Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Loss of TGF-β signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation

Oncogene volume 31, pages 3322–3332 (2012)Cite this article

Abstract

The molecular mechanisms that contribute to the initiation and progression of head and neck squamous cell carcinoma (HNSCC) have not been completely delineated. Our observations indicate that defects in the transforming growth factor-β and PI3K/Akt signaling pathways are common in human HNSCCs. Conditional activation of the PI3K/Akt pathway due to Pten deletion in the mouse head and neck epithelia gives rise to hyperproliferation, but only a few lesions progress to HNSCC. However, Pten-deficient mice developed full-penetrance HNSCC in combination with type I TGF-β receptor (Tgfbr1) deletion. Molecular analysis revealed enhanced cell proliferation, decreased apoptosis, and increased expression of CCND1 in the basal layer of the head and neck epithelia, as well as in the tumors of Tgfbr1/Pten double conditional knockout (2cKO) mice. Furthermore, neoplastic transformation involves senescence evasion, and is associated with an increased number of putative cancer stem cells. In addition, the nuclear factor-κB pathway activation, myeloid-derived suppressor cell infiltration, angiogenesis and immune suppression in the tumor microenvironment, all of which are characteristics of human HNSCCs, contribute significantly to head and neck carcinogenesis in 2cKO mice. These tumors display pathology and multiple molecular alterations resembling human HNSCCs. This suggests that the Tgfbr1/Pten 2cKO mouse model is suitable for preclinical intervention, and that it has significant implications in the development of diagnostic cancer biomarkers and effective strategies for prevention and treatment of HNSCCs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Bian Y, Terse A, Du J, Hall B, Molinolo A, Zhang P et al. (2009). Progressive tumor formation in mice with conditional deletion of TGF-beta signaling in head and neck epithelia is associated with activation of the PI3K/Akt pathway. Cancer Res 69: 5918–5926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bierie B, Moses HL . (2006). Tumour microenvironment: TGF-beta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 6: 506–520.

    Article  CAS  PubMed  Google Scholar 

  • Bierie B, Stover DG, Abel TW, Chytil A, Gorska AE, Aakre M et al. (2008). Transforming growth factor-beta regulates mammary carcinoma cell survival and interaction with the adjacent microenvironment. Cancer Res 68: 1809–1819.

    Article  CAS  PubMed  Google Scholar 

  • Bornstein S, White R, Malkoski S, Oka M, Han G, Cleaver T et al. (2009). Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. J Clin Invest 119: 3408–3419.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen T, Yan W, Wells RG, Rimm DL, McNiff J, Leffell D et al. (2001). Novel inactivating mutations of transforming growth factor-beta type I receptor gene in head-and-neck cancer metastases. Int J Cancer 93: 653–661.

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M et al. (2005). Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436: 725–730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen ZG . (2009). The cancer stem cell concept in progression of head and neck cancer. J Oncol 894064. Epub 2009 Dec 3.

  • Cohen J, Chen Z, Lu SL, Yang XP, Arun P, Ehsanian R et al. (2009). Attenuated transforming growth factor beta signaling promotes nuclear factor-kappaB activation in head and neck cancer. Cancer Res 69: 3415–3424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Conery AR, Cao Y, Thompson EA, Townsend Jr CM, Ko TC, Luo K . (2004). Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol 6: 366–372.

    Article  CAS  PubMed  Google Scholar 

  • Curado MP, Hashibe M . (2009). Recent changes in the epidemiology of head and neck cancer. Curr Opin Oncol 21: 194–200.

    Article  PubMed  Google Scholar 

  • De Wever O, Mareel M . (2003). Role of tissue stroma in cancer cell invasion. J Pathol 200: 429–447.

    Article  CAS  PubMed  Google Scholar 

  • Derynck R, Zhang YE . (2003). Smad-dependent and Smad-independent pathways in TGF-beta family signaling. Nature 425: 577–584.

    Article  CAS  PubMed  Google Scholar 

  • Deshpande AM, Wong DT . (2008). Molecular mechanisms of head and neck cancer. Expert Rev Anticancer Ther 8: 799–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Engle SJ, Hoying JB, Boivin GP, Ormsby I, Gartside PS, Doetschman T . (1999). Transforming growth factor β1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis. Cancer Res 59: 3379–3386.

    CAS  PubMed  Google Scholar 

  • Guttridge DC, Albanese C, Reuther JY, Pestell RG, Baldwin Jr AS . (1999). NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol 19: 5785–5799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Henderson YC, Wang E, Clayman GL . (1998). Genotypic analysis of tumor suppressor genes PTEN/MMAC1 and p53 in head and neck squamous cell carcinomas. Laryngoscope 108: 1553–1556.

