Abstract
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 p15INK4b, p16INK4a, p27KIP1, p53 through its effector p21WAF1 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.
Highlights
There are two major ways of forming multinucleate giant cells i.e. acytokinetic cell division and cell fusion [1]
49, p 0.97) showed statistical difference between P and 10 first recurrences (1-Rec) giant cell tumor of bone (GCTB) cases, there was a trend of inverse relationship between the radiological grade of GCTB and the overall average number of GCs (NGC) (WL_vs_Ag 30, pL_vs_Ag 0.065; WA_vs_Ag 37, pA_vs_Ag 0.11) and NGC_nuclei (WL_vs_A 29, pL_vs_A 0.093)
Though multinucleated giant cells (GCs) in GCTB are thought to be of reactive phenotype formed by fusion of cells of the monocyte macrophage lineage, they had been occasionally shown to express cell proliferation related markers
Summary
There are two major ways of forming multinucleate giant cells i.e. acytokinetic cell division and cell fusion [1]. We recognized that GC nuclei may show diverse proportion of immunoreactions for the earlier detected cyclin D and p21WAF1 [5, 6], and cell cycle control proteins, and for some cell cycle licensing and promoter markers, which had not been noticed before, despite GCs are considered to be of reactive, osteoclastic phenotype [7]. Here we studied the expression of a comprehensive set of cell cycle regulatory proteins to see if GCs in GCTB are still show replicative activity and if it has a clinicopathological relevance
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