Skip Navigation LinksHome > October 2007 - Volume 2 - Issue 10 > Role of the Wnt Signaling Pathway and Lung Cancer
Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e318153fdb1
Pathway of the Month

Role of the Wnt Signaling Pathway and Lung Cancer

Tennis, Meredith†; Van Scoyk, Michelle†; Winn, Robert A.*†

Free Access
Article Outline
Collapse Box

Author Information

*Department of Medicine, University of Colorado at Denver and Health Sciences Center (UCDHSC); and †Veterans Administration Medical Center, Denver, Colorado

Address for correspondence: Robert A. Winn, MD, Division of Pulmonary and Critical Care Medicine, University of Colorado at Denver and Health Sciences Center 4200 E. Ninth Ave., Denver, CO 80262, Phone: (303) 315-0011, Fax: (303) 315-0470; Email:

The Wnt pathway plays an important role in development and in regulating adult stem cell systems. A variety of cellular processes are mediated by Wnt signaling, including proliferation, differentiation, survival, apoptosis and cell motility.1 Loss of regulation of these pathways can lead to tumorigenesis and the Wnt pathway has been implicated in the development of several types of cancers, including colon, lung, leukemia, breast, thyroid, and prostate.2–6

Back to Top | Article Outline


Wnts are a family of secreted glycoproteins with varying expression patterns and a range of functions. Four signaling pathways are typically described for Wnt proteins. The canonical Wnt-β catenin pathway, through which β-catenin dependent activity occurs, the polar cell polarity (PCP) pathway, involving activation of AP1 through JNK, an atypical receptor tyrosine kinase (RTK) pathway, and the Ca2+ pathway, which activates protein kinase C and affects cell adhesion.7 In the unstimulated canonical pathway, β-catenin is phosphorylated by glycogen synthase kinase (GSK-3) in a complex that includes adenomatous polyposis coli (APC) and axin.8 Phosphorylation targets β-catenin for ubiquitin-mediated degredation and results in decreased levels of cytosolic β-catenin (Table 1).

Table 1
Table 1
Image Tools

Binding by the Wnt ligant to the frizzled (Fzd) receptors are complexed with low density lipoprotein receptor related protein (LRP) resulting in inhibition of the GSK-3/APC/Axin complex by Disheveled (Dvl). β-catenin is not phosphorylated by the complex and accumulates in the cytoplasm where it is translocated to the nucleus and regulates gene expression through a complex with Tcf and Lef.7 In the noncanonical pathways, signaling is conducted independent of β-catenin, though there may be similar components upstream of Fzd. The activity of different Wnt proteins is dependent on the receptor context, making strict classification of Wnts as canonical or noncanonical very challenging9 (Figure 1).

Figure 1
Figure 1
Image Tools

Fzd receptors are involved in canonical and noncanonical Wnt signaling by binding Wnt at a CRD region and have been shown to specify downstream activity through G-proteins. Binding of the LRP receptor to Fzd, however, occurs only in the canonical pathway.10 Other Wnt pathway receptors include atypical RTKs Ror and Ryk. Several ligands not structurally related to Wnt also influence the Wnt signaling pathway, including antagonists sFRP, DKK, SOST, and agonists Norrin and R-spondin.11

