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Cannabis smoke can be a major risk factor for early-age laryngeal cancer—a molecular signaling-based approach

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Tumor Biology

Abstract

Epidermal growth factor receptor (EGFR) and its downstream elements are overexpressed in most cases of the head and neck squamous cell carcinoma. This study investigated the expression pattern of key proteins linked to the EGFR pathway in laryngeal carcinoma patients with a history of cannabis smoking. We selected 83 male glottic cancer patients, aged between 45 to 75 years with three distinct populations—nonsmoker, cigarette smoker, and cannabis smoker. Immunohistochemical staining was performed for EGFR, protein kinase B (PKB or Akt), nuclear factor kappa B p50 (NF-КB), and cyclooxygenase-2 (COX-2) followed by boolean scoring for statistical analysis. Experimental data showed upregulation of the selected EGFR cascade in tumor cells, stromal expression of EGFR, and nuclear localization of COX-2 in metaplastic gland cells of laryngeal cancer tissue sample. Statistical analyses indicated that overexpression of the EGFR cascade is significantly correlated to cannabis smoking. Cannabis smokers had higher expression (p < 0.01) of these onco-proteins with respect to both nonsmokers as well as cigarette smokers. Risk factor analysis showed high risk of these proteins expression in age <60 years (odds ratio (OR) > 1.5) as the lower age group had relatively higher number of cannabis smokers. This study provides evidence for a direct association between cannabis smoking and increased risk of laryngeal cancer. Higher expression of the EGFR cascade in cannabis smokers revealed that cannabis smoking may be a major cause for the early onset of aggressive laryngeal cancer.

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References

  1. Iversen L. The science of cannabis. Oxford: Oxford University Press; 2000.

    Google Scholar 

  2. Martin B, Cone E. Chemistry and pharmacology of cannabis. In: Kalant H, Corrigal W, Hall WD, Smart RG, editors. The health effects of cannabis. Toronto: Centre for Addiction and Mental Health; 1999.

    Google Scholar 

  3. Global illicit drug trends. New York: United Nations Office on Drugs and Crime; 2003. p. 136–140.

  4. Hall W, Christie M, Currow D. Cannabinoids and cancer: causation, remediation, and palliation. Lancet Oncol. 2005;6:35–42.

    Article  CAS  PubMed  Google Scholar 

  5. Hall WD, MacPhee D. Cannabis use and cancer. Addiction. 2002;97:243–7.

    Article  PubMed  Google Scholar 

  6. Zhang LR, Morgenstern H, Greenland S, et al. Cannabis smoking and lung cancer risk: pooled analysis in the International Lung Cancer Consortium. Int J Cancer. 2014. doi:10.1002/ijc.29036.

    Google Scholar 

  7. Gomez Del Pulgar T, Velasco G, Guzman M. The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. Biochem J. 2000;347:369–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. West KA, Brognard J, Clark AS, Linnoila IR, Yang X, Swain SM, et al. Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. J Clin Invest. 2003;111:81–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, et al. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature. 2001;413:527–31.

    Article  CAS  PubMed  Google Scholar 

  10. Leker RR, Shohami E, Abramsky O, Ovadia H. Dexanabinol; a novel neuroprotective drug in experimental focal cerebral ischemia. J Neurol Sci. 1999;162(2):114–9.

    Article  CAS  PubMed  Google Scholar 

  11. Roth MD, Marques-Magallanes JA, Yuan M, Sun W, Tashkin DP, Hankinson O. Induction and regulation of the carcinogen-metabolizing enzyme CYP1A1 by cannabis smoke and Delta (9)-tetrahydrocannabinol. Am J Respir Cell Mol Biol. 2001;24:339–44.

    Article  CAS  PubMed  Google Scholar 

  12. Brennan JA, Boyle JO, et al. Association between cigarette smoking and mutation of the p53 gene in squamous cell carcinoma of the head and neck. N Engl J Med. 1995;332(11):712–7.

    Article  CAS  PubMed  Google Scholar 

  13. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7(7):505–16.

    Article  CAS  PubMed  Google Scholar 

  14. Kalyankrishna S, Grandis JR. Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol. 2006;24(17):2666–72.

    Article  CAS  PubMed  Google Scholar 

  15. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358(11):1160–74.

    Article  CAS  PubMed  Google Scholar 

  16. Grandis JR, Tweardy DJ. TGF-alpha and EGFR in head and neck cancer. J Cell Biochem Suppl. 1993;17F:188–91.

    Article  CAS  PubMed  Google Scholar 

  17. Takes RP, Baatenburg de Jong RJ, Schuuring E, et al. Differences in expression of oncogenes and tumor suppressor genes in different sites of head and neck squamous cell. Anticancer Res. 1998;18(6B):4793–800.

