Aklın Doğru Karar Vermesini Etkileyen Faktörler

A etiologia do câncer colorretal é heterogênea com influências ambientais e envolvimento genético. Aproximadamente, em 80% dos casos de câncer colorretal parece que a doença é esporádica, sem evidência de comprometimento hereditário. Entretanto, permanecem 20% de casos com potencial componente hereditário envolvido. A contribuição genética para o câncer colorretal inclui o aumento do risco em indivíduos com história familiar e famílias com alterações genéticas autossômicas dominantes. A identificação de lesões pré-malignas é um requisito indispensável para o rastreamento e prevenção do câncer colorretal. Sabe-se que muitos cânceres colorretais surgem de adenomas pré-existentes, usualmente como resultado de mutações no gene APC (polipose adenomatosa colônica) caracterizada por instabilidade cromossômica (Powell et al., 1992; Kinzler e Vogelstein, 1996). Entretanto, aproximadamente 10% a 15% dos cânceres colorretais surgem via instabilidade de microssatélite (MSI) e participação de uma variedade genética característica (Aaltonen et al., 1993; Ionov et al., 1993; Thibodeau et al., 1993; Perucho, 1996; Fujiwara et al., 1998; Jass et al., 1998). Mutações no APC são menos comuns nestes tumores e quando ocorrem é após MSI (Huang et al., 1996; Konishi et al., 1996; Perucho, 1996; Olschwang et al., 1997; Samowitz e Slattery, 1997). A lesão precursora em cânceres com MSI não tem sido facilmente identificada. Nos indivíduos com defeitos hereditários herdados (MMR) como HNPCC, os adenomas apresentam perda das proteínas do

MMR, sugerindo que sejam lesões precursoras do câncer colorretal (Aaltonen et al., 1994; Jacoby et al., 1995; Jass, 1995; Konishi et al., 1996). Por outro lado, MSI no câncer colorretal é mais comum que resulte de promoção da metilação silenciosa do gene humano hMLH1 (human mut-L homologue) (Kane et al., 1997; Cunnigham et al., 1998; Herman et al., 1998). Este é um importante grupo de cânceres colorretais que surgem no cólon direito, proximalmente à flexura esplênica. Há um crescente reconhecimento de que os pólipos hiperplásicos colorretais podem ser lesões neoplásicas, por conter alterações genéticas também encontradas no câncer colorretal, incluindo mutações no K-ras e MSI (Jen et al., 1994; Lothe et al., 1995; Konishi et al., 1996; Otori et al., 1997). Também tem sido reconhecido que algumas lesões hiperplásicas típicas podem apresentar displasia, fenômeno referido como variante de adenoma serrilhado ou misto de adenoma serrilhado com hiperplásico (Longacre et al., 1990). Mais recentemente, os pólipos hiperplásicos do cólon direito têm sido referidos como potenciais precursores de câncer colorretal esporádico (Jass et al., 2000b; Jass, 2001). No estudo de Hawkins e Ward (2001) analisaram-se os adenomas tubulares, vilosos, túbulo-vilosos e adenoma de crescimento lateral. Na análise dos pólipos serrilhados, os quais apresentam um padrão histológico misto de adenoma e hiperplásico, verificaram-se perdas das expressões do hMLH1 e hMSH2. Nesse estudo, procurou-se evidenciar a hipótese de que muitos cânceres colorretais esporádicos, com MSI, surgem de lesões pré-existentes como pólipos (Hawkins e Ward, 2001).

Os resultados desta investigação não comprovam esta teoria, desde que todos os pólipos hiperplásicos estudados não apresentaram alteração de imunoexpressão de marcadores.

Ciclooxigenase e seu derivado prostaglandina E2 têm sido apresentados como estimuladores do crescimento de células tumorais e promoverem a angiogênese. No estudo de Shao et al. (2005) foi sugerido outro mecanismo onde a PGE2 pode exercer ação pró-oncogênica através da estimulação das células beta- catenina/T, fator mediador de transcrição, que desempenham um papel na carcinogênese do câncer colorretal. Em outro estudo, Adegboyega et al. (2004) propuseram que os miofibroblastos subepiteliais são a fonte de aumento da imunoexpressão da Cox-2 nos adenomas de cólon, dando suporte para que a Cox-2 inicie precocemente a fase adenomatosa da carcinogênese colorretal.

Devido à prevalência elevada de pólipos acima dos 40 anos de idade, estes marcadores podem ser úteis na diferenciação daqueles pacientes que

deverão ser submetidos à colonoscopia com maior freqüência.

Este estudo pretende contribuir com informações iniciais sobre as expressões dos genes hMLH1, hMSH2 e da expressão da Cox-2 em adenomas esporádicos de cólon. A imunohistoquímica pode ser método utilizado nos pólipos adenomatosos de cólon no sentido da prevenção e tratamento de afecções a eles associadas. Com os dados da imunohistoquímica pode-se, talvez, modificar o

colonoscópicos rotineiros. Por outro lado, a expressão da Cox-2 alterada pela imunohistoquímica poderia permitir a intervenção quimioterápica preventiva e terapêutica nestes casos selecionados.

8. _CONCLUSÕES

Dentro das condições de realização da presente investigação, pode-se concluir que:

1. As alterações de imunoexpressões de hMLH1 e Cox-2 em adenomas e adenocarcinomas de cólon, em pacientes sem história familiar, são eventos relativamente freqüentes, porém a imunoexpressão do hMSH2 não foi significativa; 2. Não houve alterações de imunoexpressão dos marcadores estudados nos pólipos hiperplásicos, sugerindo a benignidade destas lesões;

3. A imunoexpressão da Cox-2 foi mais freqüente nos adenomas múltiplos e adenocarcinomas colorretais.

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