gms | German Medical Science

Objective: To assess the relation of gene expression levels of matrix metalloproteinases (MMPs) and "A Disintegrin and Metalloprotease Domain" (ADAM) proteins with invasiveness in human pituitary adenomas, as such proteins are known to be related with invasiveness in other tumor entities.

Method: 35 consecutive cases of pituitary adenomas (9 female, 26 male patients, mean age at the time of surgery: 43.5 years (range: 18 - 86 years)) were included, of which 3 were recurrent tumors. Maximum tumor diameters were less than 10 mm (2 cases), 10 - 30 mm (24 cases) and more than 30 mm (9 cases). 18 tumors were classified invasive according to the Knosp scale. We recorded 25 nonfunctional adenomas, 3 growth hormone secreting adenomas, 3 prolactinomas refractory to conservative treatment, 3 corticotroph adenomas, and 1 gonadotroph adenoma. Quantitative real-time polymerase chain reaction (qPCR) was employed to assess relative messenger ribonucleic acid (mRNA) expression of 15 MMP and 6 ADAM genes in tumor samples. Western blots were obtained for MMP-9, pro-MMP-2, active MMP-2, pro-MMP-14, active MMP-14, pro-ADAM12, active ADAM12, cleaved ADAM12, and beta-tubulin in 4 representative samples from non-invasive and 4 representative samples from invasive tumors. Immunohistochemistry staining was carried out for MMP-2, MMP-9, and ADAM12 in samples from non-invasive and invasive tumors. Mean values, standard deviations and Pearson's correlation coefficients (r) were calculated. P less than 0.05 was considered statistically significant. Approval from the local ethics committee was obtained prior to the study.

Results: In invasive tumors, qPCR demonstrated a significantly induced expression of MMP-2, MMP-9, MMP-14, and ADAM12 as compared to other MMP and ADAM genes. In Western blots, selective enrichment for MMP-9, pro-MMP-2, active MMP-2, pro-MMP-14, active MMP-14, and active ADAM12 was observed in samples from invasive tumors. In addition, invasive tumors displayed strong immunostaining for MMP-2, MMP-9, and ADAM12 as compared to non-invasive tumors. A positive correlation was observed for co-expression of MMP-2 and MMP-14 (p < 0.0001, r = 0.78), MMP-9 and MMP-14 (p = 0.0022, r = 0.50), and ADAM12 and MMP-14 (p = 0.0001, r = 0.61).

Conclusions: The expression pattern of proteases observed here is indicative of invasiveness in pituitary adenomas. Further investigation as to the impact of particular proteases on invasiveness is warranted to define potential targets for tumor control in invasive pituitary adenomas.