Back to Top | Article Outline


Wnt signaling appears to regulate cell fate and differentiation in early embryogenesis through several components that are present in the developing lung.12 Wnt production may be specific to cell type, such as Wnt 2 in the mesenchyme, Wnt 7b in the epithelium, and Wnt 11 in both locations.8 Wnt 7b has been shown to be regulated by Thyroid Transcription Factor-1, which is important for differentiation of alveolar epithelial cells.13 Other Wnt pathway components, such as Frizzled and Tcf, have been detected in specific patterns in the developing lung.14 Wnt 7b null mice have hypoplastic lungs and impaired alveolar type I cell differentiation.15 Wnt 5a is expressed in the lung epithelium and mesenchyme early development at the distal tips. Loss of Wnt 5a in mice results in increased proliferation in the epithelium and mesenchymal compartments, increased distal branching, and thickened interstitium.16 Wnt 5a null mice have increased expression of Sonic Hedgehog, a tightly regulated protein involved in branching morphogenesis, suggesting that Wnt 5a interacts with other signaling pathways in lung development. However, a model using targeted deletion of β-catenin suggests that disruption of Wnt signaling leads to decreased branching morphogenesis.17 Continued study is needed to clarify the role of Wnt signaling in branching morphogenesis. Wnt signaling may also play a role in apical-basal polarity and organogenesis, as changes in expression of polarity complex components have been found to affect Wnt signaling and the Wnt pathway itself may affect apical basal polarity.18

Back to Top | Article Outline


Much of the research done on the Wnt pathway and cancer has been done in colon tumors, however, recent work highlights a potentially significant role for Wnt pathway components in lung cancer. Wnt 1 and Wnt 2 are overexpressed in NSCLC and their inhibition leads to apoptosis.19 Wnt 7a is of particular interest, as its re-expression has been reported to lead to growth inhibition of NSCLC cell lines through ERK5-dependent activation of Peroxisome Proliferator-Activated Receptor Gamma.20,21 This pathway seems to be required for the maintenance of normal epithelial differentiation and represents noncanonical signaling by the Wnt pathway.

Disheveled proteins are overexpressed in NSCLC and are a route for Wnt/Fzd activation of Rac and Rho, which are known to be involved in lung carcinogenesis.22 WIF-1, an antagonist of Wnt signaling, is silenced by promoter methylation in NSCLC and is able to inhibit cell growth in vitro and in vivo.23 APC and sFRP1 are also methylated in lung adenocarcinoma, often concomitantly with WIF-1.24 Evaluation of chromosomal aberrations and changes in gene expression in NSCLC found that WIF1, CTNNBIP1, and WISP2 (antagonists of the Wnt pathway) were underexpressed and LEF1 and Ruvbl1 (agonists) were overexpressed.25 DKK1, an antagonist of Wnt signaling, is expressed in NSCLC cell lines, while sFRPs are downregulated.22,26 These findings suggest roles for Wnt pathway components in tumorigenesis, though more work is needed to clarify the biological effects of pathway disruption.

Back to Top | Article Outline


The Wnt pathway may play a significant role in lung tumor initiation and progression, thus providing opportunities for therapeutic intervention. Therapuetic interference with the Wnt pathway could be conducted at several levels. Restoration of SFRP4 function in cancer cells weakens Wnt signaling and induces apoptosis in NSCLC cell lines.27 Interference with Wnt 1 signaling by siRNA or antibody induces apoptosis in cancer cells and inhibits tumor growth in vivo.28 siRNA for Wnt 2 downregulates β-catenin and induces apoptosis in NSCLC.29 Restoration of Wnt 7a expression has been shown to reverse transformation in NSCLC and may be one approach to therapy through Wnt signaling.20 Reduction of Disheveled overexpression by siRNA leads to a decrease in β-catenin expression and Tcf transcription activity in NSCLC.30 A small molecule inhibitor, ICG-001, antagonizes β-catenin/Tcf transcription activation and downregulates β-catenin/Tcf responsive genes.31

The Wnt pathway, along with the Hedgehog pathway, is activated by smoke in bronchial epithelial cells and treatment with Sulindac, a Wnt pathway specific inhibitor, resulted in decreased tumor mass and volume in mice.31 This may be an opportunity for inhibition of early stage tumorigenesis in the lungs of smokers. Proper apical/basal polarity has been implicated in cell cycle control and cell-cell adhesion, both processes disrupted in tumorigenesis, and as the role of Wnt signaling in this process is clarified, interventions in this pathway that lead to restoration of apical basal polarity may be therapeutic options.18

Investigations into the role of Wnt signaling in the lung have clearly begun to elucidate the importance of this pathway in lung cancer, however, there is still much to be done. The participation of different Wnt proteins in different pathways complicates the determination of the effects of changes in Wnt expression, as does the presence of many levels of regulation along the pathway. The diversity of Wnt signaling, however, provides a bounty of opportunity for development of desperately needed targeted therapy for lung cancer.

