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Mesenchymal stem cell transformation and sarcoma genesis

Mesenchymal stem cell transformation and sarcoma genesis MSCs are hypothesized to potentially give rise to sarcomas after transformation and therefore serve as a good model to study sarcomagenesis. Both spontaneous and induced transformation of MSCs have been reported, however, spontaneous transformation has only been convincingly shown in mouse MSCs while induced transformation has been demonstrated in both mouse and human MSCs. Transformed MSCs of both species can give rise to pleomorphic sarcomas after transplantation into mice, indicating the potential MSC origin of so-called non-translocation induced sarcomas. Comparison of expression profiles and differentiation capacities between MSCs and sarcoma cells further supports this. Deregulation of P53- Retinoblastoma-, PI3K-AKT-and MAPK pathways has been implicated in transformation of MSCs. MSCs have also been indicated as cell of origin in several types of chromosomal translocation associated sarcomas. In mouse models the generated sarcoma type depends on amongst others the tissue origin of the MSCs, the targeted pathways and genes and the differentiation commitment status of MSCs. While some insights are glowing, it is clear that more studies are needed to thoroughly understand the molecular mechanism of sarcomagenesis from MSCs and mechanisms determining the sarcoma type, which will potentially give directions for targeted therapies. Keywords: MSC, Sarcoma, Bone tumour, Soft tissue tumour, Osteosarcoma, Ewing sarcoma Introduction diseases and regenerative medicine approaches for espe- MSCs have been under intensive research and applica- cially bone and cartilage [2]. tion efforts since their first establishment by Friedenstein Cell transformation is a process during which genetic and his colleagues in 1968 [1]. Standard criteria deve- changes occur, resulting in cells with the ability to grow in- loped by the International Society for Cellular Therapy definitely and anchorage-independently and with tumori- define MSCs by three characteristics: 1) plastic adhe- genic properties upon transplantation [3-7]. Senescence rence under standard culture conditions, 2) expression of has been overcome in these transformed cells [4,8-10]. On CD105, CD73 and CD90 and no expression of CD45, one hand, the potentials of MSCs to transform, to initiate CD34, CD14, CD11b, CD79b, CD19 and HLA-DR and 3) sarcomas and under some conditions to facilitate tumour capacity to differentiate into osteoblasts, chondroblasts progression are calling for caution for MSC-based applica- and adipocytes in vitro, termed trilineage differentiation tions [5,11]. On the other hand, the transforming property potential (Figure 1) [2]. of MSCs and their possible role as sarcoma progenitors Owing to the ease of isolation, expansion, the multi- make these cells useful for studying sarcomagenesis and lineage differentiation potential and a variety of physio- progression. In this review we present an overview of the logical functions, MSCs are applied in a wide range of roles of MSCs in sarcomas, with a specific focus on experimental and medical applications. Among them are tumorigenic transformation and sarcomagenesis. the enhancement of hematopoietic stem cell engraftment, the amelioration of acute graft-versus-host disease, cardiac MSC transformation Spontaneous mouse MSC transformation Mouse MSCs have been consistently demonstrated to * Correspondence: A.M.Cleton-Jansen@lumc.nl spontaneously undergo tumorigenic transformation after Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333ZA, Leiden, the Netherlands long term ex vivo culture [4,6]. This transformation © 2013 Xiao et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Xiao et al. Clinical Sarcoma Research 2013, 3:10 Page 2 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/10 Mouse MCSs are reported to spontaneously undergo changes in morphology, proliferation rate, migration ability, cell surface marker profile, genomic constitution and most importantly tumorigenicity after long term in vitro culture [4,9,20,21]. Meanwhile, one study has also revealed that mMSCs could transform even after short term in vitro culture. Injection of passage 3 mMSCs into mice resulted in formation of tumours comparable with soft tissue sarcomas [19]. Transformed mouse MSCs always show a higher proliferation rate than the native cells [3,4]. These transformed cells exhibit tumorigenicity, as shown by anchorage-independent growth assay and xeno-transplantation in mice and zebrafish, while this is not observed with low passage mouse MSCs before their transformation [3,4,6,22]. Inter- estingly, the readiness of in vitro tumorigenic transfor- mation seems to be a unique property of mouse MSCs since it is absent in most other mouse stem cells, including hematopoietic stem cells and embryonic stem cells [23]. This readiness can be probably ascribed to the genetic instability already shown in mouse MSCs very shortly after isolation from bone marrow, although the cytoge- netic abnormalities in low passage mouse MSCs are considerably less in number than in transformed mouse MSCs [23]. Interestingly, MSC spontaneous transfor- Figure 1 Trilineage differentiation capacity of human MSCs and mation happens much less frequently in vivo,asshown representative types of sarcomas. Human MSCs are capable of by the low incidence of spontaneous sarcomagenesis in differentiating into osteoblasts, chondrocytes and adipocytes under mice. This can be possibly explained by the different proper inductions. This differentiation spectrum corresponds with the histological spectrum of different types of sarcomas, represented microenvironment of in vitro and in vivo conditions for here by osteosarcoma, chondrosarcoma and liposarcoma. This MSCs. Solid research on the role of the in vivo niche of correlation supports the hypothesis that MSCs are the cell of origin BMMSCs in guarding its genomic stability is needed to of sarcomas. A: alizarin red staining for osteoblast differentiation answer this question more exactly. assay, B: toluidine blue staining for chondrocyte differentiation assay of MSC pellets, C: oil red staining for adipocyte differentiation. D: human MSC cell culture. E: osteosarcoma, F: chondrosarcoma, Induced mouse MSC transformation G: liposarcoma. Transformation of mouse MSCs has been induced by an array of manipulations, including knockout of tumour suppressor genes, overexpression of oncogenes and drug process can also be induced by certain manipulations, administration to affect signaling pathways. The path- including both gene targeting and drug or chemical ways targeted by these manipulations are mostly in- treatment to affect crucial pathways (Table 1) [11-14]. In volved in cell cycle checkpoint control, cell survival, contrast, human MSCs do not spontaneously transform proliferation and apoptosis (Table 2) [14]. In one study, in vitro, even after long term culturing, which will be loss of tumour suppressor P21 and Tp53 in mouse adipose discussed later in more detail [9,13,15]. derived MSCs (AMSC) induced in vitro transformation Table 1 A summary of spontaneous transformation