Купить СНПЧ А7 Архангельск, оперативня доставка


Análise das Proteínas Envolvidas na Angiogênese em Desordens Potencialmente Malignas e no Carcinoma Espinocelular

DOI: http://dx.doi.org/10.15602/1983-9480/cmrs.v17nespp31-45



Carlos A. N. Bernardes1, Leonardo F. Diel1, Alessandra Magnusson1, Lisiane Bernardi1 & Marcelo L. Lamers1


Resumo: O carcinoma espinocelular é responsável por 90% das lesões orais. Os carcinomas podem se desenvolverde células epiteliais normais ou de desordens potencialmente malignas(hiperplasias e displasias). Para que estas lesões se desenvolvam é necessária a formação de novos vasos. Este processo, denominado angiogênese, envolve a regulação de diferentes fatores, como Angiopoetina1 e Trombospondina1, que podem ser influenciadas pelas células epiteliais ecomponentes do microambiente da lesão. Nosso objetivofoi descrever a expressão de angiopoetina1 e trombospondina1 em biópsias de desordens potencialmente malignas e em carcinoma espinocelular oral.A amostra composta por biópsias de hiperplasia, displasia eca r c i noma. As lâminas f oram submetidas àimunoistoquímica.Foi analisada da marcaçãoemtecido epitelial econjuntivo. Angiopoetinamarcounas células endoteliaiscom leve marcação nas células da camada basal do epitélio, sendo observada uma redução da intensidade de marcação com aumento daseveridade, aumentando em células do microambiente tumoral. Trombospondina marcouheterogeneamentenos tecidos, com um aumento da marcação em macrófagos e fibroblastos de acordo com a severidade da lesão. O perfil diferenciadodestes marcadores em células epiteliais modificadas e em células do microambiente celular evidencia a necessidade de mais estudos que explorem a diversidade celular destas lesões, para aprimorar as terapias anti-angiogênicas.

Palavras-chave: Angiopoetina, Trombospondina, Displasia, microambiente tumoral.


1 Faculdade de Odontologia da Universidade Federal do Rio Grande do Sul.


Literatura Citada

Adams, R. H. and K. Alitalo (2007). “Molecular regulation of angiogenesis and lymphangiogenesis.” Nat Rev Mol Cell Biol8(6): 464-478.

Akhter, M., S. Hossain, Q. B. Rahman and M. R. Molla (2011). “A study on histological grading of oral squamous cell carcinoma and its co-relationship with regional metastasis.” Journal of Oral and Maxillofacial Pathology : JOMFP15(2): 168-176.

Alfieri, A., A. C. M. Ong, R. A. Kammerer, T. Solanky, S. Bate, M. Tasab, N. J. Brown and Z. L. Brookes (2014). “Angiopoietin- 1 regulates microvascular reactivity and protects the microcirculation during acute endothelial dysfunction: Role of eNOS and VE-cadherin.” Pharmacological Research80: 43-51.

Amagasa, T., M. Yamashiro and N. Uzawa (2011). “Oral premalignant lesions: from a clinical perspective.” International Journal of Clinical Oncology 16(1): 5-14.

Anisimov, A., D. Tvorogov, A. Alitalo, V.-M. Leppänen, Y. An, E. C. Han, F. Orsenigo, E. I. Gaál, T. Holopainen, Y. J. Koh, T. Tammela, P. Korpisalo, S. Keskitalo, M. Jeltsch, S. Ylä-Herttuala, E. Dejana, G. Y. Koh, C. Choi, P. Saharinen and K. Alitalo (2013). “Vascular Endothelial Growth Factor-Angiopoietin Chimera With Improved Properties for Therapeutic Angiogenesis.” Circulation127(4): 424-434.

Barnes, L., W. H. Organization and I. A. f. R. o. Cancer (2005). Pathology and Genetics of Head and Neck Tumours, IARC Press.

Bonnefoy, A., R. Moura and M. F. Hoylaerts (2008). “Thrombospondins: from structure to therapeutics.” Cellular and Molecular Life Sciences65(5): 713-727.

Bridges, E. M. and A. L. Harris (2011). “The angiogenic process as a therapeutic target in cancer.” Biochemical Pharmacology81( 10): 1183-1191.

Brunckhorst, M. K., Y. Xu, R. Lu and Q. Yu (2014). “Angiopoietins Promote Ovarian Cancer Progression by Establishing a Procancer Microenvironment.” The American Journal of Pathology 184(8): 2285-2296.