Back to Top | Article Outline


1. Willert K, Jones KA. Wnt signaling: is the party in the nucleus? Genes Dev. 2006;20:1394–1404.

2. Jass JR, Barker M, Fraser L, Walsh MD, Whitehall VL, Gabrielli B, Young J, Leggett BA. APC mutation and tumour budding in colorectal cancer. J Clin Pathol. 2003;56:69–73.

3. Mikesch JH, Steffen B, Berdel WE, Serve H, Muller-Tidow C. The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia. Leukemia. 2007.

4. Turashvili G, Bouchal J, Burkadze G, Kolar Z. Wnt signaling pathway in mammary gland development and carcinogenesis. Pathobiology. 2006;73:213–223.

5. Yardy GW, Brewster SF. Wnt signaling and prostate cancer. Prostate Cancer Prostatic Dis. 2005;8:119–126.

6. Thompson MD, Monga SP. WNT/β-catenin signaling in liver health and disease. Hepatology. 2007;45:1298–1305.

7. Widelitz R. Wnt signaling through canonical and non-canonical pathways: recent progress. Growth Factors. 2005;23:111–116.

8. Pongracz JE, Stockley RA. Wnt signalling in lung development and diseases. Respir Res. 2006;7:15.

9. He X, Axelrod JD. A WNTer wonderland in Snowbird. Development. 2006;133:2597–2603.

10. Quaiser T, Anton R, Kuhl M. Kinases and G proteins join the Wnt receptor complex. Bioessays. 2006;28:339–343.

11. Kikuchi A, Yamamoto H, Kishida S. Multiplicity of the interactions of Wnt proteins and their receptors. Cell Signal. 2007;19:659–671.

12. Shannon JM, Hyatt BA. Epithelial-mesenchymal interactions in the developing lung. Annu Rev Physiol. 2004;66:625–645.

13. Minoo P, Hamdan H, Bu D, Warburton D, Stepanik P, deLemos R. TTF-1 regulates lung epithelial morphogenesis. Dev Biol. 1995;172:694–698.

14. Tebar M, Destree O, de Vree WJ, Ten Have-Opbroek AA. Expression of Tcf/Lef and sFrp and localization of β-catenin in the developing mouse lung. Mech Dev. 2001;109:437–440.

15. Shu W, Jiang YQ, Lu MM, Morrisey EE. Wnt7b regulates mesenchymal proliferation and vascular development in the lung. Development. 2002;129:4831–4842.

16. Li C, Xiao J, Hormi K, Borok Z, Minoo P. Wnt5a participates in distal lung morphogenesis. Dev Biol. 2002;248:68–81.

17. Mucenski ML, Nation JM, Thitoff AR, Besnard V, Xu Y, Wert SE, Harada N, Taketo MM, Stahlman MT, Whitsett JA. β-catenin regulates differentiation of respiratory epithelial cells in vivo. Am J Physiol Lung Cell Mol Physiol. 2005;289:L971–979.

18. Karner C, Wharton KA, Carroll TJ. Apical-basal polarity, Wnt signaling and vertebrate organogenesis. Semin Cell Dev Biol. 2006;17:214–222.

19. Daniel VC, Peacock CD, Watkins DN. Developmental signalling pathways in lung cancer. Respirology. 2006;11:234–240.

20. Winn RA, Marek L, Han SY, Rodriguez K, Rodriguez N, Hammond M, Van Scoyk M, Acosta H, Mirus J, Barry N, Bren-Mattison Y, Van Raay TJ, Nemenoff RA, Heasley LE. Restoration of Wnt-7a expression reverses non-small cell lung cancer cellular transformation through frizzled-9-mediated growth inhibition and promotion of cell differentiation. J Biol Chem. 2005;280:19625–19634.