studies with mouse BMMSCs Transformation after Type of sarcoma Associated genetic event(s) Reference Osteosarcoma Aneuploidy + CDKN2A/p16 loss [4] Abnormal karyotype [6] Long term culture Fibrosarcoma p53 mutations [24] Chromosomal instability + TERT and c-myc expression [16] Undiff. soft tissue sarcomas Aneuploidy + chromosomal translocations [17] Short term culture Soft tissue sarcomas Aneuploidy [18] Xiao et al. Clinical Sarcoma Research 2013, 3:10 Page 3 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/10 Table 2 A summary of induced transformation studies with mouse cells Sarcomas without specific chromosomal translocation Cell type Inactivated Expressed Type of sarcoma Reference gene(s) gene(s)/treatment mASCs p21 + p53 - “Fibrosarcoma” [20] p53 or p53 + Rb - Leiomyosarcoma [7] BM-mMSCs INK4A/ARF c-myc Osteosarcoma [24] Osteoblastic lineage p53 or p53 + Rb - Osteosarcoma [32,33] Mesenchymal cells of limb buds p53 - Osteosarcoma [23] p53 + Rb - Undifferentiated sarcoma [23] Muscle, uterus p53 orINK4A/ARF K-RAS High-grade sarcoma with myofibroblastic differentiation [25] Muscle p53 K-RAS Pleomorphic rhabdomyosarcoma [18] Smooth muscle lineage PTEN - Leiomyosarcoma [17] MSC progenitors APC - Aggressive fibromatosis [67] Sarcomas with specific chromosomal translocation Cell type Expressed fusion gene Type of sarcoma Reference BM-mMSCs EWS-FLI-1 Ewing sarcoma [63] EWS-FLI-1 Ewing sarcoma [65] FUS-CHOP Myxoid liposarcoma [11] PAX3/7-FKHR Alveolar rhabdomyosarcoma [71] mASCs FUS- CHOP Liposarcoma [11] Mesenchymal cells of limb buds EWS-FLI-1 Ewing sarcoma [65] Differentiated muscle cells PAX3-FKHR Liposarcoma [70] (MYF6-expressing cells) and in vivo so-called fibrosarcoma formation after trans- Besides, in spontaneous transformation studies of mouse plantation [24]. In another study, both Tp53−/− Rb−/− MSCs, defects in Tp53 or Cdkn2a genes were frequently and Tp53−/− mouse AMSCs were generated through Cre found [18]. P53 and P14, proteins encoded by these two mediated excision of loxP flanked loci. Leiomyosarcoma- genes, are both important members of P53 pathway, fur- like tumours were developed in the in vivo tumori- ther corroborating the crucial role of P53 pathway in genicity assays of these 2 types of mouse AMSCs [8]. mouse MSC transformation [4,25]. Upregulated onco- The combination of Cdkn2a loss and C-myc genic pathways have also been shown to induce or overexpression in mouse BMMSCs gave rise to osteosar- potentiate mouse MSC transformation. Fos is an oncogene comas accompanied by the loss of adipogenic differenti- encoding a transcription factor downstream of many ation capacity in transformed mouse BMMSCs [16]. growth factor pathways. The Fos overexpression trans- Besides directly targeting in vitro cultured MSCs, several genicmiceresultedinthe developmentof bonetu- genetically engineered mouse models have been developed mours, with chondrosarcomas as the main type [26]. to investigate the effects of genes on transformation This is puzzling as the driver mutation in human process. A conditional mouse model with Tp53 homozy- central chondrosarcoma is IDH1 or IDH2 [27], while gous deletion has been created by crossing Prx1-Cre in peripheral chondrosarcomas this is not known transgenic mice to mice bearing alleles of Tp53 flanked by [27,28], but no indication for involvement of Fos is loxP. Prx1 is specifically expressed in the early mesenchy- found [28,29]. The PI3K-AKT pathway is crucially in- mal tissues of embryonic limb buds [17]. In these P53- volved in apoptosis and proliferation. In a study a deficient mice many types of sarcomas occurred in the mouse model with homozygous loss of Pten,anega- mesenchymal cells of limb buds and osteosarcoma was tive regulator of the PI3K-AKT pathway in smooth the most common type. A mouse model with loss of RB muscle lineage cells developed leiomyosarcomas [30,31]. generated also through Cre-loxP system was not found to The MAPK pathway is principally responsible for mitosis. display tumorigenesis. However, loss of RB accelerated Overexpression of K-ras, a component of the MARK tumorigenesis in P53-deficient mice [17]. These induced pathway in addition to P53 loss induced sarcoma for- transformation studies established the importance of the mation in mice more efficiently than in mice with P53 pathway in preventing mouse MSC transformation. P53 loss alone [32,33]. These studies underscore the Xiao et al. Clinical Sarcoma Research 2013, 3:10 Page 4 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/10 role of different oncogenic pathways to promote mouse translocation driven subtypes. In the non-translocation MSC transformation. -driven sarcoma types, the correspondence between the differentiation capacity of MSCs and the histological Human MSC transformation spectrum of different types of sarcomas is reflected Human MSCs have not been shown to undergo spon- (Figure 1). Approaches and methods have also been taneous transformation in vitro [9,15,43]. There have used to investigate this hypothesis, including differenti- been few reports on spontaneous human MSC in vitro ation assays, expression profiling and Immunohistochem- transformation, of which two turned out to be caused by istry [52-54]. Based on the site of presentation, sarcomas contamination by tumour cell lines and were retracted can be categorized into bone tumours and soft tissue afterwards [34,35,44]. Meanwhile, there are several stud- tumours. Based on genetic profiles, sarcomas can be cate- ies demonstrating that human MSCs did not go through gorized into two groups, one with relatively simple genetic transformation in spite of long term in vitro culturing alterations, either being associated with point mutations [12,15]. For the possibility of in vivo spontaneous trans- or reciprocal translocations, and the other with extensive formation, there have been few cases of osteosarcoma genetic changes. Examples of the cytogenetically relatively genesis in patients infused with bone marrow MSCs for simple group are alveolar rhabdomyosarcoma, myxoid other diseases [45-47]. The majority studies of human liposarcoma, Ewing sarcoma and synovial sarcoma. Exam- MSC transformation are based on genetic approaches to ples of the other group are leiomyosarcoma, undifferenti- knock out important tumour suppressor genes and ated pleomorphic sarcoma and osteosarcoma [55]. overexpress certain oncogenes Table 3) [14]. In contrast MSC differentiation towards a defined and differenti- to mouse MSC studies, four of the induced human MSC ated cell type is a process with a lot of different signaling transformation studies consist of the exogenous expres- pathways and differentiation stages involved (Figure 2). sion of hTERT in human cells [38,48-50]. This may be The sarcoma type arising from in vitro transformed attributed to the much shorter telomeres in human MSCs after inoculation into mice seems to be dependent MSCs than their mouse counterparts, the much shorter on many factors, including the originating tissue of the life span of mice than human and the difference in telo- MSCs, the differentiation commitment status of the mere damage signaling pathways between mouse and targeted cell and also the targeted molecular pathways. human [41,50,51]. Consistent with mouse MSC studies, In most cases with bone marrow derived mouse MSCs the disruption of cell cycle control machineries, exempli- (BMMSC) or osteochondro progenitors osteosarcoma- fied by P53 and RB pathways are also important for hu- like tumours were formed. With AMSCs or smooth man MSC transformation. For instance, the introduction muscle cell progenitors leiomyosarcomas were mostly of SV40-LT, which perturbs both P53 and RB proteins formed (Table 4) [8,16,24]. BMMSCs from aged mice potently promoted human MSC transformation [38]. tend to spontaneously give rise to so-called fibrosarco- Furthermore, the overexpression of some oncogenes has mas instead of osteosarcomas as in most spontaneous also been shown to contribute to the transformation, transformation studies [25]. It must be added that such as H-RAS [5-7]. Although the definite spontaneous according to the present view fibrosarcomas is a poorly transformation capacity of mouse MSCs is not a mim- defined histological entity. It is necessary to perform icry of human MSCs, the signaling pathways underlying large scale studies to specifically address the relationship their tumorigenic transformation show high consistency, between tissue origin, targeted pathways and the sar- including the P53 pathway, RB pathway, PI3K-AKT coma type generated, which is currently lacking. pathway and MAPK pathway and so on. Bone sarcomas MSCs as the origin of sarcomas and tumour type Ewing sarcoma specificity Ewing sarcoma arises predominantly in bone but in soft There is substantial evidence supporting a MSC origin tissues as well. It is a type of a poorly differentiated of a spectrum of sarcomas, both pleomorphic as well as tumour known to be associated with a the expression of Table 3 A summary of human BMMSCs transformation without specific chromosomal translocation Type of sarcomas Expressed gene(s)/treatment Reference hTERT + HPV16 E6/E7 + SV40-ST + H-RAS [44] Undifferentiated spindle cell sarcoma hTERT + SV40-LT + H-RAS [13] hTERT + H-RAS + BMI-1 [43] Tumors with smooth muscle and bone properties hTERT4 [33] Undifferentiated pleomorphic sarcomas DKK1 + SV40-LT [14] Xiao et al. Clinical Sarcoma Research 2013, 3:10 Page 5 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/10 fibroblast myoblast self renewal neuronal cell MSC bipotential tripotential progenitor progenitor cell cell CBFA1, osterix multipotent progenitor cell osteocyte osteoblast SOX9, PPARγ 2 SOX5, SOX6 chondroblast adipocyte chondrocyte Figure 2 MSC differentiation scheme. Under different signaling regulations, MSCs can differentiate into different types of cells. The differentiation process involves sequential signaling regulation and many different stages. EWSR1–ETS fusions or rarely other chimeras [59-62]. transformation of mouse MSCs [64]. Similar manipula- The exogenous expression of the fusion gene EWS-FLI1 tions have been also applied on human MSCs. Human alone in mouse MSCs has been shown to transform MSCs with exogenous EWS-FLI1 expression transformed these cells, demonstrated by in vitro immortalization and these transformed cells expressed neuroectodermal and in vivo sarcomatous tumour formation after inocula- markers [65]. Moreover, the knockdown of EWS-FLI1 ex- tion in immunocompetent mice [63]. In another study a pression in Ewing sarcoma cell lines restored the in vitro secondary genetic alteration was needed for the induced trilineage differentiation ability of the cells [52]. In a Table 4 A summary of sarcoma types from different transformation studies in mice Sarcoma type Cell of origin Targeted genes Reference Mouse BMMSCs - [4] -[6] C-myc overexpression and Ink4a/Arf knockout [16] Osteosarcoma Mouse osteoblast precursors Tp53, Rb double knockout [56] Mouse osteoblasts Tp53knockout [57] Tp53 and Rb double knockout [57] Tp53 knockout [17] Mouse AMSCs Tp53 knockout [14] Tp53 knockout [24] Leiomyosarcomas Tp53 and Rb double knockout [8] Mouse smooth muscle lineage cells Pten knockout [30] Mouse BMMSCs - [58] “Fibrosarcoma” Aged mouse BMMSCs - [25] Mouse AMSCs P21 knockout, Tp53 heterozygous knockout [24] Mouse skeletal muscle cells K-ras overexpression and Tp53 knockout [32] Pleomorphic rhabdomyosarcoma K- ras overexpression and Tp53 heterozygous knockout [32] Xiao et al. Clinical Sarcoma Research 2013, 3:10 Page 6 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/10 transgenic mouse model, by expressing EWS-FLI1 gene explained by the fact that although considered as muscle specifically in the mesoderm-originated tissues in limbs specific Myf5 can also be expressed in some MSCs du- and simultaneous Tp53 knockout, sarcomas with similar ring development. characteristics as Ewing sarcoma occurred while with only Tp53 knockout the primary sarcoma type was osteosar- Other soft tissue sarcomas coma [66]. In brief, Ewing sarcoma, originally considered Similar results as described above were seen in a mouse as tumours arising from the neuroectodermal lineage and model of liposarcoma, where FUS -CHOP was able to not considered of mesenchymal origin could be experi- induce liposarcoma genesis in MSCs, whereas no mentally derived directly from MSCs, but only upon liposarcoma was formed when FUS-CHOP gene was introducing the typical translocation. This strongly sup- manipulated to be only expressed in differentiated, ports an MSC origin of Ewing sarcoma [67]. aP2-expressing adipocytes. This study again under- scores the exact cell status as a crucial factor in Osteosarcoma sarcomagenesis [42,70]. However other studies show that Osteosarcoma is the most common primary malignant there is considerate plasticity in the different lineages since bone tumour among children. It is characterized by the rhadomyosarcoma, an aggressive skeletal muscle tumour production of osteoid and extensive cytogenetic instabi- can be generated from adipocytes by activation of Sonic lity [36]. Different studies have supported the MSC ori- Hedgehog signaling [71]. A third soft tissue sarcoma gin of osteosarcoma [4,16]. Both spontaneous and model is that of clear cell sarcoma, characterized by induced MSC models for osteosarcoma have been melanoma-like features and an EWSR1/ATF1 transloca- discussed above. Osteosarcomas mainly arise in the tion. Conditional expression of the human EWSR1/ATF1 metaphyses of long bones and the peak incidence is in the fusion gene in mouse gives rise to tumorigenesis with ex- second decade of human life, correlating with the rapid treme brief latency. The most stem-like MSCs give rise to bone growth during puberty, a process in which MSCs are fully melanoma-like lesions, whereas more differentiated crucially involved [37]. In both human osteosarcoma cells cells result in a less clear cell sarcoma phenotype [72]. and transformed MSCs, frequent aberrations in genes encoding components of P53 pathway have been identi- Discussion fied [4,39]. In Tp53 knockout mice many types of sarco- Until now there have not been many studies addressing mas developed and osteosarcoma was the main type [17]. the effect of MSCs of different tissues and different ways of preparation on the role of MSCs as a model for Chondrosarcoma sarcoma genesis. The conspicuous difference between A study compared the