Bryne, M., H. S. Koppang, R. Lilleng and A. Kjaerheim (1992). “Malignancy grading of the deep invasive margins of oral squamous cell carcinomas has high prognostic value.” Journal of Pathology166(4): 375-381.


Carmeliet, P. (2005). “Angiogenesis in life, disease and medicine.” Nature 438(7070): 932-936.

Carnelio, S., G. S. Rodrigues, R. Shenoy and D. Fernandes (2011). “A Brief Review of Common Oral Premalignant Lesions with Emphasis on Their Management and Cancer Prevention.” The Indian Journal of Surgery73(4): 256-261.

Carreras-Torras, C. and C. Gay-Escoda (2015). “Techniques for early diagnosis of oral squamous cell carcinoma: Systematic review.” Medicina Oral, Patología Oral y Cirugía Bucal 20(3): e305-e315.

Chien, C.-Y., C.-Y. Su, H.-C. Chuang, F.-M. Fang, H.-Y. Huang, C.-M. Chen, C.-H. Chen and C.-C. Huang (2008). “Angiopoietin-1 and -2 expression in recurrent squamous cell carcinoma of the oral cavity.” Journal of Surgical Oncology97( 3): 273-277.

Clydesdale, G. J., G. W. Dandie and H. K. Muller (2001). “Ultraviolet light induced injury: Immunological and inflammatory effects.”Immunol Cell Biol79(6): 547-568.

DE LIMA, P. O., C. C. JORGE, D. T. OLIVEIRA and M. C. PEREIRA (2014). “Hypoxic Condition and Prognosis in Oral Squamous Cell Carcinoma.” Anticancer Research 34(2): 605-612.

De Palma, M. and L. Naldini (2011). “Angiopoietin-2 TIEs Up Macrophages in Tumor Angiogenesis.” Clinical Cancer Research 17(16): 5226-5232.

Detmar, M. (2000). “Tumor Angiogenesis.” J Investig Dermatol Symp Proc 5(1): 20-23.

Dionne, K. R., S. Warnakulasuriya, R. Binti Zain and S. C. Cheong (2015). “Potentially malignant disorders of the oral cavity: Current practice and future directions in the clinic and laboratory.” International Journal of Cancer136( 3): 503-515.

Eklund, L. and P. Saharinen (2013). “Angiopoietin signaling in the vasculature.” Experimental Cell Research319(9): 1271-1280.

El-Kenawi, A. E. and A. B. El-Remessy (2013). “Angiogenesis inhibitors in cancer therapy: mechanistic perspective on classification and treatment rationales.” British Journal of Pharmacology 170(4): 712-729.

Emeus, I., M. Bonsquenaud, B. Lenoir, Y. Devaux and D. R. Wagner (2015). “Adenosine stimulates angiogenesis by up-regulating production of thrombospondin-1 by macrophages.” Journal of Leukocyte Biology 97(1): 9-18.

Fagiani, E. and G. Christofori (2013). “Angiopoietins in angiogenesis.” Cancer Letters 328(1): 18-26.

Feinberg, A. P., R. Ohlsson and S. Henikoff (2006). “The epigenetic progenitor origin of human cancer.” Nat Rev Genet 7(1): 21-33.

Gacche, R. N. and R. J. Meshram (2013). “Targeting tumor micro-environment for design and development of novel anti-angiogenic agents arresting tumor growth.” Progress in Biophysics and Molecular Biology113(2): 333-354.

Giuliano, S. and G. Pagès (2013). “Mechanisms of resistance to anti-angiogenesis therapies.” Biochimie 95(6): 1110- 1119.

Hao, N.-B., M.-H. Lü, Y.-H. Fan, Y.-L. Cao, Z.-R. Zhang and S.-M. Yang (2012). “Macrophages in Tumor Microenviron ments and the Progression of Tumors.” Clinical and Developmental Immunology2012: 948098.

Hayashido, Y., M. Nakashima, K. Urabe, H. Yoshioka, Y. Yoshioka, T. Hamana, H. Kitano, K. Koizumi and T. Okamoto (2003). “Role of stromal thrombospondin-1 in motility and proteolytic activity of oral squamous cell carcinoma cells.” International journal of molecular medicine 12(4): 447-452.

