Abstract
BACKGROUND: Brain metastases are the most common intracranial tumors in adults. Patients with breast cancer (BC) and pulmonary cancer (PC) regularly present with cerebral metastases. Dormant tumor cells resemble a population of non-apoptotic, low proliferating, “silent” tumor cells, which have the ability to be reactivated and are considered to be the source of recurrence. The Natural Killer Group 2, member D (NKG2D) receptor-ligand system is a major part of tumor immunogenicity. To date, the immunological characteristics of dormant tumor cells in cerebral malignancies are mostly unknown. MATERIAL AND METHODS: We analyzed the expression profile and localization of NKG2DL (MICA, MICB, ULBP1, ULBP2) and several central (ephrin A5, insulin-like growth factor binding protein 5 and histone H2B type 1-K) and peripheral (platelet-derived growth factor β, fibroblast growth factor 2 and hypoxia-inducible factor 1 α) dormancy markers in solid human brain metastases of breast and pulmonary cancer patients using two color immuno-staining and quantitative RT-PCR. RESULTS: All investigated dormancy markers were detected in the investigated patients via qRT-PCR and immuno-staining. Expression of HIF1α and PDGFβ was higher than EphaA5 in PC and PC. All NKG2DL were expressed at stable levels. MICA expression was significantly higher than ULBP2 and 3 in PB. Immunostaining revealed a broad costaining of MICA and MICB with most peripheral dormancy markers in BC and PC. ULBP1 and 2 showed costaining with most central dormancy markers in both entities. Central dormancy markers showed a broad costaining with each other and a partial costaining with peripheral dormancy markers. This effect was more pronounced in PC. Costaining of dormancy markers and Ki-67 was not detected. Expression of peripheral dormancy markers was positively correlated with expression of NKG2DL, which was more pronounced in BC; we observed a negative correlation between expression of central and peripheral dormancy markers in BC, and with only some central dormancy markers in PC. CONCLUSION: There are differences between the different tumor entities; overall brain metastases seem to resemble a more peripheral type of dormancy rather than a central type. Due to their solid (co)-expression in the investigated samples, NKG2DL might play an important role in survival of dormant cells in cerebral metastases.