BERKELEY, CA (UroToday.com) - Transitional cell bladder cancer is the most common malignancy of the urinary tract and about 75% of these tumours are low stage (Ta-T1), non-muscle invasive malignancies (NMIBC). Current treatments are frequently associated with low efficacy leading to tumour progression and recurrence. Active, specific immunotherapy-targeting antigens predominantly expressed by tumour cells may provide a valid option for patients with NMIBC.
Cancer-testis antigens (CTA) are tumour-associated antigens expressed in various types of cancer and in a very limited number of healthy tissues such as testicular germ cells, thymus, and placenta.[3, 4, 5] MAGE-A10 CTA is a highly immunogenic antigen of the MAGE-A family[6, 7, 8] expressed in different types of cancer,[8, 9, 10, 11, 12, 13] therefore representing an attractive target of active specific immunotherapy. The gene encoding MAGE-A10 was recently shown to be expressed in more than one-third of high-grade transitional cell bladder carcinomas.
In our study, we showed that MAGE-A10 gene expression is specifically detectable in 24 of 74 (32.43%) of NMIBC specimen but not in the adjacent normal tissues, and that its expression correlates significantly with tumour grade. At the protein level, MAGE-A10 is exclusively detectable in the nucleus of NMIBC cells. Most of all, specific staining is also significantly more frequently observed in high-grade as compared to low-grade tumours, and in tumours invading subepithelial tissue or the lamina propria (stage T1) as compared to non-invasive malignancies (stage Ta). The strong correlation between specific staining score in NMIBC and tumour grade and stage suggests that MAGE-A10 protein expression might represent a feature of aggressive NMIBC.
Functions of CTA are still obscure.[15, 16, 17] Recent data suggest that proteins from the MAGE-A family might inhibit p53 tumour suppressor functions, thereby promoting the survival of proliferating tumour cells.[18, 19, 20] Indeed, MAGE-A proteins were demonstrated by Yang et al. to be able to form complexes with the KRAB-associated protein1 (KAP1) known to be a co-repressor of p53. The induction of the inhibition of p53 expression and function, resulting in apoptosis suppression, may suggest an active contribution of MAGE-A proteins to tumour development. Similarly, MAGE-A proteins -- and in particular MAGE-A2 -- were shown to repress p53 function also by forming complexes with HDAC3. These data suggest a high ability of MAGE-A proteins, frequently co-expressed in tumour tissues, to regulate p53 functions.
In about half of human cancers, wild-type p53 is either lost or mutated, allowing uncontrolled cell proliferation and tumour development.
These findings urged us to verify whether the expression of p53 in tissues from patients bearing NMIBC is associated with MAGE-A10 expression. We therefore evaluated the expression of the gene encoding the wild-type p53.
As shown in Figure 1, panels A and B, expression of the p53 gene is detectable in NMIBC tissues. Interestingly, levels of p53 gene expression are significantly lower in stage T1 (n=38) as compared to stage Ta (n=28) NMIBC (p=0.01; figure 1, panel A), as well as in high-grade (n=28) as compared to low-grade (n=38) NMIBC (p=0.04; figure 1, panel B). Remarkably, as shown in figure 1, panel C, our results show that levels of expression of the gene encoding wild-type p53 are significantly lower in the group of NMIBC concomitantly expressing MAGE-A10 gene as compared to MAGE-A10 negative cases. All in all, expression of p53 gene in NMIBC tissues is inversely correlated to MAGE-A10 gene expression (R=-0.36, p < 0.01, n=66).
Decreased p53 gene expression in high-grade NMIBC might promote the survival of proliferating malignant cells. Further studies are warranted to clarify whether MAGE-A10 plays an active role in the inhibition of p53 gene expression in NMIBC.
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Chantal Mengus, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.