    Article  CAS  PubMed  Google Scholar 

  • Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J et al. (2006). Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res 66: 1123–1131.

    Article  CAS  PubMed  Google Scholar 

  • Jemal A, Siegel R, Xu J, Ward E . (2010). Cancer statistics, 2010. CA Cancer J Clin 59: 225–249.

    Article  Google Scholar 

  • Kim JS, Lee C, Bonifant CL, Ressom H, Waldman T . (2007). Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA. Mol Cell Biol 27: 662–677.

    Article  CAS  PubMed  Google Scholar 

  • Kusmartsev S, Nagaraj S, Gabrilovich DI . (2005). Tumor associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J Immunol 175: 4583–4592.

    Article  CAS  PubMed  Google Scholar 

  • Lee JI, Soria JC, Hassan KA, El-Naggar AK, Tang X, Liu DD et al. (2001). Loss of PTEN expression as a prognostic marker for tongue cancer. Arch Otolaryngol Head Neck Surg 127: 1441–1445.

    Article  CAS  PubMed  Google Scholar 

  • Lee JY, Kang MB, Jang SH, Qian T, Kim HJ, Kim CH et al. (2009). Id-1 activates Akt-mediated Wnt signaling and p27(Kip1) phosphorylation through PTEN inhibition. Oncogene 28: 824–831.

    Article  CAS  PubMed  Google Scholar 

  • Levy L, Hill CS . (2006). Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev 17: 41–58.

    Article  CAS  PubMed  Google Scholar 

  • Licitra L, Perrone F, Bossi P, Suardi S, Mariani L, Artusi R et al. (2006). High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 24: 5630–5636.

    Article  CAS  PubMed  Google Scholar 

  • Loercher A, Lee TL, Ricker JL, Howard A, Geoghegen J, Chen Z et al. (2004). Nuclear factor-kappaB is an important modulator of the altered gene expression profile and malignant phenotype in squamous cell carcinoma. Cancer Res 64: 6511–6523.

    Article  CAS  PubMed  Google Scholar 

  • Lu SL, Herrington H, Reh D, Weber S, Bornstein S, Wang D et al. (2006). Loss of transforming growth factor-beta type II receptor promotes metastatic head-and-neck squamous cell carcinoma. Genes Dev 20: 1331–1342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu SL, Reh D, Li AG, Woods J, Corless CL, Kulesz-Martin M et al. (2004). Overexpression of transforming growth factor beta1 in head and neck epithelia results in inflammation, angiogenesis, and epithelial hyperproliferation. Cancer Res 64: 4405–4410.

    Article  CAS  PubMed  Google Scholar 

  • Mao L, Hong WK, Papadimitrakopoulou VA . (2004). Focus on head and neck cancer. Cancer Cell 5: 311–316.

    Article  CAS  PubMed  Google Scholar 

  • Massagué J . (2008). TGF-β in Cancer. Cell 134: 215–230.

    Article  PubMed  PubMed Central  Google Scholar 

  • Massagué J, Gomis RR . (2006). The logic of TGF-β signaling. FEBS Lett 580: 2811–2820.

    Article  PubMed  Google Scholar 

  • Molinolo AA, Amornphimoltham P, Squarize CH, Castilho RM, Patel V, Gutkind JS . (2009). Dysregulated molecular networks in head and neck carcinogenesis. Oral Oncol 45: 324–334.

    Article  CAS  PubMed  Google Scholar 

  • Moral M, Segrelles C, Lara MF, Martínez-Cruz AB, Lorz C, Santos M et al. (2009). Akt activation synergizes with Trp53 loss in oral epithelium to produce a novel mouse model for head and neck squamous cell carcinoma. Cancer Res 69: 1099–1108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moustakas A, Heldin CH . (2009). The regulation of TGF-β signal transduction. Development 136: 3699–3714.

    Article  CAS  PubMed  Google Scholar 

  • Pasche B, Knobloch TJ, Bian Y, Liu J, Phukan S, Rosman D et al. (2005). Somatic acquisition and signaling of TGFBR1*6A in cancer. JAMA 294: 1634–1646.

    Article  CAS  PubMed  Google Scholar 

  • Pedrero JM, Carracedo DG, Pinto CM, Zapatero AH, Rodrigo JP, Nieto CS et al. (2005). Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma. Int J Cancer 114: 242–248.

    Article  CAS  PubMed  Google Scholar 

  • Piek E, Roberts AB . (2001). Suppressor and oncogenic roles of transforming growth factor-beta and its signaling pathways in tumorigenesis. Adv Cancer Res 83: 1–54.