gene expression profiles of chon- mouse and human MSCs in spontaneous transformation drosarcomas of different differentiation degree [53]. Less can be possibly explained by many factors. In human differentiated chondrosarcomas were shown to have cells, the telomeric DNA is often 5–10 kb long and more similarity with MSCs of pre-chondrogenic stages mouse cells have a telomeric DNA length of 30–40 kb and more differentiated chondrosarcomas share more [41,51]. The longer telomeres in mouse MSCs allow cells similarity with fully differentiated chondrocytes. This sug- to proliferate many generations before reaching reaching gests that chondrosarcoma progression probably parallels the telomere length limit, giving higher chance for deregulated chondrocytes differentiation process of MSCs cell to acquire aberrations [41,51]. Since mice have a [40,53]. shorter life span than humans, the genome mainte- nance in mouse cells is also less stringent than in hu- Soft tissue sarcomas man cells [73]. Synovial sarcoma Niche is one of the most important factors in the de- In synovial sarcoma, exogenous expression of SYT-SSX2 termination of stem cell characteristics. The function of fusion gene in the skeletal-muscle-specific Myf5 expres- niche in stem cell differentiation and pluripotency main- sing lineage induced the formation of synovial sarcomas tenance is well known. There has also been research in vivo. Remarkably, when this fusion gene was intro- showing that the low oxygen tension is important for duced into cells more differentiated than myoblasts syn- multipotency maintenance of MSCs, while normal oxy- ovial sarcoma did not occur [68]. This fact emphasizes gen level will induce differentiation [74]. Besides, niche the important role of cell status in the genesis of specific has also been indicated to be involved in tumorigenesis type of sarcomas. On the other hand, fusion gene silen- [75]. This suggests the important role of niche in ge- cing in primary synovial sarcoma cells restored both the nomic instability and therefore tumourigenetic ability. trilineage differentiation capacity and the MSC marker One special feature of the bone marrow niche is the expression, strongly suggesting cells of MSC lineage as partnership of MSCs and haematopoietic stem cells, the origin of synovial sarcoma [69]. This may be which deserves further exploration [76,77]. Xiao et al. Clinical Sarcoma Research 2013, 3:10 Page 7 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/10 Future considerations 5. Mohseny AB, Hogendoorn PCW: Concise review: mesenchymal tumors: when stem cells go mad. Stem Cells 2011, 29:397–403. The numerous but well documented studies on MSCs gi- 6. Tolar J, Nauta AJ, Osborn MJ, Panoskaltsis MA, McElmurry RT, Bell S, et al: ving rise to sarcomas in experimental set-up provide ex- Sarcoma derived from cultured mesenchymal stem cells. Stem Cells 2007, cellent models to study this devastating malignancy in a 25:371–379. 7. Chanda D, Kumar S, Ponnazhagan S: Therapeutic potential of adult bone systematic and controlled way. This offers opportunities marrow-derived mesenchymal stem cells in diseases of the skeleton. for preclinical testing of experimental therapies, thereby J Cell Biochem 2010, 111:249–257. providing convincing data that may facilitate application 8. Rubio R, Garcia-Castro J, Gutierrez-Aranda I, Paramio J, Santos M, Catalina P, et al: Deficiency in p53 but not retinoblastoma induces the in actual clinical trials despite small patient cohorts. transformation of mesenchymal stem cells in vitro and initiates leiomyosarcoma in vivo. Cancer Res 2010, 70:4185–4194. Conclusions 9. Choumerianou DM, Dimitriou H, Perdikogianni C, Martimianaki G, Riminucci M, Kalmanti M: Study of oncogenic transformation in ex vivo expanded Although mouse MSCs have exhibited definite readiness mesenchymal cells, from paediatric bone marrow. Cell Prolif 2008, to transform in vitro, human MSCs do not go through 41:909–922. transformation in ex vivo expansion and need additional 10. Zheng Y, He L, Wan Y, Song J: H3K9me-enhanced DNA hypermethylation of the p16(INK4a) gene: an epigenetic signature for spontaneous manipulation before progression into sarcomas. There- transformation of rat mesenchymal stem cells. Stem Cells Dev 2013, fore, although there are few cases of osteosarcoma 22:256–267. genesis in patients infused with bone marrow MSCs 11. Rodriguez R, Rubio R, Gutierrez-Aranda I, Melen GJ, Elosua C, Garcia-Castro J, et al: FUS-CHOP fusion protein expression coupled to p53 deficiency [45-47], it is considered generally safe to use human induces liposarcoma in mouse but not in human adipose-derived MSCs in clinic. mesenchymal stem/stromal cells. Stem Cells 2011, 29:179–192. 12. Aguilar S, Nye E, Chan J, Loebinger M, Spencer-Dene B, Fisk N, et al: Murine Abbreviations but not human mesenchymal stem cells generate osteosarcoma-like AKT: v-akt murine thymoma viral oncogene homolog; AMSC: Adipose tissue lesions in the lung. Stem Cells 2007, 25:1586–1594. derived MSC; APC: Adenomatous polyposis coli; BMI-1: B lymphoma Mo-MLV 13. Rosland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll H, insertion region 1 homolog; BMMSC: Bone marrow derived MSC; C-myc: v- et al: Long-term cultures of bone marrow-derived human mesenchymal myc myelocytomatosis viral oncogene; Cdkn2a: Cyclin-dependent kinase stem cells frequently undergo spontaneous malignant transformation. inhibitor A; CHOP: C/EBP homologous protein; DKK1: dickkopf 1 homolog; Cancer Res 2009, 69:5331–5339. EWS: Ewing Sarcoma; ETS: E-twenty six; FKHR: Forkhead in 14. Rodriguez R, Rubio R, Menendez P: Modeling sarcomagenesis using rhabdomyosarcoma; FLI1: Friend leukemia integration 1; Fos: FBJ murine multipotent mesenchymal stem cells. Cell Res 2012, 22:62–77. osteosarcoma viral oncogene; FUS: Fused in sarcoma; H-RAS: v-Ha-ras Harvey 15. Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, et al: rat sarcoma viral oncogene homolog; HLA-DR: Human leukocyte antigen-DR Human bone marrow derived mesenchymal stem cells do not undergo chain; HPV: Human papillomavirus; hTERT: Human telomerase reverse transformation after long-term in vitro culture and do not exhibit telomere transcriptase; IDH: Isocitrate dehydrogenase; INK4A/ARF: Inhibitor of CDK4 A/ maintenance mechanisms. Cancer Res 2007, 67:9142–9149. Alternative Reading Frame; K-ras: v-Ki-ras2 Kirsten rat sarcoma viral oncogene 16. Shimizu T, Ishikawa T, Sugihara E, Kuninaka S, Miyamoto T, Mabuchi Y, et al: homolog; MAPK: Mitogen-activated protein kinase; MSC: Mesenchymal Stem c-MYC overexpression with loss of Ink4a/Arf transforms bone marrow Cell; MYF6: Myogenic factor 6; PAX3/7: Paired box 3/7; stromal cells into osteosarcoma accompanied by loss of adipogenesis. 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Nature 2010, 466:829–834. doi:10.1186/2045-3329-3-10 Cite this article as: Xiao et al.: Mesenchymal stem cell transformation and sarcoma genesis. Clinical Sarcoma Research 2013 3:10. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Sarcoma Research Springer Journals

Mesenchymal stem cell transformation and sarcoma genesis

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Copyright © 2013 by Xiao et al.; licensee BioMed Central Ltd.