    CAS  PubMed  Google Scholar 

  18. Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62(24):7350–6.

    CAS  PubMed  Google Scholar 

  19. Kim S, Grandis JR, Rinaldo A, et al. Emerging perspectives in epidermal growth factor receptor targeting in head and neck cancer. Head Neck. 2008;30(5):667–74.

    Article  PubMed  Google Scholar 

  20. Ford AC, Grandis JR. Targeting epidermal growth factor receptor in head and neck cancer. Head Neck. 2003;25(1):67–73.

    Article  PubMed  Google Scholar 

  21. Lothaire P, de Azambiya E, Dequanter D, et al. Molecular markers of head and neck squamous cell carcinoma: promising signs in need of prospective evaluation. Head Neck. 2006;28(3):256–69.

    Article  PubMed  Google Scholar 

  22. Reuter CW, Morgan MA, Eckardt A. Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck. Br J Cancer. 2007;96(3):408–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Scaltriti M, Baselga J. The epidermal growth factor rececptor pathway: a model for targeted therapy. Clin Cancer Res. 2006;12(18):5268–72.

    Article  CAS  PubMed  Google Scholar 

  24. Loercher A, Lee TL, Ricker JL, et al. Nuclear factor-kappaB is an important modulator of the altered gene expression profile and malignant phenotype in squamous cell carcinoma. Cancer Res. 2004;64(18):6511–23.

    Article  CAS  PubMed  Google Scholar 

  25. Chen Z, Malhotra PS, Thomas GR, et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res. 1999;5(6):1369–79.

    CAS  PubMed  Google Scholar 

  26. Ondrey FG, Dong G, Sunwoo J, et al. Constitutive activation of transcription factors NF-(kappa)B, AP-1, and NF-IL6 in human head and neck squamous cell carcinoma cell lines that express pro-inflammatory and pro-angiogenic cytokines. Mol Carcinog. 1999;26(2):119–29.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang PL, Pellitteri PK, Law A, et al. Overexpression of phosphorylated nuclear factor-kappa B in tonsillar squamous cell carcinoma and high-grade dysplasia is associated with poor prognosis. Mod Pathol. 2005;18(7):924–32.

    Article  CAS  PubMed  Google Scholar 

  28. Anto RJ, Mukhopadhyay A, Shishodia S, et al. Cigarette smoke condensate activates nuclear transcription factor-kappaB through phosphorylation and degradation of IkappaB(alpha): correlation with induction of cyclooxygenase-2. Carcinogenesis. 2002;23(9):1511–8.

    Article  CAS  PubMed  Google Scholar 

  29. Lin SC, Lu SY, Lee SY, et al. Areca (betel) nut extract activates mitogen-activated protein kinases and NF-kappaB in oral keratinocytes. Int J Cancer. 2005;116(4):526–35.

    Article  CAS  PubMed  Google Scholar 

  30. Karmali RA, Wustrow T, Thaler HT, Strong EW. Prostaglandins in carcinomas of the head and neck. Cancer Lett. 1984;22:333–6.

    Article  CAS  PubMed  Google Scholar 

  31. Jung TTK, Berlinger NT, Juhn SK. Prostaglandins in squamous cell carcinoma of the head and neck: a preliminary study. Laryngoscope. 1985;95:307–12.

    Article  CAS  PubMed  Google Scholar 

  32. Sheng H, Shao J, Morrow JD, Beauchamp RD, DuBois RN. Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res. 1998;58:362–6.

    CAS  PubMed  Google Scholar 

  33. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell. 1998;93:705–16.

    Article  CAS  PubMed  Google Scholar 

  34. Huang M, Stolina M, et al. Non-small cell lung cancer cyclooxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: upregulation of interleukin 10 and down-regulation of interleukin 12 production. Cancer Res. 1998;58:1208–16.

    CAS  PubMed  Google Scholar 

  35. Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase. Cell. 1995;83:493–501.

    Article  CAS  PubMed  Google Scholar 

  36. Tsujii M, Kawano S, DuBois RN. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci U S A. 1997;94:3336–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Janot F, Massaad L, Ribrag V, de Waziers I, Beaune PH, Luboinski B, et al. Principal xenobiotic-metabolizing enzyme systems in human head and neck squamous cell carcinoma. Carcinogenesis. 1993;14:1279–83.

    Article  CAS  PubMed  Google Scholar 

  38. Zhang ZF, Morgenstern H, Spitz RM, et al. Cannabis use and increased risk of squamous cell carcinoma of the head and neck. Cancer Epidemiol Biomarkers Prev. 1999;8:1071–8.

