumors arising in mice that lack Tgfbr2 and/or Pten specifically in the intestinal epithelium. We found that lack of Tgfbr2 (Tgfbr2IEKO) alone is not sufficient for intestinal tumor formation and lack of Pten (PtenIEKO) alone had a weak effect on intestinal tumor induction. However, the combination of Tgfbr2 inactivation with Pten loss (PtenIEKO;Tgfbr2IEKO) led to malignant tumors in both the small intestine and colon in 86% of the mice and to metastases in 8% of the tumor-bearing mice. Moreover, these tumors arose via a β-catenin-independent mechanism. Inactivation of TGF-β signaling and loss of Pten in the tumors led to increased cell proliferation, decreased apoptosis and decreased expression of cyclin-dependent kinase inhibitors. Thus, inactivation of TGF-β signaling and loss of PTEN cooperate to drive intestinal cancer formation and progression by suppressing cell cycle inhibitors.
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Abbreviations
- ACA:
-
adenocarcinoma
- CRC:
-
colorectal cancer
- CDK:
-
cyclin-dependent kinase
- Dcr2:
-
decoy receptor of the TNF-related factor TRAIL
- ERK:
-
extracellular signal-regulated kinase
- MAPK:
-
mitogen-activated protein kinase
- MSI:
-
microsatellite instability
- PTEN :
-
phosphatase and tensin homolog deleted on chromosome 10
- qRT–PCR:
-
real-time quantitative reverse transcription polymerase chain reaction
- TGF-β:
-
transforming growth factor-beta
- TGFBR1:
-
transforming growth factor-beta type I receptor
- TGFBR2:
-
transforming growth factor-beta type II receptor.
References
Siegel R, Naishadham D, Jemal A . Cancer statistics, 2012. CA Cancer J Clin 2012; 62: 10–29.
Kinzler KW, Vogelstein B . Lessons from hereditary colorectal cancer. Cell 1996; 87: 159–170.
Su LK, Kinzler KW, Vogelstein B, Preisinger AC, Moser AR, Luongo C et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 1992; 256: 668–670.
Levy DB, Smith KJ, Beazer-Barclay Y, Hamilton SR, Vogelstein B, Kinzler KW . Inactivation of both APC alleles in human and mouse tumors. Cancer Res 1994; 54: 5953–5958.
Samowitz WS, Powers MD, Spirio LN, Nollet F, van Roy F, Slattery ML . Beta-catenin mutations are more frequent in small colorectal adenomas than in larger adenomas and invasive carcinomas. Cancer Res 1999; 59: 1442–1444.
Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988; 319: 525–532.
Parsons DW, Wang TL, Samuels Y, Bardelli A, Cummins JM, DeLong L et al. Colorectal cancer: mutations in a signalling pathway. Nature 2005; 436: 792.
Pritchard CC, Grady WM . Colorectal cancer molecular biology moves into clinical practice. Gut 2011; 60: 116–129.
Grady WM, Carethers JM . Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 2008; 135: 1079–1099.
Jass JR . Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 2007; 50: 113–130.
Liu XQ, Rajput A, Geng L, Ongchin M, Chaudhuri A, Wang J . Restoration of transforming growth factor-beta receptor II expression in colon cancer cells with microsatellite instability increases metastatic potential in vivo. J Biol Chem 2011; 286: 16082–16090.
Liu P, Cheng H, Roberts TM, Zhao JJ . Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009; 8: 627–644.
Luo J, Manning BD, Cantley LC . Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 2003; 4: 257–262.
Engelman JA . Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Rev Cancer 2009; 9: 550–562.
Maehama T, Dixon JE . The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998; 273: 13375–13378.
Di Cristofano A, Pandolfi PP . The multiple roles of PTEN in tumor suppression. Cell 2000; 100: 387–390.
Naguib A, Cooke JC, Happerfield L, Kerr L, Gay LJ, Luben RN et al. Alterations in PTEN and PIK3CA in colorectal cancers in the EPIC Norfolk study: associations with clinicopathological and dietary factors. BMC Cancer 2011; 11: 123.
Zhou XP, Loukola A, Salovaara R, Nystrom-Lahti M, Peltomaki P, de la Chapelle A et al. PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers. AmJ Pathol 2002; 161: 439–447.
Shin I, Bakin AV, Rodeck U, Brunet A, Arteaga CL . Transforming growth factor beta enhances epithelial cell survival via Akt-dependent regulation of FKHRL1. Mol Biol Cell 2001; 12: 3328–3339.
Fearon ER . Molecular genetics of colorectal cancer. Ann Rev Pathol 6: 479–507.
Song MS, Salmena L, Pandolfi PP . The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 2012; 13: 283–296.