21. Winn RA, Van Scoyk M, Hammond M, Rodriguez K, Crossno JT, Heasley LE, Nemenoff RA. Antitumorigenic effect of Wnt 7a and Fzd 9 in non-small cell lung cancer cells is mediated through ERK-5-dependent activation of peroxisome proliferator-activated receptor gamma. J Biol Chem. 2006;281:26943–26950.

22. Mazieres J, He B, You L, Xu Z, Jablons DM. Wnt signaling in lung cancer. Cancer Lett. 2005;222:1–10.

23. Kim J, You L, Xu Z, Kuchenbecker K, Raz D, He B, Jablons D. Wnt inhibitory factor inhibits lung cancer cell growth. J Thorac Cardiovasc Surg. 2007;133:733–737.

24. Tang M, Torres-Lanzas J, Lopez-Rios F, Esteller M, Sanchez-Cespedes M. Wnt signaling promoter hypermethylation distinguishes lung primary adenocarcinomas from colorectal metastasis to the lung. Int J Cancer. 2006;119:2603–2606.

25. Dehan E, Ben-Dor A, Liao W, Lipson D, Frimer H, Rienstein S, Simansky D, Krupsky M, Yaron P, Friedman E, Rechavi G, Perlman M, Aviram-Goldring A, Izraeli S, Bittner M, Yakhini Z, Kaminski N. Chromosomal aberrations and gene expression profiles in non-small cell lung cancer. Lung Cancer. 2007;56:175–184.

26. Forget MA, Turcotte S, Beauseigle D, Godin-Ethier J, Pelletier S, Martin J, Tanguay S, Lapointe R. The Wnt pathway regulator DKK1 is preferentially expressed in hormone-resistant breast tumours and in some common cancer types. Br J Cancer. 2007;96:646–653.

27. He B, Lee AY, Dadfarmay S, You L, Xu Z, Reguart N, Mazieres J, Mikami I, McCormick F, Jablons DM. Secreted frizzled-related protein 4 is silenced by hypermethylation and induces apoptosis in β-catenin-deficient human mesothelioma cells. Cancer Res. 2005;65:743–748.

28. You L, Kim J, He B, Xu Z, McCormick F, Jablons DM. Wnt-1 signal as a potential cancer therapeutic target. Drug News Perspect. 2006;19:27–31.

29. You L, He B, Xu Z, Uematsu K, Mazieres J, Mikami I, Reguart N, Moody TW, Kitajewski J, McCormick F, Jablons DM. Inhibition of Wnt-2-mediated signaling induces programmed cell death in non-small-cell lung cancer cells. Oncogene. 2004;23:6170–6174.

30. Uematsu K, He B, You L, Xu Z, McCormick F, Jablons DM. Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression. Oncogene. 2003;22:7218–7221.

31. Emami KH, Nguyen C, Ma H, Kim DH, Jeong KW, Eguchi M, Moon RT, Teo JL, Kim HY, Moon SH, Ha JR, Kahn M. A small molecule inhibitor of β-catenin/CREB-binding protein transcription [corrected]. Proc Natl Acad Sci U S A. 2004;101:12682–12687.

32. Chen G, Shukeir N, Potti A, Sircar K, Aprikian A, Goltzman D, Rabbani SA. Up-regulation of Wnt-1 and β-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications. Cancer. 2004;101:1345–1356.

33. Rhee CS, Sen M, Lu D, Wu C, Leoni L, Rubin J, Corr M, Carson DA. Wnt and frizzled receptors as potential targets for immunotherapy in head and neck squamous cell carcinomas. Oncogene. 2002;21:6598–6605.

34. Wong SC, Lo SF, Lee KC, Yam JW, Chan JK, Wendy Hsiao WL. Expression of frizzled-related protein and Wnt-signalling molecules in invasive human breast tumours. J Pathol. 2002;196:145–153.