HILLBERTZ, N. S., J.-M. HIRSCH, J. JALOULI, M. M. JALOULI and L. SAND (2012). “Viral and Molecular Aspects of Oral Cancer.” Anticancer Research32(10): 4201-4212.

Hoff, P. M. and K. K. Machado (2012). “Role of angiogenesis in the pathogenesis of cancer.” Cancer Treatment Reviews38(7): 825-833.

Jayachandran, A., M. Anaka, P. Prithviraj, C. Hudson, S. J. McKeown, P.-H. Lo, L. J. Vella, C. R. Goding, J. Cebon and A. Behren (2014). “Thrombospondin 1 promotes an aggressive phenotype through epithelial-to-mesenchymal transition in human melanoma.” Oncotarget 5(14): 5782-5797.

Jerjes, W., T. Upile, H. Radhi, A. Petrie, J. Abiola, A. Adams, P. Kafas, J. Callear, R. Carbiner, K. Rajaram and C. Hopper (2012). “The effect of tobacco and alcohol and their reduction/ cessation on mortality in oral cancer patients: short communication.” Head & Neck Oncology4: 6-6.

Johnson, N. W., P. Jayasekara and A. A. H. K. Amarasinghe (2011). “Squamous cell carcinoma and precursor lesions of the oral cavity: epidemiology and aetiology.” Periodontology 200057(1): 19-37.

Joyce, J. A. and J. W. Pollard (2009). “Microenvironmental regulation of metastasis.” Nat Rev Cancer9(4): 239-252.

Kaur, S. and P. Bajwa (2014). “A ‘tête-à tête’ between cancer stem cells and endothelial progenitor cells in tumor angiogenesis.” Clinical and Translational Oncology16(2): 115-121.

Khan, A. A., V. K. Sandhya, P. Singh, D. Parthasarathy, A. Kumar, J. Advani, R. Gattu, D. V. Ranjit, R. Vaidyanathan, P. P. Mathur, T. S. K. Prasad, F. Mac Gabhann, A. Pandey, R. Raju and H. Gowda (2014). “Signaling Network Map of Endothelial TEK Tyrosine Kinase.” Journal of SignalTransduction 2014: 173026.

Klozar, J., R. Tachezy, E. Rotnáglová, E. Košlabová, M. Saláková and E. Hamšíková (2010). “Human papillomavirus in head and neck tumors: epidemiological, molecular and clinical aspects.” Wiener Medizinische Wochenschrift160(11-12): 305-309.

Koh, G. Y. (2013). “Orchestral actions of angiopoietin-1 in vascular regeneration.” Trends in Molecular Medicine19( 1): 31-39.

Koontongkaew, S. (2013). “The Tumor Microenvironment Contribution to Development, Growth, Invasion and Metastasis of Head and Neck Squamous Cell Carcinomas.” Journal of Cancer4(1): 66-83.

Kumar, A., L. Cascarini, J. A. McCaul, C. J. Kerawala, D. Coombes, D. Godden and P. A. Brennan (2013). “How should we manage oral leukoplakia?” British Journal of Oral and Maxillofacial Surgery 51(5): 377-383.

Lamouille, S., J. Xu and R. Derynck (2014). “Molecular mechanisms of epithelial–mesenchymal transition.” Nat Rev Mol Cell Biol15(3): 178-196.

Lawler, P. R. and J. Lawler (2012). “Molecular Basis for the Regulation of Angiogenesis by Thrombospondin-1 and-2.” Cold Spring Harbor Perspectives in Medicine2(5):a006627.

Li, C., C.-j. Sun, J.-c. Fan, N. Geng, C.-h. Li, J. Liao, K. Mi, G.-q. Zhu, H. Ma, Y.-f. Song, Y.-l. Tang and Y. Chen (2013). “Angiopoietin-2 expression is correlated with angiogenesis and overall survival in oral squamous cell carcinoma.” Medical Oncology30(2): 1-10.

Li, H., J. Zhang, S.-W. Chen, L.-l. Liu, L. Li, F. Gao, S.-M. Zhuang, L.-p. Wang, Y. Li and M. Song (2015). “Cancer-associated fibroblasts provide a suitable microenvironment for tumor development and progression in oral tongue squamous cancer.” Journal of Translational Medicine13: 198.

Liu, Y.-T., L.-W. Lin, C.-Y. Chen, C.-P. Wang, H.-P. Liu, J.-Y. Houng, F.-M. Chung and T.-Y. Shieh (2012). “Polymorphism of angiotensin I-converting enzyme gene is related to oral cancer and lymph node metastasis in male betel quid chewers.” Oral Oncology48(12): 1257-1262.

