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Cetuximab has an inhibitory effect on cell motility in SCC-4 oral squamous cell carcinoma cell line
Corresponding Author(s) : V. O. Crema
Cellular and Molecular Biology,
Vol. 63 No. 9: Issue 9
Abstract
Cetuximab is a chimeric monoclonal antibody that acts as a competitive antagonist, by binding to EGFR. This cell signalling pathways regulates tumor progression. The oral squamous cell carcinoma undergoes to regional spreading and distant metastasis. This study aimed to evaluate the effect of treatment with Cetuximab on cell migration and invasion in OSCC cells, by using the SCC-4 cell line. Cell migration and cell invasion assay were performed and actin cytoskeleton of control and treated with Cetuximab cells were evaluated. Differences were considered significant when p<0.05.Cetuximab inhibited the migration of SCC-4 cells at three concentrations: 1 µg/mL, 50 µg/mL and 100 µg/mL (p<0.0001) in a dose-dependent manner. The number of SCC-4 treated cells with 1 μg/mL that migrated through the membrane was statistically different from 50 μg/mL (p<0.001) and 100 μg/mL (p<0.0001), and between 50 μg/mL and 100 μg/mL (p<0.01). Cetuximab 50 μg/mL inhibited cell invasion through the MatrigelTM compared with SCC-4 control cells (p<0.01). Cetuximab 50 μg/mL affected the organization of the actin cytoskeleton. Cetuximab has an inhibitory effect on actin cytoskeleton organization, cell migration and invasion, suggesting that Cetuximab treatment can be important to avoid oral squamous cell carcinoma metastasis.
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- Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:359-86. doi: 10.1002/ijc.29210.
- Scully C, Bagan J. Oral squamous cell carcinoma: overview of current understanding of aetiopathogenesis and clinical implications. Oral Dis. 2009;15:388-99. doi: 10.1111/j.1601-0825.2009.01563.
- Broumand V, Lozano TE, Gomez JA. Evaluation and staging of oral cancer. Oral Maxillofac Surg Clin North Am. 2006;18:435-44. doi: 10.1016/j.coms.2006.07.001.
- Massano J, Regateiro FS, Januario G, Ferreira A. Oral squamous cell carcinoma: review of prognostic and predictive factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102:67-76. doi: 10.1016/j.tripleo.2005.07.038.
- Lim MS. Re: Correlational of oral tongue cancer inversion with matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) expression, by Kim S-H, Cho NH, Kim K, et al. J Surg Oncol. 2006;93(4):253-4. doi: 10.1002/jso.20462.
- Rubin Grandis J, Melhem MF, Gooding WE, Day R, Holst VA, Wagener MM, et al. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst. 1998;90:824-32.
- Burtness B. The role of cetuximab in the treatment of squamous cell cancer of the head and neck. Expert Opin Biol Ther. 2005;5:1085-93. doi: 10.1517/14712598.5.8.1085.
- Sacco AG, Worden FP. Molecularly targeted therapy for the treatment of head and neck cancer: a review of the ErbB family inhibitors. Onco Targets Ther. 2016;9:1927-43. doi: 10.2147/OTT.S93720.
- Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther. 2005;315:971-9. doi: 10.1124/jpet.105.084145.
- Dillman RO. Cancer immunotherapy. Cancer Biother Radiopharm. 2011;26:1-64. doi: 10.1089/cbr.2010.0902.
- Perri F, Longo F, Ionna F, Caponigro F. Recent results of cetuximab use in the treatment of squamous cell carcinoma of the head and neck. Onco Targets Ther. 2009;2:243-50.
- Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567-78. doi: 10.1056/NEJMoa053422.
- Bettendorf O, Piffko J, Bankfalvi A. Prognostic and predictive factors in oral squamous cell cancer: important tools for planning individual therapy? Oral Oncol. 2004;40:110-9.
- Kalmar JR. Advances in the detection and diagnosis of oral precancerous and cancerous lesions. Oral Maxillofac Surg Clin North Am. 2006;18:465-82. doi: 10.1016/j.coms.2006.06.013.
- Alorabi M, Shonka NA, Ganti AK. EGFR monoclonal antibodies in locally advanced head and neck squamous cell carcinoma: What is their current role? Crit Rev Oncol Hematol. 2016;99:170-9. doi: 10.1016/j.critrevonc.2015.12.006.
- Dancey J. Epidermal growth factor receptor inhibitors in clinical development. Int J Radiat Oncol Biol Phys. 2004;58:1003-7. doi: 10.1016/j.ijrobp.2003.07.011.
- Dequanter D, Shahla M, Paulus P, Lothaire P. Cetuximab in the treatment of head and neck cancer: preliminary results outside clinical trials. Cancer Manag Res. 2010;2:165-8.
- Hall A. Rho GTPases and the control of cell behaviour. Biochem Soc Trans. 2005;33:891-5. doi: 10.1042/BST20050891.
- Jiang L, Liu X, Kolokythas A, Yu J, Wang A, Heidbreder CE, et al. Downregulation of the Rho GTPase signaling pathway is involved in the microRNA-138-mediated inhibition of cell migration and invasion in tongue squamous cell carcinoma. Int J Cancer. 2010;127:505-12. doi: 10.1002/ijc.25320.