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Biomedicine; Cancer Research; Oncology; Surgical Oncology
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Abstract

MSCs are hypothesized to potentially give rise to sarcomas after transformation and therefore serve as a good model to study sarcomagenesis. Both spontaneous and induced transformation of MSCs have been reported, however, spontaneous transformation has only been convincingly shown in mouse MSCs while induced transformation has been demonstrated in both mouse and human MSCs. Transformed MSCs of both species can give rise to pleomorphic sarcomas after transplantation into mice, indicating the potential MSC origin of so-called non-translocation induced sarcomas. Comparison of expression profiles and differentiation capacities between MSCs and sarcoma cells further supports this. Deregulation of P53- Retinoblastoma-, PI3K-AKT-and MAPK pathways has been implicated in transformation of MSCs. MSCs have also been indicated as cell of origin in several types of chromosomal translocation associated sarcomas. In mouse models the generated sarcoma type depends on amongst others the tissue origin of the MSCs, the targeted pathways and genes and the differentiation commitment status of MSCs. While some insights are glowing, it is clear that more studies are needed to thoroughly understand the molecular mechanism of sarcomagenesis from MSCs and mechanisms determining the sarcoma type, which will potentially give directions for targeted therapies. Keywords: MSC, Sarcoma, Bone tumour, Soft tissue tumour, Osteosarcoma, Ewing sarcoma Introduction diseases and regenerative medicine approaches for espe- MSCs have been under intensive research and applica- cially bone and cartilage [2]. tion efforts since their first establishment by Friedenstein Cell transformation is a process during which genetic and his colleagues in 1968 [1]. Standard criteria deve- changes occur, resulting in cells with the ability to grow in- loped by the International Society for Cellular Therapy definitely and anchorage-independently and with tumori- define MSCs by three characteristics: 1) plastic adhe- genic properties upon transplantation [3-7]. Senescence rence under standard culture conditions, 2) expression of has been overcome in these transformed cells [4,8-10]. On CD105, CD73 and CD90 and no expression of CD45, one hand, the potentials of MSCs to transform, to initiate CD34, CD14, CD11b, CD79b, CD19 and HLA-DR and 3) sarcomas and under some conditions to facilitate tumour capacity to differentiate into osteoblasts, chondroblasts progression are calling for caution for MSC-based applica- and adipocytes in vitro, termed trilineage differentiation tions [5,11]. On the other hand, the transforming property potential (Figure 1) [2]. of MSCs and their possible role as sarcoma progenitors Owing to the ease of isolation, expansion, the multi- make these cells useful for studying sarcomagenesis and lineage differentiation potential and a variety of physio- progression. In this review we present an overview of the logical functions, MSCs are applied in a wide range of roles of MSCs in sarcomas, with a specific focus on experimental and medical applications. Among them are tumorigenic transformation and sarcomagenesis. the enhancement of hematopoietic stem cell engraftment, the amelioration of acute graft-versus-host disease, cardiac MSC transformation Spontaneous mouse MSC transformation Mouse MSCs have been consistently demonstrated to * Correspondence: A.M.Cleton-Jansen@lumc.nl spontaneously undergo tumorigenic transformation after Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333ZA, Leiden, the Netherlands long term ex vivo culture [4,6]. This transformation © 2013 Xiao et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Xiao et al. Clinical Sarcoma Research 2013, 3:10 Page 2 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/10 Mouse MCSs are reported to spontaneously undergo changes in morphology, proliferation rate, migration ability, cell surface marker profile, genomic constitution and most importantly tumorigenicity after long term in vitro culture [4,9,20,21]. Meanwhile, one study has also revealed that mMSCs could transform even after short term in vitro culture. Injection of passage 3 mMSCs into mice resulted in formation of tumours comparable with soft tissue sarcomas [19]. Transformed mouse MSCs always show a higher proliferation rate than the native cells [3,4]. These transformed cells exhibit tumorigenicity, as shown by anchorage-independent growth assay and xeno-transplantation in mice and zebrafish, while this is not observed with low passage mouse MSCs before their transformation [3,4,6,22]. Inter- estingly, the readiness of in vitro tumorigenic transfor- mation seems to be a unique property of mouse MSCs since it is absent in most other mouse stem cells, including hematopoietic stem cells and embryonic stem cells [23]. This readiness can be probably ascribed to the genetic instability already shown in mouse MSCs very shortly after isolation from bone marrow, although the cytoge- netic abnormalities in low passage mouse MSCs are considerably less in number than in transformed mouse MSCs [23]. Interestingly, MSC spontaneous transfor- Figure 1 Trilineage differentiation capacity of human MSCs and mation happens much less frequently in vivo,asshown representative types of sarcomas. Human MSCs are capable of by the low incidence of spontaneous sarcomagenesis in differentiating into osteoblasts, chondrocytes and adipocytes under mice. This can be possibly explained by the different proper inductions. This differentiation spectrum corresponds with the histological spectrum of different types of sarcomas, represented microenvironment of in vitro and in vivo conditions for here by osteosarcoma, chondrosarcoma and liposarcoma. This MSCs. Solid research on the role of the in vivo niche of correlation supports the hypothesis that MSCs are the cell of origin BMMSCs in guarding its genomic stability is needed to of sarcomas. A: alizarin red staining for osteoblast differentiation answer this question more exactly. assay, B: toluidine blue staining for chondrocyte differentiation assay of MSC pellets, C: oil red staining for adipocyte differentiation. D: human MSC cell culture. E: osteosarcoma, F: chondrosarcoma, Induced mouse MSC transformation G: liposarcoma. Transformation of mouse MSCs has been induced by an array of manipulations, including knockout of tumour suppressor genes, overexpression of oncogenes and drug process can also be induced by certain manipulations, administration to affect signaling pathways. The path- including both gene targeting and drug or chemical ways targeted by these manipulations are mostly in- treatment to affect crucial pathways (Table 1) [11-14]. In volved in cell cycle checkpoint control, cell survival, contrast, human MSCs do not spontaneously transform proliferation and apoptosis (Table 2) [14]. In one study, in vitro, even after long term culturing, which will be loss of tumour suppressor P21 and Tp53 in mouse adipose discussed later in more detail [9,13,15]. derived MSCs (AMSC) induced in vitro transformation Table 1 A summary of spontaneous transformation studies with mouse BMMSCs Transformation after Type of sarcoma Associated genetic event(s) Reference Osteosarcoma Aneuploidy + CDKN2A/p16 loss [4] Abnormal karyotype [6] Long term culture Fibrosarcoma p53 mutations [24] Chromosomal instability + TERT and c-myc expression [16] Undiff. soft tissue sarcomas Aneuploidy + chromosomal translocations [17] Short term culture Soft tissue sarcomas Aneuploidy [18] Xiao et al. Clinical Sarcoma Research 2013, 3:10 Page 3 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/10 Table 2 A summary of induced transformation studies with mouse cells Sarcomas without specific chromosomal translocation Cell type Inactivated Expressed Type of sarcoma Reference gene(s) gene(s)/treatment mASCs p21 + p53 - “Fibrosarcoma” [20] p53 or p53 + Rb - Leiomyosarcoma [7] BM-mMSCs INK4A/ARF c-myc Osteosarcoma [24] Osteoblastic lineage p53 or p53 + Rb - Osteosarcoma [32,33] Mesenchymal cells of limb buds p53 - Osteosarcoma [23] p53 + Rb - Undifferentiated sarcoma [23] Muscle, uterus p53 orINK4A/ARF K-RAS High-grade sarcoma with myofibroblastic differentiation [25] Muscle p53 K-RAS Pleomorphic rhabdomyosarcoma [18] Smooth muscle lineage PTEN - Leiomyosarcoma [17] MSC progenitors APC - Aggressive fibromatosis [67] Sarcomas with specific chromosomal translocation Cell type Expressed fusion gene Type of sarcoma Reference BM-mMSCs EWS-FLI-1 Ewing sarcoma [63] EWS-FLI-1 Ewing sarcoma [65] FUS-CHOP Myxoid liposarcoma [11] PAX3/7-FKHR Alveolar rhabdomyosarcoma [71] mASCs FUS- CHOP Liposarcoma [11] Mesenchymal cells of limb buds EWS-FLI-1 Ewing sarcoma [65] Differentiated muscle cells PAX3-FKHR Liposarcoma [70] (MYF6-expressing cells) and in vivo so-called fibrosarcoma formation after trans- Besides, in spontaneous transformation studies of mouse plantation [24]. In another study, both Tp53−/− Rb−/− MSCs, defects in Tp53 or Cdkn2a genes were frequently and Tp53−/− mouse AMSCs were generated through Cre found [18]. P53 and P14, proteins encoded by these two mediated excision of loxP flanked loci. Leiomyosarcoma- genes, are both important members of P53 pathway, fur- like tumours were developed in the in vivo tumori- ther corroborating the crucial role of P53 pathway in genicity assays of these 2 types of mouse AMSCs [8]. mouse MSC transformation [4,25]. Upregulated onco- The combination of Cdkn2a loss and C-myc genic pathways have also been shown to induce or overexpression in mouse BMMSCs gave rise to osteosar- potentiate mouse MSC transformation. Fos is an oncogene comas accompanied by the loss of adipogenic differenti- encoding a transcription factor downstream of many ation capacity in transformed mouse BMMSCs [16]. growth factor pathways. The Fos overexpression trans- Besides directly targeting in vitro cultured MSCs, several genicmiceresultedinthe developmentof bonetu- genetically engineered mouse models have been developed mours, with chondrosarcomas as the main type [26]. to investigate the effects of genes on transformation This is puzzling as the driver mutation in human process. A conditional mouse model with Tp53 homozy- central chondrosarcoma is IDH1 or IDH2 [27], while gous deletion has been created by crossing Prx1-Cre in peripheral chondrosarcomas this is not known transgenic mice to mice bearing alleles of Tp53 flanked by [27,28], but no indication for involvement of Fos is loxP. Prx1 is specifically expressed in the early mesenchy- found [28,29]. The PI3K-AKT pathway is crucially in- mal tissues of embryonic limb buds [17]. In these P53- volved in apoptosis and proliferation. In a study a deficient mice many types of sarcomas occurred in the mouse model with homozygous loss of Pten,anega- mesenchymal cells of limb buds and osteosarcoma was tive regulator of the PI3K-AKT pathway in smooth the most common type. A mouse model with loss of RB muscle lineage cells developed leiomyosarcomas [30,31]. generated also through Cre-loxP system was not found to The MAPK pathway is principally responsible for mitosis. display tumorigenesis. However, loss of RB accelerated Overexpression of K-ras, a component of the MARK tumorigenesis in P53-deficient mice [17]. These induced pathway in addition to P53 loss induced sarcoma for- transformation studies established the importance of the mation in mice more efficiently than in mice with P53 pathway in preventing mouse MSC transformation. P53 loss alone [32,33]. These studies underscore the Xiao et al. Clinical Sarcoma Research 2013, 3:10 Page 4 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/10 role of different oncogenic pathways to promote mouse translocation driven subtypes. In the non-translocation MSC transformation. -driven sarcoma types, the correspondence between the differentiation capacity of MSCs and the histological Human MSC transformation spectrum of different types of sarcomas is reflected Human MSCs have not been shown to undergo spon- (Figure 1). Approaches and methods have also been taneous transformation in vitro [9,15,43]. There have used to investigate this hypothesis, including differenti- been few reports on spontaneous human MSC in vitro ation assays, expression profiling and Immunohistochem- transformation, of which two turned out to be caused by istry [52-54]. Based on the site of presentation, sarcomas contamination by tumour cell lines and were retracted can be categorized into bone tumours and soft tissue afterwards [34,35,44]. Meanwhile, there are several stud- tumours. Based on genetic profiles, sarcomas can be cate- ies demonstrating that human MSCs did not go through gorized into two groups, one with relatively simple genetic transformation in spite of long term in vitro culturing alterations, either being associated with point mutations [12,15]. For the possibility of in vivo spontaneous trans- or reciprocal translocations, and the other with extensive formation, there have been few cases of osteosarcoma genetic changes. Examples of the cytogenetically relatively genesis in patients infused with bone marrow MSCs for simple group are alveolar rhabdomyosarcoma, myxoid other diseases [45-47]. The majority studies of human liposarcoma, Ewing sarcoma and synovial sarcoma. Exam- MSC transformation are based on genetic approaches to ples of the other group are leiomyosarcoma, undifferenti- knock out important tumour suppressor genes and ated pleomorphic sarcoma and osteosarcoma [55]. overexpress certain oncogenes Table 3) [14]. In contrast MSC differentiation towards a defined and differenti- to mouse MSC studies, four of the induced human MSC ated cell type is a process with a lot of different signaling transformation studies consist of the exogenous expres- pathways and differentiation stages involved (Figure 2). sion of hTERT in human cells [38,48-50]. This may be The sarcoma type arising from in vitro transformed attributed to the much shorter telomeres in human MSCs after inoculation into mice seems to be dependent MSCs than their mouse counterparts, the much shorter on many factors, including the originating tissue of the life span of mice than human and the difference in telo- MSCs, the differentiation commitment status of the mere damage signaling pathways between mouse and targeted cell and also the targeted molecular pathways. human [41,50,51]. Consistent with mouse MSC studies, In most cases with bone marrow derived mouse MSCs the disruption of cell cycle control machineries, exempli- (BMMSC) or osteochondro progenitors osteosarcoma- fied by P53 and RB pathways are also important for hu- like tumours were formed. With AMSCs or smooth man MSC transformation. For instance, the introduction muscle cell progenitors leiomyosarcomas were mostly of SV40-LT, which