Contrary to earlier reports of absence of KIT expression in meningiomas, the present study showed its expression in 20.6% cases [18
]. Of these studies, the one on human solid tumors analyzed only 8 meningioma samples using the DAKO antibody we used in the present study but the staining protocol was not described in sufficient details [18
]. The second study was conducted on germinomas using the same antibody and similar protocol for KIT detection as those used in the present study. However, only one meningioma sample was examined [19
]. The third study systematically evaluated KIT expression in 37 meningiomas employing a similar staining protocol but a different anti-KIT antibody (MBL, Nagoya, Japan) [20
]. Therefore, it is difficult to attribute specific reason(s) to the observed deviation or to compare present study with the earlier ones.
We selected the anti-KIT antibody (DAKO) over other commercial antibodies based on its wide spread usage by different groups working on closely related fields [25
]. Nevertheless, wide variations are practised with regard to antigen retrieval methods and reagents used; and therefore a consensus staining protocol is yet to be established. Employing HIER, the DAKO antibody showed reduced KIT staining in soft tissue sarcomas, however staining of GISTs remained unaffected with or without antigen retrieval [25
]. Further, there are conflicting reports about effect of antigen retrieval on KIT staining observed in desmoids tumors [25
]. Therefore, in absence of a standard protocol, especially for meningiomas, the vendor’s specifications were followed with careful optimization in the present study. It is noteworthy that the relevant controls showed appropriate staining patterns and the KIT staining results were substantiated by immunoblotting using the same anti-KIT antibody (DAKO).
Graded co-expression of KIT and Zonulin (marker for degraded blood brain barrier) in different grades of brain tumors (5 GBMs and one case each of astrocytoma WHO III and meningioma WHO III) was reported earlier [37
]. A meningioma WHO I used as control lacked KIT expression but showed some Zonulin expression. Further, by co-staining Zonulin with a marker for blood vessels (GSI), it was demonstrated that the blood brain barrier was degraded in meningioma WHO III unlike meningioma WHO I. The current finding on the single meningioma grade III being KIT negative reflects a chance occurrence. Use of additional grade III tumor samples for KIT expression analyses would fully resolve this issue.
expression quantification in meningiomas was not performed thus far. To the best of our knowledge, data regarding KIT/KITLG expression in the context of meningioma cell lines is not available in public expression database (Array Express on EMBL-EBI). Reportedly, endogenous KITLG co-expression leads to activation of KIT receptors in glioma cell lines and other cancers [38
]. In the present study, quantification of KIT
transcripts revealed significant co-expression in the immunoreactive cases (Figures B and ). Further, with no discernible activating KIT
mutations in immunopositive meningioma cases, the receptor could possibly get activated via autocrine and/or paracrine modes in these tumors.
Remarkable concordance was observed between KIT immunoexpression and elevated KIT
transcript levels (Figures C and ). Incidentally, correlation between protein and mRNA expression levels was not always corroborative as in the cases of M10 and 37 (Figure ). It needs to be determined whether genetic, post-transcriptional or translational mechanisms; regulated in turn by molecules governing KIT expression, underlie these observations. Similar discordance between expression of gene at the transcript and protein levels has been reported earlier [41
]. Interestingly, case M29, despite loss of KIT
allele in the tumor tissue showed strong immunostaining and 1.61 fold higher levels of its transcript (Figure , Additional file 4
). This could be due to: i) altered pre-transcriptional regulation, ii) some unascertained post-transcriptional modification(s) or mutation(s) in the mRNA and/or iii) post-translational modification(s) in the protein leading to their respective stabilization.
M541L substitution observed in the transmembrane domain in a solitary meningioma case (M16) has also been reported amongst healthy individuals [42
]. This substitution was shown to be non-activating in vitro,
though this observation may not fully reconcile with an in vivo
Taken together, it would be of interest to pursue whether the enhanced KIT expression in subset of meningioma cases acts as a catalyst in, complicit to or as a consequence of the meningeal neoplastic process. Further, it would be vital to determine whether KIT immunopositive meningioma cases, indeed have an activated oncoprotein. Owing to insufficient quantum of resected tissues, this aspect could not be pursued during the present study. Also, due to varying incidence rates of meningioma grades/sub-types, patient accrual and sample collection are slow processes. These limitations pose impediment for a study on fair distribution of all the pathologic subtypes.