c-Fos induces chondrogenic tumor formation in immortalized human mesenchymal progenitor cells

Abstract

Mesenchymal progenitor cells (MPCs) have been hypothesized as cells of origin for sarcomas, and c-Fos transcription factor has been showed to act as an oncogene in bone tumors. In this study, we show c-Fos is present in most sarcomas with chondral phenotype, while multiple other genes are related to c-Fos expression pattern. To further define the role of c-Fos in sarcomagenesis, we expressed it in primary human MPCs (hMPCs), immortalized hMPCs and transformed murine MPCs (mMPCs). In immortalized hMPCs, c-Fos expression generated morphological changes, reduced mobility capacity and impaired adipogenic- and osteogenic-differentiation potentials. Remarkably, immortalized hMPCs or mMPCs expressing c-Fos generated tumors harboring a chondrogenic phenotype and morphology. Thus, here we show that c-Fos protein has a key role in sarcomas and that c-Fos expression in immortalized MPCs yields cell transformation and chondrogenic tumor formation.

Usefulness of Mesenchymal Cell Lines for Bone and Cartilage Regeneration Research

“…Importantly, transformed iMSCs lost their phenotype and experienced changes in their differentiation potential, with c-Fos-transformed iMSCs showing reduced adipogenic and osteogenic potential and a conserved ability to specifically differentiate towards the chondrogenic lineage, as well as forming chondrogenic tumors in IDM. However, 3 Hits hMPCs did not display tumorigenic features despite accumulating oncogenic mutations in hTERT and E6/E7 genes [102], thus confirming that iMSCs need further signals to initiate carcinogenesis [106].…”

“…For example, Abarrategi et al (2018) noticed a lowering of CD73 and CD105 expression in iMSCs in comparison with primary MSCs [102], and Alexander et al (2015) observed that cranial periosteum-derived TAg cells were less CD105-positive, but more CD146-positive than primary cells [51]. Adipose-tissue-derived hASCs-TS and hASCs-TE showed the same decrease in CD105 expression and an increase in CD146 expression [85].…”

“…Positive for APS and bone sialoprotein (BSP) upregulation [98] Not tested/shown Not tested/shown UE6E7T-2 (same parental cells as UE6E7-16) Not tested/shown Tested by ABS in 2D culture; negative under employed conditions [99] Not tested/shown imhMSCs Positive for VKS and upregulation of osteogenesis-related genes [18] Weak positivity for ABS and with weak upregulation of chondrogenesis-related genes (similarly to primary parental cells); tested in pellet culture [18] Positive for OROS and PPARγ upregulation [18] 3 Hits hMPC Positive for ARS [102,103], APS [101,102] and Runx2 upregulation [102] Positive for ABS [102,103] and TBS [101] in pellet culture, but reduced compared with primary MSCs…”

“…Positive for OROS [101][102][103], but reduced compared with primary MSCs UE7T-13 (same parental cells as UE6E7-16)…”

“…The tumorigenicity of 18 out of 38 iMSC lines included in this review was investigated by either soft agar colony formation assay or in vivo tumorigenicity test in immunodeficient mice (IDM). There were only two cases in which these cells showed signs of tumorigenicity; c-Fos-transduced 3 Hits hMPCs [102] and high passaged UE6E7T-3 [96], as seen in Table 1. In the case of 3 Hits hMPCs, it is not surprising that the transduction of the proto-oncogene c-Fos led to oncogenic transformation of iMSCs already transduced with hTERT and E6/E7 genes.…”