perturbs both P53 and RB proteins formed (Table 4) [8,16,24]. BMMSCs from aged mice potently promoted human MSC transformation [38]. tend to spontaneously give rise to so-called fibrosarco- Furthermore, the overexpression of some oncogenes has mas instead of osteosarcomas as in most spontaneous also been shown to contribute to the transformation, transformation studies [25]. It must be added that such as H-RAS [5-7]. Although the definite spontaneous according to the present view fibrosarcomas is a poorly transformation capacity of mouse MSCs is not a mim- defined histological entity. It is necessary to perform icry of human MSCs, the signaling pathways underlying large scale studies to specifically address the relationship their tumorigenic transformation show high consistency, between tissue origin, targeted pathways and the sar- including the P53 pathway, RB pathway, PI3K-AKT coma type generated, which is currently lacking. pathway and MAPK pathway and so on. Bone sarcomas MSCs as the origin of sarcomas and tumour type Ewing sarcoma specificity Ewing sarcoma arises predominantly in bone but in soft There is substantial evidence supporting a MSC origin tissues as well. It is a type of a poorly differentiated of a spectrum of sarcomas, both pleomorphic as well as tumour known to be associated with a the expression of Table 3 A summary of human BMMSCs transformation without specific chromosomal translocation Type of sarcomas Expressed gene(s)/treatment Reference hTERT + HPV16 E6/E7 + SV40-ST + H-RAS [44] Undifferentiated spindle cell sarcoma hTERT + SV40-LT + H-RAS [13] hTERT + H-RAS + BMI-1 [43] Tumors with smooth muscle and bone properties hTERT4 [33] Undifferentiated pleomorphic sarcomas DKK1 + SV40-LT [14] Xiao et al. Clinical Sarcoma Research 2013, 3:10 Page 5 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/10 fibroblast myoblast self renewal neuronal cell MSC bipotential tripotential progenitor progenitor cell cell CBFA1, osterix multipotent progenitor cell osteocyte osteoblast SOX9, PPARγ 2 SOX5, SOX6 chondroblast adipocyte chondrocyte Figure 2 MSC differentiation scheme. Under different signaling regulations, MSCs can differentiate into different types of cells. The differentiation process involves sequential signaling regulation and many different stages. EWSR1–ETS fusions or rarely other chimeras [59-62]. transformation of mouse MSCs [64]. Similar manipula- The exogenous expression of the fusion gene EWS-FLI1 tions have been also applied on human MSCs. Human alone in mouse MSCs has been shown to transform MSCs with exogenous EWS-FLI1 expression transformed these cells, demonstrated by in vitro immortalization and these transformed cells expressed neuroectodermal and in vivo sarcomatous tumour formation after inocula- markers [65]. Moreover, the knockdown of EWS-FLI1 ex- tion in immunocompetent mice [63]. In another study a pression in Ewing sarcoma cell lines restored the in vitro secondary genetic alteration was needed for the induced trilineage differentiation ability of the cells [52]. In a Table 4 A summary of sarcoma types from different transformation studies in mice Sarcoma type Cell of origin Targeted genes Reference Mouse BMMSCs - [4] -[6] C-myc overexpression and Ink4a/Arf knockout [16] Osteosarcoma Mouse osteoblast precursors Tp53, Rb double knockout [56] Mouse osteoblasts Tp53knockout [57] Tp53 and Rb double knockout [57] Tp53 knockout [17] Mouse AMSCs Tp53 knockout [14] Tp53 knockout [24] Leiomyosarcomas Tp53 and Rb double knockout [8] Mouse smooth muscle lineage cells Pten knockout [30] Mouse BMMSCs - [58] “Fibrosarcoma” Aged mouse BMMSCs - [25] Mouse AMSCs P21 knockout, Tp53 heterozygous knockout [24] Mouse skeletal muscle cells K-ras overexpression and Tp53 knockout [32] Pleomorphic rhabdomyosarcoma K- ras overexpression and Tp53 heterozygous knockout [32] Xiao et al. Clinical Sarcoma Research 2013, 3:10 Page 6 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/10 transgenic mouse model, by expressing EWS-FLI1 gene explained by the fact that although considered as muscle specifically in the mesoderm-originated tissues in limbs specific Myf5 can also be expressed in some MSCs du- and simultaneous Tp53 knockout, sarcomas with similar ring development. characteristics as Ewing sarcoma occurred while with only Tp53 knockout the primary sarcoma type was osteosar- Other soft tissue sarcomas coma [66]. In brief, Ewing sarcoma, originally considered Similar results as described above were seen in a mouse as tumours arising from the neuroectodermal lineage and model of liposarcoma, where FUS -CHOP was able to not considered of mesenchymal origin could be experi- induce liposarcoma genesis in MSCs, whereas no mentally derived directly from MSCs, but only upon liposarcoma was formed when FUS-CHOP gene was introducing the typical translocation. This strongly sup- manipulated to be only expressed in differentiated, ports an MSC origin of Ewing sarcoma [67]. aP2-expressing adipocytes. This study again under- scores the exact cell status as a crucial factor in Osteosarcoma sarcomagenesis [42,70]. However other studies show that Osteosarcoma is the most common primary malignant there is considerate plasticity in the different lineages since bone tumour among children. It is characterized by the rhadomyosarcoma, an aggressive skeletal muscle tumour production of osteoid and extensive cytogenetic instabi- can be generated from adipocytes by activation of Sonic lity [36]. Different studies have supported the MSC ori- Hedgehog signaling [71]. A third soft tissue sarcoma gin of osteosarcoma [4,16]. Both spontaneous and model is that of clear cell sarcoma, characterized by induced MSC models for osteosarcoma have been melanoma-like features and an EWSR1/ATF1 transloca- discussed above. Osteosarcomas mainly arise in the tion. Conditional expression of the human EWSR1/ATF1 metaphyses of long bones and the peak incidence is in the fusion gene in mouse gives rise to tumorigenesis with ex- second decade of human life, correlating with the rapid treme brief latency. The most stem-like MSCs give rise to bone growth during puberty, a process in which MSCs are fully melanoma-like lesions, whereas more differentiated crucially involved [37]. In both human osteosarcoma cells cells result in a less clear cell sarcoma phenotype [72]. and transformed MSCs, frequent aberrations in genes encoding components of P53 pathway have been identi- Discussion fied [4,39]. In Tp53 knockout mice many types of sarco- Until now there have not been many studies addressing mas developed and osteosarcoma was the main type [17]. the effect of MSCs of different tissues and different ways of preparation on the role of MSCs as a model for Chondrosarcoma sarcoma genesis. The conspicuous difference between A study compared the gene expression profiles of chon- mouse and human MSCs in spontaneous transformation drosarcomas of different differentiation degree [53]. Less can be possibly explained by many factors. In human differentiated chondrosarcomas were shown to have cells, the telomeric DNA is often 5–10 kb long and more similarity with MSCs of pre-chondrogenic stages mouse cells have a telomeric DNA length of 30–40 kb and more differentiated chondrosarcomas share more [41,51]. The longer telomeres in mouse MSCs allow cells similarity with fully differentiated chondrocytes. This sug- to proliferate many generations before reaching reaching gests that chondrosarcoma progression