35. Watanabe O, Imamura H, Shimizu T, Kinoshita J, Okabe T, Hirano A, Yoshimatsu K, Konno S, Aiba M, Ogawa K. Expression of twist and wnt in human breast cancer. Anticancer Res. 2004;24:3851–3856.

36. Dejmek J, Dejmek A, Safholm A, Sjolander A, Andersson T. Wnt-5a protein expression in primary dukes B colon cancers identifies a subgroup of patients with good prognosis. Cancer Res. 2005;65:9142–9146.

37. Blanc E, Goldschneider D, Douc-Rasy S, Benard J, Raguenez G. Wnt-5a gene expression in malignant human neuroblasts. Cancer Lett. 2005;228:117–123.

38. Kremenevskaja N, von Wasielewski R, Rao AS, Schofl C, Andersson T, Brabant G. Wnt-5a has tumor suppressor activity in thyroid carcinoma. Oncogene. 2005;24:2144–2154.

39. Jonsson M, Dejmek J, Bendahl PO, Andersson T. Loss of Wnt-5a protein is associated with early relapse in invasive ductal breast carcinomas. Cancer Res. 2002;62:409–416.

40. Kirikoshi H, Katoh M. Expression of WNT7A in human normal tissues and cancer, and regulation of WNT7A and WNT7B in human cancer. Int J Oncol. 2002;21:895–900.

41. Bui TD, Zhang L, Rees MC, Bicknell R, Harris AL. Expression and hormone regulation of Wnt2, 3, 4, 5a, 7a, 7b and 10b in normal human endometrium and endometrial carcinoma. Br J Cancer. 1997;75:1131–1136.

42. Calvo R, West J, Franklin W, Erickson P, Bemis L, Li E, Helfrich B, Bunn P, Roche J, Brambilla E, Rosell R, Gemmill RM, Drabkin HA. Altered HOX and WNT7A expression in human lung cancer. Proc Natl Acad Sci U S A. 2000;97:12776–12781.

43. Watanabe T, Kobunai T, Toda E, Kanazawa T, Kazama Y, Tanaka J, Tanaka T, Yamamoto Y, Hata K, Kojima T, Yokoyama T, Konishi T, Okayama Y, Sugimoto Y, Oka T, Sasaki S, Ajioka Y, Muto T, Nagawa H. Gene expression signature and the prediction of ulcerative colitis-associated colorectal cancer by DNA microarray. Clin Cancer Res. 2007;13:415–420.

44. Kirikoshi H, Sekihara H, Katoh M. Expression profiles of 10 members of Frizzled gene family in human gastric cancer. Int J Oncol. 2001;19:767–771.

45. Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM, Kipps TJ, Corr M, Carson DA. Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2004;101:3118–3123.

46. Janssens N, Andries L, Janicot M, Perera T, Bakker A. Alteration of frizzled expression in renal cell carcinoma. Tumour Biol. 2004;25:161–171.

47. Merle P, Kim M, Herrmann M, Gupte A, Lefrancois L, Califano S, Trepo C, Tanaka S, Vitvitski L, de la Monte S, Wands JR. Oncogenic role of the frizzled-7/β-catenin pathway in hepatocellular carcinoma. J Hepatol. 2005;43:854–862.

48. Zhang Z, Schittenhelm J, Guo K, Buhring HJ, Trautmann K, Meyermann R, Schluesener HJ. Upregulation of frizzled 9 in astrocytomas. Neuropathol Appl Neurobiol. 2006;32:615–624.

49. Shih YL, Hsieh CB, Lai HC, Yan MD, Hsieh TY, Chao YC, Lin YW. SFRP1 suppressed hepatoma cells growth through Wnt canonical signaling pathway. Int J Cancer. 2007.

50. Marsit CJ, Karagas MR, Schned A, Kelsey KT. Carcinogen exposure and epigenetic silencing in bladder cancer. Ann N Y Acad Sci. 2006;1076:810–821.