- Malliri A, Collard JG. Role of Rho-family proteins in cell adhesion and cancer. Curr Opin Cell Biol. 2003;15:583-9.
- Hall A. The cytoskeleton and cancer. Cancer Metastasis Rev. 2009;28:5-14. doi: 10.1007/s10555-008-9166-3.
- Chen Z, Sun J, Pradines A, Favre G, Adnane J, Sebti SM. Both farnesylated and geranylgeranylated RhoB inhibit malignant transformation and suppress human tumor growth in nude mice. J Biol Chem. 2000;275:17974-8. doi: 10.1074/jbc.C000145200.
- Ridley AJ, Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell. 1992;70:389-99.
- Chiou WF, Yau-Chik Shum A, Peng CH, Chen CF, Chou CJ. Piperlactam S suppresses macrophage migration by impeding F-actin polymerization and filopodia extension. Eur J Pharmacol. 2003;458:217-25.
- Adnane J, Muro-Cacho C, Mathews L, Sebti SM, Munoz-Antonia T. Suppression of rho B expression in invasive carcinoma from head and neck cancer patients. Clin Cancer Res. 2002;8:2225-32.
- Hamada M, Miki T, Iwai S, Shimizu H, Yura Y. Involvement of RhoA and RalB in geranylgeranyltransferase I inhibitor-mediated inhibition of proliferation and migration of human oral squamous cell carcinoma cells. Cancer Chemother Pharmacol. 2011;68:559-69. doi: 10.1007/s00280-010-1520-9.
- Islam M, Lin G, Brenner JC, Pan Q, Merajver SD, Hou Y, et al. RhoC expression and head and neck cancer metastasis. Mol Cancer Res. 2009;7:1771-80. doi: 10.1158/1541-7786.MCR-08-0512.
- Kleer CG, Teknos TN, Islam M, Marcus B, Lee JS, Pan Q, et al. RhoC GTPase expression as a potential marker of lymph node metastasis in squamous cell carcinomas of the head and neck. Clin Cancer Res. 2006;12:4485-90. doi: 10.1158/1078-0432.CCR-06-0376.
- Liu YH, Zhu WL. Effects of cetuximab combined with afatinib on the expression of KDR and AQP1 in lung cancer. Genet Mol Res. 2015;14:16652-61. doi: 10.4238/2015.
- Chang JW, Kang SU, Shin YS, Seo SJ, Kim YS, Yang SS, et al. Combination of NTP with cetuximab inhibited invasion/migration of cetuximab-resistant OSCC cells: Involvement of NF-κB signaling. Sci Rep. 2015;5:18208.
- Qian M, Qian D, Jing H, Li Y, Ma C, Zhou Y. Combined cetuximab and celecoxib treatment exhibits a synergistic anticancer effect on human oral squamous cell carcinoma in vitro and in vivo. Oncol Rep. 2014;32:1681-8.
- Jedlinski A, Garvin S, Johansson AC, Edqvist PH, Ponten F, Roberg K. Cetuximab sensitivity of head and neck squamous cell carcinoma xenografts is associated with treatment-induced reduction in EGFR, pEGFR, and pSrc. J Oral Pathol Med. 2016. doi: 10.1111/jop.12545.
- Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11:21-8.
References
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:359-86. doi: 10.1002/ijc.29210.
Scully C, Bagan J. Oral squamous cell carcinoma: overview of current understanding of aetiopathogenesis and clinical implications. Oral Dis. 2009;15:388-99. doi: 10.1111/j.1601-0825.2009.01563.
Broumand V, Lozano TE, Gomez JA. Evaluation and staging of oral cancer. Oral Maxillofac Surg Clin North Am. 2006;18:435-44. doi: 10.1016/j.coms.2006.07.001.
Massano J, Regateiro FS, Januario G, Ferreira A. Oral squamous cell carcinoma: review of prognostic and predictive factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102:67-76. doi: 10.1016/j.tripleo.2005.07.038.
Lim MS. Re: Correlational of oral tongue cancer inversion with matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) expression, by Kim S-H, Cho NH, Kim K, et al. J Surg Oncol. 2006;93(4):253-4. doi: 10.1002/jso.20462.
Rubin Grandis J, Melhem MF, Gooding WE, Day R, Holst VA, Wagener MM, et al. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst. 1998;90:824-32.
Burtness B. The role of cetuximab in the treatment of squamous cell cancer of the head and neck. Expert Opin Biol Ther. 2005;5:1085-93. doi: 10.1517/14712598.5.8.1085.
Sacco AG, Worden FP. Molecularly targeted therapy for the treatment of head and neck cancer: a review of the ErbB family inhibitors. Onco Targets Ther. 2016;9:1927-43. doi: 10.2147/OTT.S93720.
Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther. 2005;315:971-9. doi: 10.1124/jpet.105.084145.
Dillman RO. Cancer immunotherapy. Cancer Biother Radiopharm. 2011;26:1-64. doi: 10.1089/cbr.2010.0902.