probably parallels the telomere length limit, giving higher chance for deregulated chondrocytes differentiation process of MSCs cell to acquire aberrations [41,51]. Since mice have a [40,53]. shorter life span than humans, the genome mainte- nance in mouse cells is also less stringent than in hu- Soft tissue sarcomas man cells [73]. Synovial sarcoma Niche is one of the most important factors in the de- In synovial sarcoma, exogenous expression of SYT-SSX2 termination of stem cell characteristics. The function of fusion gene in the skeletal-muscle-specific Myf5 expres- niche in stem cell differentiation and pluripotency main- sing lineage induced the formation of synovial sarcomas tenance is well known. There has also been research in vivo. Remarkably, when this fusion gene was intro- showing that the low oxygen tension is important for duced into cells more differentiated than myoblasts syn- multipotency maintenance of MSCs, while normal oxy- ovial sarcoma did not occur [68]. This fact emphasizes gen level will induce differentiation [74]. Besides, niche the important role of cell status in the genesis of specific has also been indicated to be involved in tumorigenesis type of sarcomas. On the other hand, fusion gene silen- [75]. This suggests the important role of niche in ge- cing in primary synovial sarcoma cells restored both the nomic instability and therefore tumourigenetic ability. trilineage differentiation capacity and the MSC marker One special feature of the bone marrow niche is the expression, strongly suggesting cells of MSC lineage as partnership of MSCs and haematopoietic stem cells, the origin of synovial sarcoma [69]. This may be which deserves further exploration [76,77]. Xiao et al. Clinical Sarcoma Research 2013, 3:10 Page 7 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/10 Future considerations 5. Mohseny AB, Hogendoorn PCW: Concise review: mesenchymal tumors: when stem cells go mad. Stem Cells 2011, 29:397–403. The numerous but well documented studies on MSCs gi- 6. Tolar J, Nauta AJ, Osborn MJ, Panoskaltsis MA, McElmurry RT, Bell S, et al: ving rise to sarcomas in experimental set-up provide ex- Sarcoma derived from cultured mesenchymal stem cells. Stem Cells 2007, cellent models to study this devastating malignancy in a 25:371–379. 7. Chanda D, Kumar S, Ponnazhagan S: Therapeutic potential of adult bone systematic and controlled way. This offers opportunities marrow-derived mesenchymal stem cells in diseases of the skeleton. for preclinical testing of experimental therapies, thereby J Cell Biochem 2010, 111:249–257. providing convincing data that may facilitate application 8. Rubio R, Garcia-Castro J, Gutierrez-Aranda I, Paramio J, Santos M, Catalina P, et al: Deficiency in p53 but not retinoblastoma induces the in actual clinical trials despite small patient cohorts. transformation of mesenchymal stem cells in vitro and initiates leiomyosarcoma in vivo. Cancer Res 2010, 70:4185–4194. Conclusions 9. Choumerianou DM, Dimitriou H, Perdikogianni C, Martimianaki G, Riminucci M, Kalmanti M: Study of oncogenic transformation in ex vivo expanded Although mouse MSCs have exhibited definite readiness mesenchymal cells, from paediatric bone marrow. Cell Prolif 2008, to transform in vitro, human MSCs do not go through 41:909–922. transformation in ex vivo expansion and need additional 10. Zheng Y, He L, Wan Y, Song J: H3K9me-enhanced DNA hypermethylation of the p16(INK4a) gene: an epigenetic signature for spontaneous manipulation before progression into sarcomas. There- transformation of rat mesenchymal stem cells. Stem Cells Dev 2013, fore, although there are few cases of osteosarcoma 22:256–267. genesis in patients infused with bone marrow MSCs 11. Rodriguez R, Rubio R, Gutierrez-Aranda I, Melen GJ, Elosua C, Garcia-Castro J, et al: FUS-CHOP fusion protein expression coupled to p53 deficiency [45-47], it is considered generally safe to use human induces liposarcoma in mouse but not in human adipose-derived MSCs in clinic. mesenchymal stem/stromal cells. Stem Cells 2011, 29:179–192. 12. Aguilar S, Nye E, Chan J, Loebinger M, Spencer-Dene B, Fisk N, et al: Murine Abbreviations but not human mesenchymal stem cells generate osteosarcoma-like AKT: v-akt murine thymoma viral oncogene homolog; AMSC: Adipose tissue lesions in the lung. Stem Cells 2007, 25:1586–1594. derived MSC; APC: Adenomatous polyposis coli; BMI-1: B lymphoma Mo-MLV 13. Rosland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll H, insertion region 1 homolog; BMMSC: Bone marrow derived MSC; C-myc: v- et al: Long-term cultures of bone marrow-derived human mesenchymal myc myelocytomatosis viral oncogene; Cdkn2a: Cyclin-dependent kinase stem cells frequently undergo spontaneous malignant transformation. inhibitor A; CHOP: C/EBP homologous protein; DKK1: dickkopf 1 homolog; Cancer Res 2009, 69:5331–5339. EWS: Ewing Sarcoma; ETS: E-twenty six; FKHR: Forkhead in 14. Rodriguez R, Rubio R, Menendez P: Modeling sarcomagenesis using rhabdomyosarcoma; FLI1: Friend leukemia integration 1; Fos: FBJ murine multipotent mesenchymal stem cells. Cell Res 2012, 22:62–77. osteosarcoma viral oncogene; FUS: Fused in sarcoma; H-RAS: v-Ha-ras Harvey 15. Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, et al: rat sarcoma viral oncogene homolog; HLA-DR: Human leukocyte antigen-DR Human bone marrow derived mesenchymal stem cells do not undergo chain; HPV: Human papillomavirus; hTERT: Human telomerase reverse transformation after long-term in vitro culture and do not exhibit telomere transcriptase; IDH: Isocitrate dehydrogenase; INK4A/ARF: Inhibitor of CDK4 A/ maintenance mechanisms. Cancer Res 2007, 67:9142–9149. Alternative Reading Frame; K-ras: v-Ki-ras2 Kirsten rat sarcoma viral oncogene 16. Shimizu T, Ishikawa T, Sugihara E, Kuninaka S, Miyamoto T, Mabuchi Y, et al: homolog; MAPK: Mitogen-activated protein kinase; MSC: Mesenchymal Stem c-MYC overexpression with loss of Ink4a/Arf transforms bone marrow Cell; MYF6: Myogenic factor 6; PAX3/7: Paired box 3/7; stromal cells into osteosarcoma accompanied by loss of adipogenesis. PI3K: Phosphatidylinositol-3-kinase; Prx1: Peroxiredoxin 1; Pten: Phosphatase Oncogene 2010, 29:5687–5699. and tensin homolog; Rb: Retinoblastoma; SSX2: Synovial sarcoma 17. Lin PP, Pandey MK, Jin FH, Raymond AK, Akiyama H, Lozano G: Targeted translocation 2; SV40-LT: Simian virus 40-large antigen; SYT: Synaptotagmin; mutation of p53 and Rb in mesenchymal cells of the limb bud produces TERT: Telomerase reverse transcriptase. sarcomas in mice. Carcinogenesis 2009, 30:1789–1795. 18. Sandberg AA, Bridge JA: Updates on the cytogenetics and molecular Competing interests genetics of bone and soft tissue tumors: osteosarcoma and related The authors declare that they have no competing interests. tumors. Cancer Genet Cytogenet 2003, 145:1–30. 19. Zhou YF, Bosch-Marce M, Okuyama H, Krishnamachary B, Kimura H, Zhang Authors’ contributions L, et al: Spontaneous transformation of cultured mouse bone marrow- Wei Xiao drafted the manuscript. Alexander B. 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Nature 2010, 466:829–834. doi:10.1186/2045-3329-3-10 Cite this article as: Xiao et al.: Mesenchymal stem cell transformation and sarcoma genesis. Clinical Sarcoma Research 2013 3:10. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit

Journal

Clinical Sarcoma ResearchSpringer Journals

Published: Jul 23, 2013

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