6 COMENTÁRIOS, CRÍTICAS E CONCLUSÕES

Na pesquisa, focando nesses fatores prognósticos, optamos em avaliar 6 marcadores imunohistoquímicos e correlacionar com os fatores clínico-patológicos dos cânceres colorretais. Os marcadores imunohistoquímicos que participam na progressão tumoral (E-Caderina, Beta catenina e Galectina 3), invasão tumoral (MMP-2 e MMP-9) e angiogênese tumoral (VEGF-α) apontaram correlação com o prognóstico do paciente.

O objetivo deste estudo foi identificar as características clínicas e patológi- cas do CCR de registros hospitalares no Brasil e correlacioná-las com proteínas de progressão tumoral, invasão tumoral e angiogênese tumoral pela técnica de imuno- histoquímica.

Podemos explicitar os seguintes méritos desta pesquisa: a técnica de Tissue Microarray para o armazenamento das amostras dos tumores colorretais na USP, a realização da imunohistoquímica no nosso laboratório da Universidade Federal do Rio Grande do Norte e a originalidade para análise dos fatores de riscos proteicos de progressão tumoral, disseminação e angiogênese no estado do RN.

Vale ressaltar que a falta de informação dos prontuários limitou um pouco os estudos desta pesquisa baseados em bancos de dados probabilísticos.

Dentre as dificuldades encontradas, há o fato de se ter feito a TMA em São Paulo (USP), já que isso aumentou os custos, devido à distância e aos gastos associados ao deslocamento e hospedagem. Esse deslocamento ocorreu, porque a TMA é uma técnica não realizada nos nossos nosocômios.

Como perspectivas de estudos posteriores, algumas perguntas podem ser res- pondidas em trabalhos futuros relacionados aos mesmos marcadores proteicos e com novos marcadores. Podemos destacar, por exemplo, outras proteínas, como Ki-67, Cicloxigenase-2, Caspase-3 e Bcl-2 que participam na proliferação tumoral e que po- derão ser inseridas em futuras pesquisas para análise imunohistoquímica nos CCR.

Em conclusão, nossos resultados confirmam repetidamente o papel crítico da E-caderina, β-catenina, galectina-3, MMP-2, MMP-9 e VEGF alfa na carcinogê- nese colorretal. Além disso, os padrões de expressão são confiáveis para prever o potencial de câncer colorretal prognóstico. Portanto, o método pode ter implicações relevantes no manejo terapêutico destes cânceres.

REFERÊNCIAS

1.Jemal A, et al. Cancer statistics. Cancer J Clin, v.58, p.71-90, 2008.

2.Kohler BA, Sherman RL, Howlader N, Jemal Ahmedin, Ryerson AB, Henry KA, Boscoe FP, Cronin KA, Lake A, Noone AM, Henley J, Eheman CR, Anderson RN, Penberthy L. Annual Re- port to the Nation on the Status of Cancer, 1975 -2011, Featuring Incidence of Breast Can- cer Subtypes by Race/Ethnicity, Poverty, and State. J Natl Ca Inst., v.107, n.6, Mar, 2015.

3. Medeiros FJ. Manual de sobrevivência para nutrição clínica. Rio de Janeiro: Guana-

bara Koogan, 2009.

4. Han SA, Chun H, Park CM, Kang SJ, Kim SH, Sohn D, Yun SH, Lee WY. Prognostic significance of beta-catenin in colorectal cancer with liver metastasis. Clin Oncol (R

Coll Radiol), v.18, n.10, p.761-7, 2006.

5. Levin B. Colorectal cancer. ACP Medicine. p. 1-16, 2006.

6. INCA - Instituto Nacional de Câncer. Estimativa 2014. Rio de Janeiro: INCA, 2015. Dis-

ponivél em: <http://www.inca.gov.br/estimativa/2014/index.asp?ID=1>. Acesso e: 05 abr 15. 7. Hughes KS, Simon R, Songhorabodi S, Adson MA, Ilstrup DM, Fortner JG, et al. Resec- tion of the liver for colorectal carcinoma metastases: a multi-institutional study of patterns of recurrence. Surgery, v.100, n.2: p.278-84, 1986.

8. Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, et al. Bevaci- zumab plus oxaliplatin-based chemo- therapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol, v.13, n.12, p.1225-33, 2012.

9. Hwang M, Jayakrishnan TT, Green DE, George B, Thomas JP, Groeschl RT, Erickson B, Pappas SG, Gamblin TC and Turaga KK. Systematic review of outcomes of patients undergoing resection for colorectal liver metastases in the setting of extra hepatic disease. Eur J Cancer, v.50, n.10, p.1747-57, 2014.

10. NCCN, 2015. Disponivel em: <http://www.nccn.org/professionals/physician_gls/pdf/co- lon.pdf>. Acesso em: 07 abr 15.

11. Bolocan A, Ion D, Ciocan DN, Paduraru DN. Prognostic and Predictive Factors in Colorectal Cancer. Chirurgia, v.107, n.5, p.555-563, sep-oct, 2012.

12. WCRF - World Cancer Research Fund / American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Wash-

13. Treanor, D., Quirke P. Pathology of Colorectal Cancer. Clinical Oncology, v.19, p.769

-76, 2006.

14. Divitiis CD, Nasti G, Montano M, Fisichelle R, Laffaioli RV, Berretta M. Prognostic fac- tors in colorectal cancer patients. World J Gastroenterol, v.20, n.41, November 7, 2014.

15. Coppedè F, Lopomo A, Spisni R, Migliore L. Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer. World J Gastroenterol. V.20,

n.4, 943-956, January 28, 2014.

16. Hanahan D, Weinberg RA. The Hallmarks of Cancer. Cell, v.100, p.57–70, January 7,

2000.

17. Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell, v.144,

March 4, 2011.

18.Chen S, Liu J, Li G, Mo F, Xu X, Zhang T, Li J, Han X, Sun Y. Altered distribution of betacatenin and prognostic roles in colorectal carcinogenesis. Scandinavian journal of

gastroenterology, v.43, n.4, p.456-64, 2008.

19.Tsuboi K, Shimura T, Masuda N, Ide M, Tsutsumi S, Yamuguchi S, Asao T, Kuwano H.

Galectin-3 Expression in Colorectal Cancer: Relation to Invasion and Metastasis. An-

ticancer Res, v.27, n.4B, p.2289-96, jul-aug, 2007.

20.Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogen- esis. Nature, v.473, p.298-307, 2011.

21. Shi M, Yu B, Gao H, Mu J, Ji C. Matrix metalloproteinase 2 overexpression and prognosis in colorectal cancer: a meta-analysis. Mol Biol Rep, v.40, p.617–623, 2013.

22. Li CY, Yuan P, Lin SS, Song CF, Guan Wy, Yuan L, Lai RB, Gao Y, Wang Y. Matrix metal- loproteinase 9 expression and prognosis in colorectal cancer: a meta-analysis. Tumor

Biol, v.34, p.735–741, 2013.

23. Said AH, Raufman JP, Xie G. The Role of Matrix Metalloproteinases in Colorectal Cancer. Cancers, v.6, p.366-375, 2014.

24. Zlobec I, Lugli J. Prognostic and predictive factors in colorectal cancer. J Clin Pathol,

v.61, n.5, p.561-9, maio, 2008.

25. Vogel U. Overview on Techniques to Construct Tissue Arrays with Special Empha- sis on Tissue Microarrays. Microarrays, v.3, p.103-136, 2014.

26. Araújo Jr RF, Lira GA, Guedes, HG, Cardoso MA, Cavalcante FJ, Araújo ALM, Ramos

CCO, Araújo AA. Lifestyle and family history influence cancer prognosis in Brazilian individuals. Pathology – Research and Practice, v.209, p.753-757, 2013.

27. Araújo Jr RF, Lira GA, Vilaça JÁ, Guedes HG, Leitão MCA, Lucena HF, Ramos CCO.

Prognostic and diagnostic implications of MMP-2, MMP-9, and VERGF expressions in colorectal cancer. Pathology – Research and Practice, v.211, p.71-77, 2015.

28. Araújo Jr RF, Lira GA, Souto KKO, Ramos CCO, Santos VM, Pinheiro LV, Araújo AA.

Expression of E-Cadherin, B-catenin and galectin-3 influence prognosis in colorectal cancer. Annals of Human Biology, 2015.

