BCL-2 Family protein expression in initial and recurrent glioblastomas: modulation by radiochemotherapy

Abstract

Objective-In vitro studies indicate a role of apoptosis regulatory proteins of the BCL-2 family in the resistance of glioblastoma multiforme to irradiation and chemotherapy. To date, no study has compared the expression of these proteins in initial and recurrent tumours. The diVerences of expression of BCL-2, BCL-X, BAX, and MCL-1 proteins of paired first resection and recurrence glioblastoma specimens were examined. Methods-Immunohistochemistry was performed in 37 cases of glioblastoma multiforme with paraYn embedded tissue from first resections and their recurrences in three treatment groups (15 radiochemotherapy, 15 irradiation, seven untreated). Ten high power fields were evaluated with an arbitrary score (< 5%=1, 5-50%=2, >50%=3), and cumulative scores for each antigen calculated. Results-In the whole group, we found a significant up regulation of antiapoptotic BCL-2 (median cumulative score of 15 in the primary, 19 at recurrence; p<0.0001 in the Wilcoxon test), BCLX (median scores 20 and 25, respectively, p<0.0001), and MCL-1 (median scores 11 and 14, p=0.0395), and a significant down regulation of proapoptotic BAX (median scores 14 and 11, p<0.0001). In the subgroups, these trends were also found. No association between protein expression and treatment regimen was found, although significant changes were restricted to the subgroups that received adjuvant chemotherapy. No significant correlation with clinical prognosis was detected with the Kaplan-Meier method. Conclusions-In the development from initial to recurrent glioblastoma multiforme, the BCL-2 family rheostat shifts towards antiapoptotic adjustment in vivo. Importantly, the changes in BCL-2 family protein expression characterised here were also seen in the subgroup of patients who did not receive adjuvant radiotherapy or chemotherapy, suggesting that the changes of BCL-2 family protein expression result not only from radiochemotherapy but also reflect the natural course of disease.

What drives intense apoptosis resistance and propensity for necrosis in glioblastoma? A role for Bcl2L12 as a multifunctional cell death regulator

“…In the progression from initial to recurrent GBM, anti-apoptotic Bcl-2 proteins are upregulated and pro-apoptotic members are downregulated. 13 In support of a role for Bcl-2 in GBM, antisense-mediated neutralization resulted in decreased cell growth in vitro; 14 however, increased Bcl-2 expression in high-grade gliomas has been shown to correlate positively with survival. 15 Bcl-x L , another anti-apoptotic family member, is upregulated as a result of overexpression of activated mutant EGFR (EGFRvIII) to increase resistance to the chemotherapeutic agent cisplatin.…”

High expression of XIAP and Bcl-2 may inhibit programmed cell death in glioblastomas

“…Our results support this hypothesis, demonstrating a significant difference in the expression of XIAP and Bcl-2, both anti-apoptotic genes, in glioblastomas, and it can suggest that the cellular death triggered by the apoptosis intrinsic pathway was inhibited in these tumors. Strik et al, also showed that the changes in Bcl-2 family protein expression can result from radiochemotherapy, but also reflect the natural course of disease 19 . Several proteins are released from the mitochondrial intermembrane space into the cytoplasm, including cytochrome C and Smac/DIABLO.…”

Expressão das proteínas BCL-2 e BAX em tumores astrocíticos humanos

“…Fels et al (9) haviam detectado propensão similar quanto à positividade para BCL-2 nos tumores astrocíticos de alto grau (48% no grau III; 51% no IV), ao passo que Ellison et al (8) descreveram inclinação oposta (44% no grau II; 42% no III; 28% no IV). Recentemente, Strik et al (22) e Kraus et al (15) confirmaram a tendência de maior positividade entre os astrocitomas grau IV (94,6% e 60,25%, respectivamente), reforçando o perfil aqui reportado. Possíveis comparações semiquantitativas acerca da expressão de BCL-2 em tumores astrocíticos foram impossibilitadas pela inexistência de estudos anteriores de moléculas relacionadas à apoptose (10) , consolidando as diferenças entre os tumores do grau I estudados (astrocitomas pilocíticos) e os astrocitomas grau II, esses últimos sabidamente propensos à progressão para fenótipos mais malignos (13) .…”

“…Todavia essas variações podem ser mais bem compreendidas quando avaliadas ante o equilíbrio entre as tendências pró e antiapoptótica (25) . Os escassos estudos até então publicados acerca da expressão imuno-histoquímica de BAX nos tumores astrocíticos relatam apenas a alta freqüência da detecção de BAX nos glioblastomas (78% (22) , 94% (4) , 98% (14) ), diferentemente da moderada positividade reportada no presente estudo (47,62% (18) .…”