Transformation potential of bone marrow stromal cells into undifferentiated high-grade pleomorphic sarcoma

Li, Qing; Hisha, Hiroko; Takaki, Takashi; Adachi, Yasushi; Li, Ming; Song, Changye; Feng, Wei; Okazaki, Satoshi; Mizokami, Tomomi; Katô, Junko; Inaba, Muneo; Hosaka, Naoki; Maki, Masahiko; Ikehara, Susumu

doi:10.1007/s00432-009-0723-0

Cited by 16 publications

(19 citation statements)

References 27 publications

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“…Interestingly, transformation of dermal MSC resulted in formation of UPS, consistent with previous reports which used bone marrow MSC. 5,7 At the same time, Rodriguez et al 35 reported formation of fibrosarcomas with areas of adipose tissue differentiation after subcutaneous injection of MSC derived from adipose tissue of p21 Ϫ/Ϫ p53 Ϫ/Ϫ mice into immunodeficient mice. These variations in tumor type may reflect either different differentiation potential of MSC derived from different locations or gene-dependent differentiation potential.…”

Section: Discussionmentioning

confidence: 99%

“…Consistently, formation of UPS was reported after transplantation of bone marrow-derived mouse MSC treated with 2-methylcholanthrene. 7 Intriguingly, it has been reported that according to cell lineage tracing experiments in irradiation chimeras, spontaneous fibrosarcomas arise from bone marrow-derived cells in the mouse. 74 To evaluate a possibility of bone marrow origin of STS in our model, we have performed irradiation chimera experiments in which donor and recipient cells carried floxed copies of p53 and Rb.…”

Section: Discussionmentioning

confidence: 99%

“…The majority of those studies have been based on MSC derived from the bone marrow. [5][6][7][8] The possibility that STS may develop from bone marrow MSC has been raised by a report that, according to cell lineage tracing experiments in irradiation chimeras, STS arise from bone marrow-derived cells. 9 Genetically, STS can be divided into two groups.…”

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confidence: 99%

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Local Mesenchymal Stem/Progenitor Cells Are a Preferential Target for Initiation of Adult Soft Tissue Sarcomas Associated with p53 and Rb Deficiency

Choi

Curtis

Roy

et al. 2010

The American Journal of Pathology

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The cell of origin and pathogenesis of the majority of adult soft tissue sarcomas (STS) remains poorly understood. Because mutations in both the P53 and RB tumor suppressor genes are frequent in STS in humans, we inactivated these genes by Cre-loxP-mediated recombination in mice with floxed p53 and Rb. Ninety-three percent of mice developed spindle cell/ pleomorphic sarcomas after a single subcutaneous injection of adenovirus carrying Cre-recombinase. Similar to human STS, these sarcomas overexpress Cxcr4, which contributes to their invasive properties. Using irradiation chimeras generated by transplanting bone marrow cells from mice carrying either the Rosa26Stop loxP LacZ or the Z/EG reporter , as well as the floxed p53 and Rb genes , into irradiated p53 loxP/loxP Rb loxP/loxP mice, it was determined that sarcomas do not originate from bone marrow-derived cells, such as macrophages, but arise from the local resident cells. At the same time , dermal mesenchymal stem cells isolated by strict plastic adherence and low levels of Sca-1 expression (Sca-1 low , CD31 neg CD45 neg ) have shown enhanced potential for malignant transformation according to soft agar, invasion, and tumorigenicity assays, after the conditional inactivation of both p53 and Rb. Sarcomas formed after transplantation of these cells have features typical for undifferentiated high-grade pleomorphic sarcomas. Taken together, our studies indicate that local Sca-1 low dermal mesenchymal stem/progenitor cells are preferential targets for malignant transformation associated with deficiencies in both p53 and Rb. (Am J

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Local Mesenchymal Stem/Progenitor Cells Are a Preferential Target for Initiation of Adult Soft Tissue Sarcomas Associated with p53 and Rb Deficiency

Choi

Curtis

Roy

et al. 2010

The American Journal of Pathology

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“…Sarcomas are relatively rare, and many types tend to occur in childhood and adolescents with poor prognosis. Most of sarcomas, probably not all, are considered to be originated from mesenchymal stem/progenitor cells (22), and there have been several reports indicating MSCs could transform some type of sarcoma cells (23)(24)(25). However, there have been few reports regarding the MSCs as tumor stroma in sarcoma tissues (26).…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal stem cells promote tumor engraftment and metastatic colonization in rat osteosarcoma model