Lopez-Dee, Z., K. Pidcock and L. S. Gutierrez (2011). “Thrombospondin-1: Multiple Paths to Inflammation.” Mediators of Inflammation2011: 296069.

Loughna, S. and T. N. Sato (2001). “Angiopoietin and Tie signaling pathways in vascular development.” Matrix Biology20( 5–6): 319-325.

Loureiro, A. P. M., P. Di Mascio and M. H. G. Medeiros (2002). “Exocyclic DNA adducts: Implications in mutagenesis and carcinogenesis.” Quimica Nova25(5): 777-793.

Marocchio, L. S., J. Lima, F. F. Sperandio, L. Corrêa and S. O. M. de Sousa (2010). “Oral squamous cell carcinoma: an analysis of 1,564 cases showing advances in early detection.” Journal of Oral Science 52(2): 267-273.

Metheny-Barlow, L. J. and L. Y. Li (2003). “The enigmatic role of angiopoietin-1 in tumor angiogenesis.” Cell Res 13(5): 309-317.

Monk, B. J., A. Poveda, I. Vergote, F. Raspagliesi, K. Fujiwara, D.-S. Bae, A. Oaknin, I. Ray-Coquard, D. M. Provencher, B. Y. Karlan, C. Lhommé, G. Richardson, D. G. Rincón, R. L. Coleman, T. J. Herzog, C. Marth, A. Brize, M. Fabbro, A. Redondo, A. Bamias, M. Tassoudji, L.

Navale, D. J. Warner and A. M. Oza (2014). “Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial.” The Lancet Oncology15(8): 799-808.

Muthu Rama Krishnan, M., P. Shah, M. Pal, C. Chakraborty, R. R. Paul, J. Chatterjee and A. K. Ray (2010). “Structural markers for normal oral mucosa and oral sub-mucous fibrosis.” Micron 41(4): 312-320.

Patel, A. S., A. Smith, S. Nucera, D. Biziato, P. Saha, R. Q. Attia, J. Humphries, K. Mattock, S. P. Grover, O. T. Lyons, L. G. Guidotti, R. Siow, A. Ivetic, S. Egginton, M. Waltham, L. Naldini, M. De Palma and B. Modarai (2013). “TIE2-expressingmonocytes/macrophages regulate revascularization of the ischemic limb.” EMBO Molecular Medicine 5(6): 858-869.

Patel, S. G. and J. P. Shah (2005). “TNM Staging of Cancers of the Head and Neck: Striving for Uniformity Among Diversity.” CA: A Cancer Journal for Clinicians55(4): 242-258. Potente, M., H. Gerhardt and P. Carmeliet (2011). “Basic and Therapeutic Aspects of Angiogenesis.” Cell146(6): 873-887.

Qin, Q., J. Qian, L. Ge, L. Shen, J. Jia, J. Jin and J. Ge (2014). “Effect and Mechanism of Thrombospondin-1 on the Angiogenesis Potential in Human Endothelial Progenitor Cells: An In Vitro Study.” PLoS ONE9(2): e88213.

Resovi, A., D. Pinessi, G. Chiorino and G. Taraboletti (2014). “Current understanding of the thrombospondin-1 interactome.” Matrix Biology 37: 83-91.

Rivera, C. and B. Venegas (2014). “Histological and molecular aspects of oral squamous cell carcinoma (Review).” Oncology Letters8(1): 7-11.

Roodink, I. and W. P. J. Leenders (2010). “Targeted therapies of cancer: Angiogenesis inhibition seems not enough.” Cancer Letters299(1): 1-10.

Rosca, E. V., J. E. Koskimaki, C. G. Rivera, N. B. Pandey, A. P. Tamiz and A. S. Popel (2011). “Anti-angiogenic peptides for cancer therapeutics.” Current pharmaceutical biotechnology 12(8): 1101-1116.

Sasahira, T., T. Kirita and H. Kuniyasu (2014). “Update of molecular pathobiology in oral cancer: a review.” International Journal of Clinical Oncology19(3): 431-436.

Sawazaki-Calone, I., A. Rangel, A. G. Bueno, C. F. Morais, H. M. Nagai, R. P. Kunz, R. L. Souza, L. Rutkauskis, T. Salo, A. Almangush and R. D. Coletta (2015). “The prognostic value of histopathological grading systems in oral squamous cell carcinomas.” Oral Diseases21(6): 755-761.

