Osteosarcoma originates from mesenchymal stem cells in consequence of aneuploidization and genomic loss of Cdkn2

Abstract

High-grade osteosarcoma is characterized by extensive genetic instability, thereby hampering the identification of causative gene mutations and understanding of the underlying pathological processes. It lacks a benign precursor lesion and reports on associations with hereditary predisposition or germline mutations are uncommon, despite the early age of onset. Here we demonstrate a novel comprehensive approach for the study of premalignant stages of osteosarcoma development in a murine mesenchymal stem cell (MSC) system that formed osteosarcomas upon grafting. By parallel functional and phenotypic analysis of normal MSCs, transformed MSCs and derived osteosarcoma cells, we provide substantial evidence for a MSC origin of osteosarcoma. In a stepwise approach, using COBRA-FISH karyotyping and array CGH in different passages of MSCs, we identified aneuploidization, translocations and homozygous loss of the cdkn2 region as the key mediators of MSC malignant transformation. We then identified CDKN2A/p16 protein expression in 88 osteosarcoma patients as a sensitive prognostic marker, thereby bridging the murine MSCs model to human osteosarcoma. Moreover, occasional reports in patients mention osteosarcoma formation following bone marrow transplantation for an unrelated malignancy. Our findings suggest a possible hazard for the clinical use of MSCs; however, they also offer new opportunities to study early genetic events in osteosarcoma genesis and, more importantly, to modulate these events and record the effect on tumour progression. This could be instrumental for the identification of novel therapeutic strategies, since the success of the current therapies has reached a plateau phase.

Osteosarcoma

“…(17) A separate line of evidence comes from the observation that serially passaged murine mesenchymal stem cells will undergo rare spontaneous transformation resulting in an osteosarcoma-like tumor, suggesting that these cells are the cell of origin. (18,19) With the existing available data, it is not possible to define whether osteosarcoma derives from mesenchymal stem cells or a more differentiated progenitor. The rarity of osteosarcoma may be related to a small pool of cells being capable of producing the cancer.…”

“…The aforementioned observation of spontaneous transformation of murine mesenchymal cells into osteosarcoma has been used to study pathogenesis. (18) A parallel and functional phenotypic analysis of the parental mesenchymal stem cells, transformed mesenchymal stem cells, and resulting osteosarcoma suggested aneuploidization, translocations, and homozygous loss of the cdkn2 region as the major mediators of malignant transformation. (18) This same research group has performed expression profiling of these cell types and has suggested that downregulation of Wnt signaling has an important role in osteosarcoma pathogenesis.…”

“…(18) A parallel and functional phenotypic analysis of the parental mesenchymal stem cells, transformed mesenchymal stem cells, and resulting osteosarcoma suggested aneuploidization, translocations, and homozygous loss of the cdkn2 region as the major mediators of malignant transformation. (18) This same research group has performed expression profiling of these cell types and has suggested that downregulation of Wnt signaling has an important role in osteosarcoma pathogenesis. (20) When the Wnt pathway was activated using a GSK3b inhibitor in osteosarcoma cell lines, proliferation was inhibited, and osteogenic differentiation was observed.…”

Modeling sarcomagenesis using multipotent mesenchymal stem cells

“…Mouse MSCs Mouse MSCs (mMSCs) are especially predisposed to acquiring transformation events after long-term in vitro culture favoring clonal selection of transformed cells [15][16][17][18][19] (Table 1). Upon inoculation into immunodeficient mice, spontaneously transformed mMSCs promote the formation of sarcomas resembling the histopathological properties of fibrosarcoma [15,16] and osteosarcoma [17,18].…”

Active TGF-β signaling and decreased expression of PTEN separates angiosarcoma of bone from its soft tissue counterpart

“…34,35 Moreover, inactivation of CDKN2A is associated with a more aggressive behavior in many cancers, including for instance Ewing sarcoma 34,36,37 and osteosarcoma. 38,39 Here, we demonstrate that also patients with angiosarcoma of bone showing loss of Signaling pathways in angiosarcomas expression of CDKN2A have a significantly worse prognosis. To date, few studies have reported the possible role of CDKN2A and TP53 in tumor development in a subset of angiosarcomas of soft tissue.…”