    Article  CAS  PubMed  Google Scholar 

  • Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P et al. (2007). Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 104: 973–978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Remy I, Montmarquette A, Michnick SW . (2004). PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. Nat Cell Biol 6: 358–365.

    Article  CAS  PubMed  Google Scholar 

  • Rocco JW, Leong CO, Kuperwasser N, DeYoung MP, Ellisen LW . (2006). p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis. Cancer Cell 9: 45–56.

    Article  CAS  PubMed  Google Scholar 

  • Shao X, Tandon R, Samara G, Kanki H, Yano H, Close LG et al. (1998). Mutational analysis of the PTEN gene in head and neck squamous cell carcinoma. Int J Cancer 77: 684–688.

    Article  CAS  PubMed  Google Scholar 

  • Squarize CH, Castilho RM, Gutkind JS . (2008). Chemoprevention and treatment of experimental Cowden's disease by mTOR inhibition with rapamycin. Cancer Res 68: 7066–7072.

    Article  CAS  PubMed  Google Scholar 

  • Swarbrick A, Roy E, Allen T, Bishop JM . (2008). Id1 cooperates with oncogenic Ras to induce metastatic mammary carcinoma by subversion of the cellular senescence response. Proc Natl Acad Sci USA 105: 5402–5407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang B, Vu M, Booker T, Santner SJ, Miller FR, Anver MR et al. (2003). TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression. J Clin Invest 112: 1116–1124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang B, Yoo N, Vu M, Mamura M, Nam JS, Ooshima A et al. (2007). Transforming growth factor-beta can suppress tumorigenesis through effects on the putative cancer stem or early progenitor cell and committed progeny in a breast cancer xenograft model. Cancer Res 67: 8643–8652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vijayachandra K, Higgins W, Lee J, Glick A . (2009). Induction of p16ink4a and p19ARF by TGFbeta1 contributes to growth arrest and senescence response in mouse keratinocytes. Mol Carcinog 48: 181–186.

    Article  CAS  PubMed  Google Scholar 

  • Wakefield LM, Roberts AB . (2002). TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 12: 22–29.

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Yang L, Yang J, Kuropatwinski K, Wang W, Liu XQ et al. (2008). Transforming growth factor beta induces apoptosis through repressing the phosphoinositide 3-kinase/AKT7sol;surviving pathway in colon cancer cells. Cancer Res 68: 3152–3160.

    Article  CAS  PubMed  Google Scholar 

  • White RA, Malkoski SP, Wang XJ . (2010). TGF-β signaling in head and neck squamous cell carcinoma. Oncogene 29: 5437–5446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie W, Bharathy S, Kim D, Haffty BG, Rimm DL, Reiss M . (2003). Frequent alterations of Smad signaling in human head and neck squamous cell carcinomas: a tissue microarray analysis. Oncol Res 14: 61–73.

    Article  CAS  PubMed  Google Scholar 

  • Yang L, Pang Y, Moses HL . (2010). TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol 31: 220–227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang YE . (2009). Non-Smad pathways in TGF- β signaling. Cell Res 19: 128–139.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Dr Stefan Karlsson for providing us with the Tgfbr1 flox mice, Drs Raj Puri and Lalage Wakefield for critical reading of the manuscript, Drs Juan Du, Ping Zhang, Zhong Chen and Anita Terse for technical help, and Shelagh Johnson for the expert editorial assistance. This work was supported by the Divisions of Intramural Research, National Institute of Dental and Craniofacial Research (Z01-DE-000698), and National Institute on Deafness and Communication Disorders (ZIA-DC-000073), NIH.

Author information

Author notes

  1. B Hall and Z-J Sun: These authors contributed equally to this work.

Authors and Affiliations

  1. Functional Genomics Section, Laboratory of Cell and Developmental Biology, Bethesda, MD, USA

    Y Bian, B Hall, Z-J Sun & A B Kulkarni

  2. Oral and Pharyngeal Cancer Branch, Bethesda, MD, USA

    A Molinolo & J S Gutkind

  3. Mucosal Immunity Section, Oral Immunity and Infection Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA

    W Chen

  4. Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA

    Y Bian & C V Waes

Authors
  1. Y Bian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B Hall
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Z-J Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Molinolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J S Gutkind
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C V Waes
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A B Kulkarni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A B Kulkarni.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bian, Y., Hall, B., Sun, ZJ. et al. Loss of TGF-β signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation. Oncogene 31, 3322–3332 (2012). https://doi.org/10.1038/onc.2011.494

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.494

Keywords

This article is cited by

Search

Advanced search

Quick links