29. Kelley RK, Venook AP. Prognostic and Predictive Markers in Stage II Colon Cancer: Is There a Role for Gene Expression Profiling? Clinical Colorectal Cancer, v.10, n.2,

p.73-80, 2011.

30.Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell, v.141,

n.7, p.1117-34, jun, 2010.

31.Witsch E, Sela M, Yarden Y. Roles for growth factors in cancer progression. Physiol-

ogy, v.25, p.85-101, 2010.

32. Hynes NE, MacDonald G. ErbB receptors and signaling pathways in cancer. Curr

Opin Cell Biol, v.21, n.2, p.177-84, apr, 2009.

33. Birchmeier W, Weidner KM, Hulsken J, Behrens J. Molecular mechanisms leading to cell junction (cadherin) deficiency in invasive carcinomas. Seminars in cancer biology.

v.4, n.4, p.231-9, 1993.

34. Bruun J, Kolberg M, Nesland JM, Svindland, Nesbakken A, Lothe RA. Prognostic sig- nificance of β-catenin, E-cadherin, and SOX9 in colorectal cancer: results from a large population-representative series. Front Oncol, v.4, n.118, mayo, 2014.

35. Christinger HW, Muller YA, Berleau LT, Keyt BA, Cunningham BC, Ferrara N, Vos AB.

Crystallization of the receptor binding domain of vascular endothelial growth factor.

Proteins: Structure, Function, and Genetics, v.26, n.3, p. 353–357, 1996.

36. Dannenberg AJ, Altorki NK, Boyle JO, Dang C, Howe LR, Weksler BB, Subbaramaiah

K. Cyclo-oxygenase 2: a pharmacological target for the prevention of cancer. Lancet

Oncol, v.2, n.9, p. 544-51, 2001.

37. Jain RK. Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviat- ing Hypoxia. Cancer Cell, v.26, nov, 2014.

38. Jakob C, Liersch T, Meyer W, Becker H, Baretton GB, Aust DE. Predictive value of Ki67 and p53 in locally advanced rectal cancer: Correlation with thymidylate synthase and histopathological tumor regression after neoadjuvant 5-FU-based chemoradiothera- py. World J Gastroentero, v.14, n.7, p.1060-6, 2008.

39. Smith ML, Hawcroft G, Hull MA. The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: evidence of different mechanisms of action. Eur J

Cancer, v.36, n.5, p.664-74, 2000.

40. Cunningham, D. et al. Colorectal cancer. Lancet, v.375, n.9719, p.1030-47, 2010.

41. Duarte-Franco, E.; Franco, E. L. Epidemiologia e fatores de risco em câncer colorre- tal. In: Rossi, B. M. et al. Câncer de cólon, reto e ânus. São Paulo: Lemar Tecmedd Editora;

2004. p. 3-21.

42. Ferrigno, R. et al. Neoadjuvant radiochemotherapy in the treatment of fixed and semi-fixed rectal tumors. Analysis of results and prognostic factors. Radiat Oncol. v.1, n.5,

2006.

43. García-Aguilar, J. et al. A pathologic complete response to preoperative chemoradi- ation is associated with lower local recurrence and improved survival in rectal cancer patients treated by mesorectal excision. Dis Colon Rectum, v.46, n.3, p.298-304, 2003.

44. Heald, R. J.; Rvall, R. D. Recurrence and survival after total mesorectal excision for rectal cancer. Lancet, v.1, n.8496, p.1479-82, 1986.

45. Kapiteiin, E. et al. Preoperative radiotherapy combined with total mesorectal exci- sion for resectable rectal cancer. N Engl J Med., v.345, n.9, p.638-46, 2001.

46. Nakagawa, W. T. et al. Chemoradiation instead of surgery to treat mid and low rec- tal tumors: is it safe? Ann Surg Oncol. v.9, n.6, p.568-73, 2002.

47. Vieira, R. A. et al. Prognostic factors in locally advanced colon câncer treated by extended resection. Rev. Hosp. Clin. Fac. Med., São Paulo, v.59, n.6, p.361-368, 2004.