Pituitary adenomas are regarded generally as benign tumours, but some of them can invade the cavernous sinus. On the other hand, matrix metalloproteinase-9 (MMP-9), which is a type IV collagenase, recently has been found to be expressed in matastases and to be related to the invasiveness of various malignant tumours including brain tumours. In order to investigate some characteristic features of pituitary adenomas which invade the cavernous sinus, we examined immunohistological studies for MMP-9 in seven pituitary adenomas for type IV collagen in a dura mater and assayed for type IV collagenase activity in seven adenomas using type IV collagen labelled with fluorescein isothiocyaniate (FITC). We found immunopositive adenoma cells for MMP-9 in all invasive adenoma and immunopositive spindle like cells for type IV collagen in the dura mater. All three invasive adenomas had high levels of type IV collagenase activity (0.57-0.72 U/ml), but the four adenomas which did not invade the cavernous sinus had low levels of type IV collagenase activity (0.0-0.10 U/ml). These results suggest that the level of type IV collagenase activity in a pituitary adenoma may be related to its ability to invade the cavernous sinus.

The presence of the progesterone receptor (PR) in meningioma tissue has been confirmed by previous investigations. Studies have shown that the antiprogesterone drug, mifepristone, is a potent agent that inhibits the growth of cultured meningioma cells and reduces the size of meningiomas in experimental animal models and humans. However, these studies have not fully examined the relationship between the antitumor effects of an antiprogesterone agent and the expression of the PR. The present study examined the antitumor effects of mifepristone and a new potent antiprogesterone agent, onapristone; a correlation between the antitumor effects of these antiprogesterones and the presence of PR's in meningiomas in vitro and in vivo was also investigated. Meningioma tissue surgically removed from 13 patients was used in this study. In the in vitro arm of the study, mifepristone and onapristone exhibited cytostatic and cytocidal effects against cultured meningioma cells, regardless of the presence or absence of PR's; however, three PR-negative meningiomas showed no response to any dose of mifeprestone and/or onapristone. In the in vivo arm, meningioma cells, embedded in a collagen gel, were implanted into the renal capsules of nude mice. Antiprogesterone treatment resulted in a marked reduction of the tumor volume regardless of the presence or absence of PR's. No histological changes in the meningioma cells suggestive of necrosis or apoptosis were detected in any of the mice treated with antiprogesterones. These findings suggest that mifepristone and onapristone have an antitumor effect against meningioma cells via the PR's and/or another receptor, such as the glucocorticoid receptor.

Pituitary adenomas generally are regarded as benign tumours, but a part of them can invade the cavernous sinus and recur. We examined 43 pituitary adenomas for the following factors: tumour volume, endocrinological function, cavernous sinus invasion, and growth rates examined by using anti-proliferating cell nuclear antigen (PCNA) and MIB1 (a novel anti-Ki-67) as markers. There was significant correlation between PCNA- and MIB1-positive cell rates and PCNA- and MIB1-positive cell rates were higher in the three cases with rapid regrowth than in the other cases. Staining was stronger and more distinct for MIB1 than for anti-PCNA; thus, MIB1-positive cells were easily distinguished by their intense immunoreactivity. MIB1 may be useful for detecting those rare cases with rapid regrowth even when initially regarded as benign tumours. Adenomas with cavernous sinus invasion were significantly larger than those demonstrating no invasion. However, no significant difference was found in the frequency of PCNA- or MIB1-positive cells between adenomas with and without cavernous sinus invasion. These findings suggest that cavernous sinus invasion and growth rate are independent biological factors. Therefore, cavernous sinus invasion may be due to chemical factors produced by the tumour itself rather than as a result of rapid tumour growth.

Twenty-two pituitary adenomas were examined on the secretion of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) using a cell immunoblot assay, and discussed regarding an association between cavernous sinus invasion and the secretion of these proteins. The cell immunoblot assay, a kind of immunoblot procedure, is able to detect proteins at the single cell level and to detect the incidence of tumour cells secreting the target proteins in the total tumour cell population. The incidence of tumour cells secreting MMP-9 was significantly higher in invasive adenomas than in noninvasive ones. On the other hand, TIMP-1 secretion was not detected in any adenomas in this study. This result suggested that MMP-9 secretion, and especially the number of MMP-9-secreting cells, may be associated with cavernous sinus invasion of pituitary adenomas.

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