Seok, S. H., J. I. Heo, J. H. Hwang, Y. R. Na, J. H. Yun, E. H. Lee, J. W. Park and C. H. Cho (2013). “Angiopoietin-1 elicits pro-inflammatory responses in monocytes and differentiating macrophages.” Molecules and cells35(6): 550-556.

Shojaei, F. (2012). “Anti-angiogenesis therapy in cancer: Current challenges and future perspectives.” Cancer Letters320( 2): 130-137.

Szabo, C. (2015). “Editorial: Old dog, new tricks: proangiogenic effect of adenosine via stimulation of thrombospondin- 1 in macrophages.” Journal of Leukocyte Biology97(1): 3-5.

Tanaka, T. and R. Ishigamori (2011). “Understanding Carcinogenesis for Fighting Oral Cancer.” Journal of Oncology2011: 603740.

Tsantoulis, P. K., N. G. Kastrinakis, A. D. Tourvas, G. Laskaris and V. G. Gorgoulis (2007). “Advances in the biology of oral cancer.” Oral Oncology43(6): 523-534.

Vairaktaris, E., C. Yapijakis, A. Vylliotis, S. Derka, S. Vassiliou, E. Nkenke, Z. Serefoglou, V. Ragos, E. Critselis, D. Avgoustidis, F. Neukam and E. Patsouris (2008). “Angiotensinogen polymorphism is associated with risk for malignancy but not for oral cancer.” Anticancer Research28(3 A): 1675-1679.

van der Waal, I. (2014). “Oral potentially malignant disorders: Is malignant transformation predictable and preventable?” Medicina Oral, Patología Oral y Cirugía Bucal19(4): e386-e390.

Vasudev, N. and A. Reynolds (2014). “Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions.” Angiogenesis17(3): 471-494.

Wang, T. N., X.-h. Qian, M. S. Granick, M. P. Solomon, V. L. Rothman and G. P. Tuszynski (1995). “The effect of thrombospondin on oral squamous carcinoma cell invasion of collagen.” The American Journal of Surgery 170(5): 502-505.

Warnakulasuriya, S., T. Dietrich, M. M. Bornstein, E. C. Peidró, P. M. Preshaw, C. Walter, J. L. Wennström and J. Bergström (2010). “Oral health risks of tobacco use and effects of cessation.” International Dental Journal60(1): 7-30.

Weis, S. M. and D. A. Cheresh (2011). “Tumor angiogenesis: molecular pathways and therapeutic targets.” Nat Med 17(11): 1359-1370.

Welti, J., S. Loges, S. Dimmeler and P. Carmeliet (2013). “Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer.” The Journal of Clinical Investigation123(8): 3190-3200.

Wenig, B. M. (2002). “Squamous Cell Carcinoma of the Upper Aerodigestive Tract: Precursors and Problematic Variants.” Mod Pathol 15(3): 229-254.

William Jr, W. N. (2012). “Oral premalignant lesions: Any progress with systemic therapies?” Current Opinion in Oncology24(3): 205-210.

William, W. N. J. (2012). “Oral premalignant lesions: any progress with systemic therapies?” Current Opinion in Oncology24(3): 205-210.

Yao, L., Y.-L. Zhao, S. Itoh, S. Wada, L. Yue and I. Furuta (2000). “Thrombospondin-1 expression in oral squamous cell carcinomas: correlations with tumor vascularity, clinicopathological features and survival.” Oral Oncology36( 6): 539-544.

Yardimci, G., Z. Kutlubay, B. Engin and Y. Tuzun (2014). “Precancerous lesions of oral mucosa.” World Journal of Clinical Cases : WJCC2(12): 866-872.

Yoo, S. Y. and S. M. Kwon (2013). “Angiogenesis and Its Therapeutic Opportunities.” Mediators of Inflammation2013: 127170.

Zarei, M. R., G. Chamani and S. Amanpoor (2007). “Reactive hyperplasia of the oral cavity in Kerman province, Iran: A review of 172 cases.” British Journal of Oral and Maxillofacial Surgery45(4): 288-292.

Zulato, E., M. Curtarello, G. Nardo and S. Indraccolo (2012). “Metabolic effects of anti-angiogenic therapy in tumors.” Biochimie94(4): 925-931.