Shen WH, Balajee AS, Wang J, Wu H, Eng C, Pandolfi PP et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 2007; 128: 157–170.
Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 2005; 436: 725–730.
Alimonti A, Nardella C, Chen Z, Clohessy JG, Carracedo A, Trotman LC et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J Clin Invest 2010; 120: 681–693.
Massague J, Blain SW, Lo RS . TGF[beta] signaling in growth control, cancer, and heritable disorders. Cell 2000; 103: 295.
Cancer Genome Atlas Network, Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487: 330–337.
Grady W, Rajput A, Myeroff L, Liu D, Kwon K-H, Willis J et al. Mutation of the type II transforming growth factor-ß receptor is coincident with the transformation of human colon adenomas to malignant carcinomas. Cancer Res 1998; 58: 3101–3104.
Grady W, Myeroff L, Swinler S, Rajput A, Thiagalingam S, Lutterbaugh J et al. Mutational inactivation of transforming growth factor ß receptor type II in microsatellite stable colon cancers. Cancer Res 1999; 59: 320–324.
Bierie B, Moses HL . Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 2006; 6: 506–520.
Grady W, Markowitz SD . TGF-ß signaling pathway and tumor suppression. In: Derynck R, Miyazano K (eds). The TGF-ß Family. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, USA, 2008, pp 889–938.
Biswas S, Chytil A, Washington K, Romero-Gallo J, Gorska AE, Wirth PS et al. Transforming growth factor beta receptor type II inactivation promotes the establishment and progression of colon cancer. Cancer Res 2004; 64: 4687–4692.
Akhurst RJ, Derynck R . TGF-beta signaling in cancer—a double-edged sword. Trends Cell Biol 2001; 11: S44–S51.
Munoz NM, Upton M, Rojas A, Washington MK, Lin L, Chytil A et al. Transforming growth factor beta receptor type II inactivation induces the malignant transformation of intestinal neoplasms initiated by Apc mutation. Cancer Res 2006; 66: 9837–9844.
Trobridge P, Knoblaugh S, Washington MK, Munoz NM, Tsuchiya KD, Rojas A et al. TGF-beta receptor inactivation and mutant Kras induce intestinal neoplasms in mice via a beta-catenin-independent pathway. Gastroenterology 2009; 136: 1680–1688 e7.
Marsh V, Winton DJ, Williams GT, Dubois N, Trumpp A, Sansom OJ et al. Epithelial Pten is dispensable for intestinal homeostasis but suppresses adenoma development and progression after Apc mutation. Nat Genet 2008; 40: 1436–1444.
Byun DS, Ahmed N, Nasser S, Shin J, Al-Obaidi S, Goel S et al. Intestinal epithelial-specific PTEN inactivation results in tumor formation. Am J Physiology 2011; 301: G856–G864.
Chittenden TW, Howe EA, Culhane AC, Sultana R, Taylor JM, Holmes C et al. Functional classification analysis of somatically mutated genes in human breast and colorectal cancers. Genomics 2008; 91: 508–511.
Lesche R, Groszer M, Gao J, Wang Y, Messing A, Sun H et al. Cre/loxP-mediated inactivation of the murine Pten tumor suppressor gene. Genesis 2002; 32: 148–149.
Yilmaz M, Christofori G . Mechanisms of motility in metastasizing cells. Mol Cancer Res 2010; 8: 629–642.
Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL . Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem 2000; 275: 36803–36810.
Gomes LR, Terra LF, Wailemann RA, Labriola L, Sogayar MC . TGF-beta1 modulates the homeostasis between MMPs and MMP inhibitors through p38 MAPK and ERK1/2 in highly invasive breast cancer cells. BMC Cancer 2012; 12: 26.
Langlois MJ, Roy SA, Auclair BA, Jones C, Boudreau F, Carrier JC et al. Epithelial phosphatase and tensin homolog regulates intestinal architecture and secretory cell commitment and acts as a modifier gene in neoplasia. Faseb J 2009; 23: 1835–1844.
He XC, Zhang J, Tong WG, Tawfik O, Ross J, Scoville DH et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat Genet 2004; 36: 1117–1121.
Wielenga VJ, Smits R, Korinek V, Smit L, Kielman M, Fodde R et al. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. Am J Pathol 1999; 154: 515–523.
Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U et al. Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol 2002; 22: 1184–1193.
Muncan V, Sansom OJ, Tertoolen L, Phesse TJ, Begthel H, Sancho E et al. Rapid loss of intestinal crypts upon conditional deletion of the Wnt/Tcf-4 target gene c-Myc. Mol Cell Biol 2006; 26: 8418–8426.
Glick AB, Weinberg WC, Wu I-H, Quan W, Yuspa SH . TGF-ß1 suppresses genomic instability downstream of a G1 arrest by a p53 and Rb independent pathway. Cell 1996; 56: 3645–3650.
Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K et al. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 2002; 8: 1153–1160.
Massague J . TGFbeta in cancer. Cell 2008; 134: 215–230.
Moses H, Yang E, Pietenpol J . TGF-ß stimulation and inhibition of cell proliferation: new mechanistic insights. Cell 1990; 63: 245–247.
Chu IM, Hengst L, Slingerland JM . The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer 2008; 8: 253–267.
Abbas T, Dutta A . p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 2009; 9: 400–414.
Lee MH, Yang HY . Negative regulators of cyclin-dependent kinases and their roles in cancers. Cell Mol Life Sci 2001; 58: 1907–1922.
Shin KH, Park YJ, Park JG . PTEN gene mutations in colorectal cancers displaying microsatellite instability. Cancer Lett 2001; 174: 189–194.
Datto MB, Yu Y, Wang XF . Functional analysis of the transforming growth factor beta responsive elements in the WAF1/Cip1/p21 promoter. J Biol Chem 1995; 270: 28623–28628.
Philp AJ, Campbell IG, Leet C, Vincan E, Rockman SP, Whitehead RH et al. The phosphatidylinositol 3'-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res 2001; 61: 7426–7429.
Roy HK, Olusola BF, Clemens DL, Karolski WJ, Ratashak A, Lynch HT et al. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis 2002; 23: 201–205.
Byun DS, Ahmed N, Nasser S, Shin J, Al-Obaidi S, Goel S et al. Intestinal epithelial-specific PTEN inactivation results in tumor formation. Am J Physiol Gastrointest Liver Physiol 2011; 301: G856–G864.
Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 1998; 95: 29–39.
Leystra AA, Deming DA, Zahm CD, Farhoud M, Olson TJ, Hadac JN et al. Mice expressing activated PI3K rapidly develop advanced colon cancer. Cancer Res 2012; 72: 2931–2936.
Grady WM, Willis JE, Trobridge P, Romero-Gallo J, Munoz N, Olechnowicz J et al. Proliferation and Cdk4 expression in microsatellite unstable colon cancers with TGFBR2 mutations. Int J Cancer 2006; 118: 600–608.
Jaiswal BS, Janakiraman V, Kljavin NM, Chaudhuri S, Stern HM, Wang W et al. Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation. Cancer Cell 2009; 16: 463–474.
Panopoulou E, Murphy C, Rasmussen H, Bagli E, Rofstad EK, Fotsis T . Activin A suppresses neuroblastoma xenograft tumor growth via antimitotic and antiangiogenic mechanisms. Cancer Res 2005; 65: 1877–1886.
Jung B, Doctolero RT, Tajima A, Nguyen AK, Keku T, Sandler RS et al. Loss of activin receptor type 2 protein expression in microsatellite unstable colon cancers. Gastroenterology 2004; 126: 654–659.
Bauer J, Sporn JC, Cabral J, Gomez J, Jung B . Effects of activin and TGFbeta on p21 in colon cancer. PloS One 2012; 7: e39381.
Chen CN, Lin JJ, Chen JJ, Lee PH, Yang CY, Kuo ML et al. Gene expression profile predicts patient survival of gastric cancer after surgical resection. J Clin Oncol 2005; 23: 7286–7295.
Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M et al. Tumour biology: senescence in premalignant tumours. Nature 2005; 436: 642.
Young LC, Listgarten J, Trotter MJ, Andrew SE, Tron VA . Evidence that dysregulated DNA mismatch repair characterizes human nonmelanoma skin cancer. Br J Dermatol 2008; 158: 59–69.
Majumder PK, Grisanzio C, O'Connell F, Barry M, Brito JM, Xu Q et al. A prostatic intraepithelial neoplasia-dependent p27 Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression. Cancer Cell 2008; 14: 146–155.
Ise K, Nakamura K, Nakao K, Shimizu S, Harada H, Ichise T et al. Targeted deletion of the H-ras gene decreases tumor formation in mouse skin carcinogenesis. Oncogene 2000; 19: 2951–2956.
Acknowledgements
Support for these studies was provided by the NIH (RO1CA115513, P30CA15704, UO1CA152756, U54CA143862, and P01CA077852 WMG), a Burroughs Wellcome Fund Translational Research Award for Clinician Scientist (WMG), and an Interdisciplinary Training in Cancer Research Grant (T32 CA080416 SMM).
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Yu, M., Trobridge, P., Wang, Y. et al. Inactivation of TGF-β signaling and loss of PTEN cooperate to induce colon cancer in vivo. Oncogene 33, 1538–1547 (2014). https://doi.org/10.1038/onc.2013.102
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DOI: https://doi.org/10.1038/onc.2013.102
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