51. Marsit CJ, McClean MD, Furniss CS, Kelsey KT. Epigenetic inactivation of the SFRP genes is associated with drinking, smoking and HPV in head and neck squamous cell carcinoma. Int J Cancer. 2006;119:1761–1766.

52. Liu TH, Raval A, Chen SS, Matkovic JJ, Byrd JC, Plass C. CpG island methylation and expression of the secreted frizzled-related protein gene family in chronic lymphocytic leukemia. Cancer Res. 2006;66:653–658.

53. Lee AY, He B, You L, Dadfarmay S, Xu Z, Mazieres J, Mikami I, McCormick F, Jablons DM. Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma. Oncogene. 2004;23:6672–6676.

54. Qi J, Zhu YQ, Luo J, Tao WH. Hypermethylation and expression regulation of secreted frizzled-related protein genes in colorectal tumor. World J Gastroenterol. 2006;12:7113–7117.

55. Uematsu K, Kanazawa S, You L, He B, Xu Z, Li K, Peterlin BM, McCormick F, Jablons DM. Wnt pathway activation in mesothelioma: evidence of Dishevelled overexpression and transcriptional activity of β-catenin. Cancer Res. 2003;63:4547–4551.

56. Nielsen M, Hes FJ, Nagengast FM, Weiss MM, Mathus-Vliegen EM, Morreau H, Breuning MH, Wijnen JT, Tops CM, Vasen HF. Germline mutations in APC and MUTYH are responsible for the majority of families with attenuated familial adenomatous polyposis. Clin Genet. 2007;71:427–433.

57. Jeronimo C, Monteiro P, Henrique R, Dinis-Ribeiro M, Costa I, Costa VL, Filipe L, Carvalho AL, Hoque MO, Pais I, Leal C, Teixeira MR, Sidransky D. Quantitative hypermethylation of a small panel of genes augments the diagnostic accuracy in fine-needle aspirate washings of breast lesions. Breast Cancer Res Treat. 2007.

58. Sansom OJ, Griffiths DF, Reed KR, Winton DJ, Clarke AR. Apc deficiency predisposes to renal carcinoma in the mouse. Oncogene. 2005;24:8205–8210.

59. Zhou CX, Gao Y. Frequent genetic alterations and reduced expression of the Axin1 gene in oral squamous cell carcinoma: involvement in tumor progression and metastasis. Oncol Rep. 2007;17:73–79.

60. Laurent-Puig P, Zucman-Rossi J. Genetics of hepatocellular tumors. Oncogene. 2006;25:3778–3786.

61. Xu HT, Wang L, Lin D, Liu Y, Liu N, Yuan XM, Wang EH. Abnormal β-catenin and reduced axin expression are associated with poor differentiation and progression in non-small cell lung cancer. Am J Clin Pathol. 2006;125:534–541.

62. Willner J, Wurz K, Allison KH, Galic V, Garcia RL, Goff BA, Swisher EM. Alternate molecular genetic pathways in ovarian carcinomas of common histological types. Hum Pathol. 2007;38:607–613.

63. Yamaoka H, Ohtsu K, Sueda T, Yokoyama T, Hiyama E. Diagnostic and prognostic impact of β-catenin alterations in pediatric liver tumors. Oncol Rep. 2006;15:551–556.

64. Satoh Y, Nakadate H, Nakagawachi T, Higashimoto K, Joh K, Masaki Z, Uozumi J, Kaneko Y, Mukai T, Soejima H. Genetic and epigenetic alterations on the short arm of chromosome 11 are involved in a majority of sporadic Wilms' tumours. Br J Cancer. 2006;95:541–547.

© 2007International Association for the Study of Lung Cancer


Article Tools



Other Ways to Connect



Visit on your smartphone. Scan this code (QR reader app required) with your phone and be taken directly to the site.

 For additional oncology content, visit LWW Oncology Journals on Facebook.