    CAS  PubMed  Google Scholar 

  39. Hashibe M, Morgenstern H, Cui Y, et al. Cannabis use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case-control study. Cancer Epidemiol Biomarkers Prev. 2006;15:1829–34.

    Article  CAS  PubMed  Google Scholar 

  40. Zhu LX, Sharma S, Stolina M, et al. Delta-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. J Immunol. 2000;165:373–80.

    Article  CAS  PubMed  Google Scholar 

  41. Sarafian TA, Tashkin DP, Roth MD. Cannabis smoke and delta(9)-tetrahydrocannabinol promote necrotic cell death but inhibit Fas-mediated apoptosis. Toxicol Appl Pharmacol. 2001;174:264–72.

    Article  CAS  PubMed  Google Scholar 

  42. Guzman M. Cannabinoids: potential anticancer agents. Nat Rev Cancer. 2003;3:745–55.

    Article  CAS  PubMed  Google Scholar 

  43. Blazquez C, Casanova ML, Planas A, et al. Inhibition of tumor angiogenesis by cannabinoids. FASEB J. 2003;17:529–31.

    CAS  PubMed  Google Scholar 

  44. Barsky SH, Roth MD, Kleerup EC, Simmons M, Tashkin DP. Histopathologic and molecular alterations in bronchial epithelium in habitual smokers of cannabis, cocaine, and/or tobacco. J Natl Cancer Inst. 1998;90:1198–205.

    Article  CAS  PubMed  Google Scholar 

  45. Fligiel SE, Venkat H, Gong Jr H, Tashkin DP. Bronchial pathology in chronic cannabis smokers: a light and electron microscopic study. J Psychoactive Drugs. 1988;20:33–42.

    Article  CAS  PubMed  Google Scholar 

  46. Pupa SM, Menard S, Forti S, Tagliabue E. New insights into the role of extracellular matrix during tumor onset and progression. J Cell Physiol. 2002;192:259–67.

    Article  CAS  PubMed  Google Scholar 

  47. Yang C-M, Lee I-T, Lin C-C, Yang Y-L, Luo S-F, Kou YR, et al. Cigarette smoke extract induces COX-2 expression via a PKC a/c-Src/EGFR, PDGFR/PI3K/Akt/NF-kB pathway and p300 in tracheal smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2009;297:L892–902.

    Article  CAS  PubMed  Google Scholar 

  48. Kourelis K, Vandoros G, et al. Low COX2 in tumor and upregulation in stroma mark laryngeal squamous cell carcinoma progression. Laryngoscope. 2009;119(9):1723–9.

    Article  CAS  PubMed  Google Scholar 

  49. Lappi-Blanco E, Kaarteenaho-Wiik R, et al. COX-2 is widely expressed in metaplastic epithelium in pulmonary fibrous disorders. Am J Clin Pathol. 2006;126:717–24.

    Article  CAS  PubMed  Google Scholar 

  50. Araya J, Cambier S, Markovics JA, et al. Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients. J Clin Invest. 2007;117(11):3551–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Reis-Filho JS, Milanezi F, et al. Metaplastic breast carcinomas are basal-like tumours. Histopathology. 2006;49:10–21.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Prof. (Dr.) Jaydip Biswas, Director, CNCI, for his support throughout the entire project and the Department of Science and Technology (DST), India, for funding the project.

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Authors and Affiliations

  1. Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, 37-S.P Mukherjee Road, Kolkata, 700026, India

    Sayantan Bhattacharyya, Samir Banerjee & Nabendu Murmu

  2. Department of Pathology, Chittaranjan National Cancer Institute, 37-S.P Mukherjee Road, Kolkata, 700026, India

    Gautam Kumar Mandal

  3. Department of ENT, Chittaranjan National Cancer Institute, 37-S.P Mukherjee Road, Kolkata, 700026, India

    Anup Kumar Bhowmick

  4. Department of Epidemiology and Biostatistics, Chittaranjan National Cancer Institute, 37-S.P Mukherjee Road, Kolkata, 700026, India

    Syamsundar Mandal

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  1. Sayantan Bhattacharyya
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  4. Gautam Kumar Mandal
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Correspondence to Nabendu Murmu.

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Bhattacharyya, S., Mandal, S., Banerjee, S. et al. Cannabis smoke can be a major risk factor for early-age laryngeal cancer—a molecular signaling-based approach. Tumor Biol. 36, 6029–6036 (2015). https://doi.org/10.1007/s13277-015-3279-4

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  • DOI: https://doi.org/10.1007/s13277-015-3279-4

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