Perri F, Longo F, Ionna F, Caponigro F. Recent results of cetuximab use in the treatment of squamous cell carcinoma of the head and neck. Onco Targets Ther. 2009;2:243-50.
Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567-78. doi: 10.1056/NEJMoa053422.
Bettendorf O, Piffko J, Bankfalvi A. Prognostic and predictive factors in oral squamous cell cancer: important tools for planning individual therapy? Oral Oncol. 2004;40:110-9.
Kalmar JR. Advances in the detection and diagnosis of oral precancerous and cancerous lesions. Oral Maxillofac Surg Clin North Am. 2006;18:465-82. doi: 10.1016/j.coms.2006.06.013.
Alorabi M, Shonka NA, Ganti AK. EGFR monoclonal antibodies in locally advanced head and neck squamous cell carcinoma: What is their current role? Crit Rev Oncol Hematol. 2016;99:170-9. doi: 10.1016/j.critrevonc.2015.12.006.
Dancey J. Epidermal growth factor receptor inhibitors in clinical development. Int J Radiat Oncol Biol Phys. 2004;58:1003-7. doi: 10.1016/j.ijrobp.2003.07.011.
Dequanter D, Shahla M, Paulus P, Lothaire P. Cetuximab in the treatment of head and neck cancer: preliminary results outside clinical trials. Cancer Manag Res. 2010;2:165-8.
Hall A. Rho GTPases and the control of cell behaviour. Biochem Soc Trans. 2005;33:891-5. doi: 10.1042/BST20050891.
Jiang L, Liu X, Kolokythas A, Yu J, Wang A, Heidbreder CE, et al. Downregulation of the Rho GTPase signaling pathway is involved in the microRNA-138-mediated inhibition of cell migration and invasion in tongue squamous cell carcinoma. Int J Cancer. 2010;127:505-12. doi: 10.1002/ijc.25320.
Malliri A, Collard JG. Role of Rho-family proteins in cell adhesion and cancer. Curr Opin Cell Biol. 2003;15:583-9.
Hall A. The cytoskeleton and cancer. Cancer Metastasis Rev. 2009;28:5-14. doi: 10.1007/s10555-008-9166-3.
Chen Z, Sun J, Pradines A, Favre G, Adnane J, Sebti SM. Both farnesylated and geranylgeranylated RhoB inhibit malignant transformation and suppress human tumor growth in nude mice. J Biol Chem. 2000;275:17974-8. doi: 10.1074/jbc.C000145200.
Ridley AJ, Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell. 1992;70:389-99.
Chiou WF, Yau-Chik Shum A, Peng CH, Chen CF, Chou CJ. Piperlactam S suppresses macrophage migration by impeding F-actin polymerization and filopodia extension. Eur J Pharmacol. 2003;458:217-25.
Adnane J, Muro-Cacho C, Mathews L, Sebti SM, Munoz-Antonia T. Suppression of rho B expression in invasive carcinoma from head and neck cancer patients. Clin Cancer Res. 2002;8:2225-32.
Hamada M, Miki T, Iwai S, Shimizu H, Yura Y. Involvement of RhoA and RalB in geranylgeranyltransferase I inhibitor-mediated inhibition of proliferation and migration of human oral squamous cell carcinoma cells. Cancer Chemother Pharmacol. 2011;68:559-69. doi: 10.1007/s00280-010-1520-9.
Islam M, Lin G, Brenner JC, Pan Q, Merajver SD, Hou Y, et al. RhoC expression and head and neck cancer metastasis. Mol Cancer Res. 2009;7:1771-80. doi: 10.1158/1541-7786.MCR-08-0512.
Kleer CG, Teknos TN, Islam M, Marcus B, Lee JS, Pan Q, et al. RhoC GTPase expression as a potential marker of lymph node metastasis in squamous cell carcinomas of the head and neck. Clin Cancer Res. 2006;12:4485-90. doi: 10.1158/1078-0432.CCR-06-0376.
Liu YH, Zhu WL. Effects of cetuximab combined with afatinib on the expression of KDR and AQP1 in lung cancer. Genet Mol Res. 2015;14:16652-61. doi: 10.4238/2015.
Chang JW, Kang SU, Shin YS, Seo SJ, Kim YS, Yang SS, et al. Combination of NTP with cetuximab inhibited invasion/migration of cetuximab-resistant OSCC cells: Involvement of NF-κB signaling. Sci Rep. 2015;5:18208.
Qian M, Qian D, Jing H, Li Y, Ma C, Zhou Y. Combined cetuximab and celecoxib treatment exhibits a synergistic anticancer effect on human oral squamous cell carcinoma in vitro and in vivo. Oncol Rep. 2014;32:1681-8.
Jedlinski A, Garvin S, Johansson AC, Edqvist PH, Ponten F, Roberg K. Cetuximab sensitivity of head and neck squamous cell carcinoma xenografts is associated with treatment-induced reduction in EGFR, pEGFR, and pSrc. J Oral Pathol Med. 2016. doi: 10.1111/jop.12545.
Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11:21-8.