Cell Cycle Regulatory Protein Expression in Multinucleated Giant Cells of Giant Cell Tumor of Bone: do They Proliferate?

Autor:	Maros ME; 1 Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.; Department of Biomedical Informatics at the Center for Preventive Medicine and Digital Health, Mannheim, Germany.; Department of Neuroradiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Balla P; 1 Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary., Micsik T; 1 Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary., Sapi Z; 1 Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary., Szendroi M; Department of Orthopedics, Semmelweis University, Budapest, Hungary., Wenz H; Department of Neuroradiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Groden C; Department of Neuroradiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Forsyth RG; Department of Anatomic Pathology and Experimental Pathology, University Ziekenhuis, Brussels, Belgium., Picci P; Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy., Krenacs T; 1 Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Jazyk:	angličtina
Zdroj:	Pathology oncology research : POR [Pathol Oncol Res] 2021 May 03; Vol. 27, pp. 643146. Date of Electronic Publication: 2021 May 03 (Print Publication: 2021).
DOI:	10.3389/pore.2021.643146
Abstrakt:	Cells of the monocyte macrophage lineage form multinucleated giant cells (GCs) by fusion, which may express some cell cycle markers. By using a comprehensive marker set, here we looked for potential replication activities in GCs, and investigated whether these have diagnostic or clinical relevance in giant cell tumor of bone (GCTB). GC rich regions of 10 primary and 10 first recurrence GCTB cases were tested using immunohistochemistry in tissue microarrays. The nuclear positivity rate of the general proliferation marker, replication licensing, G1/S-phase, S/G2/M-phase, mitosis promoter, and cyclin dependent kinase (CDK) inhibitor reactions was analyzed in GCs. Concerning Ki67, moderate SP6 reaction was seen in many GC nuclei, while B56 and Mib1 positivity was rare, but the latter could be linked to more aggressive ( p = 0.012) phenotype. Regular MCM6 reaction, as opposed to uncommon MCM2, suggested an initial DNA unwinding. Early replication course in GCs was also supported by widely detecting CDK4 and cyclin E, for the first time, and confirming cyclin D1 upregulation. However, post-G1-phase markers CDK2, cyclin A, geminin, topoisomerase-2a, aurora kinase A, and phospho-histone H3 were rare or missing. These were likely silenced by upregulated CDK inhibitors p15 INK4b , p16 INK4a , p27 KIP1 , p53 through its effector p21 WAF1 and possibly cyclin G1, consistent with the prevention of DNA replication. In conclusion, the upregulation of known and several novel cell cycle progression markers detected here clearly verify early replication activities in GCs, which are controlled by cell cycle arresting CDK inhibitors at G1 phase, and support the functional maturation of GCs in GCTB. Competing Interests: MM reports non-related funding from the German Ministry for Education and Research (MI-I 01ZZ1801E) and non-related consultancy for Siemens Healthineers and SmartReporting GmbH. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Maros, Balla, Micsik, Sapi, Szendroi, Wenz, Groden, Forsyth, Picci and Krenacs.)
Databáze:	MEDLINE
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