Tsukamoto

Honoki

Fujii³

et al. 2011

Int J Oncol

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Abstract.Although mesenchymal stem cells (MSCs) are considered to be the cells of origin for most sarcomas, the role of MSCs as a source of tumor stroma is not fully understood in this tumor type. The current study investigated whether MSCs affect the tumor growth and metastatic ability in rat osteosarcoma model. Results from subcutaneous co-implantation of rat osteosarcoma COS1NR cells, established in our laboratory, with rat MSCs isolated from femur bone marrow showed that the incidence of tumor formation and tumor growth rate was higher until 5 weeks compared to COS1NR cell inoculation alone. However, no difference was observed in tumor growth afterwards and in the number of metastatic nodules at 9 weeks (0.75 vs. 1.2). Intravenous MSC injection at weeks 3 and 5 after subcutaneous inoculation of COS1NR cells significantly increased the number of lung nodules in the group with MSC injection compared to the group without MSC injection (17.33 vs. 2.0), while no difference was observed in subcutaneous tumor growth between those groups. Pathway analysis from gene expression profile identified that genes involved in focal adhesion, cytokine-cytokine receptor and extracellular matrix-receptor pathways such as CAMs (ICAM and VCAM)-integrins were highly expressed in MSCs, possibly participating in the tumor progression of osteosarcoma. These results suggest that MSCs could provide a source of microenvironments for osteosarcoma cells, and might enhance the ability of settlement and colonization which lead to early onset of growth and metastasis, possibly through their activated pathways interaction. IntroductionHistoric landmark of tumor microenvironment research was proposed as the 'seed and soil' hypothesis by Stephen Paget 120 years ago (1), and the importance of the microenvironment and stroma in the evolution and progression of solid tumors has drawn renewed interest in recent years. A complex structure of mixed cell types and tissues with endothelial cells, immune cells, stromal cells and extracellular matrix is essential for the growth and progression of solid tumors (2). Although all of these components in the tumor are integral in carcinogenesis and metastasis, the stroma is considered to be a 'co-conspirator' in the evolution and progression of the disease (3). Among the stromal elements, the progenitor cells of the stroma, the mesenchymal stem cells (MSCs), have been receiving focused attention lately.Mesenchymal stem cells (MSCs) are mainly derived from bone marrow, non-hematopoietic precursor cells possessing differentiation potential to skeletal mesodermal lineages such as osteoblasts, chondrocytes and adipocytes as well as some extra-mesodermal cell types including neural, pancreatic and hepatocytic phenotypes with strong proliferative capacity (4-6), and are of increasing interest as the future therapeutic tool in regenerative medicine (7,8). MSCs also display immune suppressive properties which could be the potentially exploited for therapeutic treatment of auto-immune diseases and the reduction of gra...

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“…Recent reports indicate that sarcoma can evolve from murine MSC cultures (Li et al 2010 ;Tolar et al 2007 ) . Karnoub and coworkers demonstrated that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft (Karnoub et al 2007 ) .…”

Section: Potential Applications For Therapiesmentioning

confidence: 99%

Mesenchymal Stem Cells – An Oversimplified Nomenclature for Extremely Heterogeneous Progenitors

Wuchter

Wagner²,

2013

Regenerative Medicine

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Mesenchymal stem cells (MSC) are plastic-adherent fi broblast-like cells that can readily be isolated from various tissues and expanded in vitro. Per de fi nitionem , they are able to differentiate into bone, cartilage and adipose tissue. In the last 15 years, a huge number of different preparative protocols have been developed to yield MSC-like cell lines from starting materials as diverse as bone marrow, fat tissue, umbilical cord blood and peripheral blood. However, these protocols as well as the resulting cell populations are heterogeneous. Furthermore, the composition of the cell products and their differentiation potential changes in the course of long-term culture expansion. There is an urgent need for the development of molecular markers and universal criteria for quality control of the starting cell populations as well as for the cell products after expansion. Nevertheless, MSC have already found their way into a huge number of clinical studies addressing a broad variety of diseases. Even though there is no convincing evidence that MSC are involved in the process of tissue repair by transdifferentiation, they probably contribute to the repair process by immunomodulatory effects and interaction with other cell types.

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Transformation potential of bone marrow stromal cells into undifferentiated high-grade pleomorphic sarcoma

Abstract: The present study suggests that UHGPSs are derived from BM stromal cells, probably mesenchymal stem cells.

Cited by 16 publications

References 27 publications

Local Mesenchymal Stem/Progenitor Cells Are a Preferential Target for Initiation of Adult Soft Tissue Sarcomas Associated with p53 and Rb Deficiency

Local Mesenchymal Stem/Progenitor Cells Are a Preferential Target for Initiation of Adult Soft Tissue Sarcomas Associated with p53 and Rb Deficiency

Mesenchymal stem cells promote tumor engraftment and metastatic colonization in rat osteosarcoma model

Mesenchymal Stem Cells – An Oversimplified Nomenclature for Extremely Heterogeneous Progenitors

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