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    • Our observation that glioblastoma tumor cells express ETA

    2022-08-04

    Our observation that glioblastoma tumor cells express ETA-R in 6/10 cases contrasts with a recent publication reporting ETB-R expression in these tumors [17]. The reason for the discrepancy between that report and the present study might be due to the fact that glioblastomas with oligodendroglial components were excluded from our study, as well as to the poor reproducibility of the WHO histological classification of gliomas [9], [12], [30]. Also, it has to be considered that the cellular resolution of in situ hybridization as used in that study [17] is much lower than that of the immunohistological analysis presented herein. Although, in our study, we could detect few ETB-R-positive cells within the solid tumor tissue of glioblastomas, the lack of obvious nuclear atypia and of nuclear labeling was suggestive of residual or reactive astrocytes rather than tumor cells. It should be noted that we also constantly observed typical reactive astrocytes with a strong cytoplasmic labeling for ETB-R, in all types of gliomas, in line with the well-documented expression of ETB-R by astrocytes in normal and injured Lomustine [26], [38]. Finally, we also detected ETB-R expression in endothelial cells from newly formed micro blood vessels present in grade B oligodendrogliomas (9/10) and grade B oligoastrocytomas (4/5). In contrast, ETB-R expression was rarely detected in glioblastoma newly formed micro blood vessels (2/10), possibly due to the aberrant neoangiogenesis and the abnormal phenotype of vascular endothelium reported in these tumors [37], [51]. These observations suggest that ET-1 system may not be directly involved in neoangiogenesis associated with glioblastoma tumor progression, in contrast to VEGF, whose expression correlates with tumor progression [49]. However, such results do not rule out a putative participation of the ET-1 system in neoangiogenesis associated with grade B oligodendrogliomas and oligoastrocytomas in line with other observations [32]. We report in the present study the expression of ETB-R (but not ETA-R) by tumor cells of most oligodendrogliomas and oligoastrocytomas, independently of WHO or Ste-Anne tumor grade (Table 1). Indeed, ETB-R expression was observed in oligodendroglial tumor cells within the infiltrated tissue (grades A and B) and the solid tumor tissue (grade B), always showing a nuclear localization (associated or not with a cytoplasmic labeling). Astrocytic components present in oligodendrogliomas and oligoastrocytomas showed a cytoplasmic ETB-R labeling, this pattern of expression together with the cell morphology being characteristic of reactive astrocytes. Similar to astrocytes, minigemistocytic cells were found to express ETB-R exclusively in the cytoplasm, clearly differing from oligodendroglial tumor cells. In contrast to oligodendrogliomas and oligoastrocytomas, no cells with a nuclear ETB-R staining were detected in glioblastomas that instead expressed ETA-R (6/10 cases), always with a nuclear localization. Several studies have reported a nuclear localization for other transmembrane receptors, including growth factor receptors: EGF, NGF, and FGF receptors [28], [29], [35], [36], and G-protein-coupled, seven transmembrane domain receptors: the chemokine receptor CXCR4, the angiotensin II AT1, bradykinin B2, and apelin receptors [8], [27], [42]. On the basis of these observations, novel roles for these receptors in cell signaling and function have been suggested. In line with this hypothesis, heterotrimeric G proteins [50] and various components of signaling pathways such as phosphoinisitols, 1,2-diacylglycerol, phospholipase C, and ERK were also detected in the cell nucleus [13], [18], [34], [48]. The presence of protein kinase activity in the nucleus was further illustrated by studies showing the phosphorylation of nuclear proteins in response to growth factors including EGF and ET-1 [6], [7]. In addition, an unanticipated role for the EGF receptor in the nucleus as a transcription factor was proposed, based on the observation that this receptor may interact with the promoter of cyclin D1, an actor of cell cycle progression [28]. In conclusion, in line with the observations reported here, the concept of the nuclear expression of functional plasma membrane receptors is now emerging, with their possible involvement in cell proliferation [28], [35].