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2017 ; 6
(2
): 512-526
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Generation of Osteosarcomas from a Combination of Rb Silencing and c-Myc
Overexpression in Human Mesenchymal Stem Cells
#MMPMID28191765
Wang JY
; Wu PK
; Chen PC
; Lee CW
; Chen WM
; Hung SC
Stem Cells Transl Med
2017[Feb]; 6
(2
): 512-526
PMID28191765
show ga
Osteosarcoma (OS) was a malignant tumor occurring with unknown etiology that made
prevention and early diagnosis difficult. Mesenchymal stem cells (MSCs), which
were found in bone marrow, were claimed to be a possible origin of OS but with
little direct evidence. We aimed to characterize OS cells transformed from human
MSCs (hMSCs) and identify their association with human primary OS cells and
patient survival. Genetic modification with p53 or retinoblastoma (Rb) knockdown
and c-Myc or Ras overexpression was applied for hMSC transformation. Transformed
cells were assayed for proliferation, differentiation, tumorigenecity, and gene
expression profile. Only the combination of Rb knockdown and c-Myc overexpression
successfully transformed hMSCs derived from four individual donors, with
increasing cell proliferation, decreasing cell senescence rate, and increasing
ability to form colonies and spheres in serum-free medium. These transformed
cells lost the expression of certain surface markers, increased in osteogenic
potential, and decreased in adipogenic potential. After injection in
immunodeficient mice, these cells formed OS-like tumors, as evidenced by
radiographic analyses and immunohistochemistry of various OS markers. Microarray
with cluster analysis revealed that these transformed cells have gene profiles
more similar to patient-derived primary OS cells than their normal MSC
counterparts. Most importantly, comparison of OS patient tumor samples revealed
that a combination of Rb loss and c-Myc overexpression correlated with a decrease
in patient survival. This study successfully transformed human MSCs to OS-like
cells by Rb knockdown and c-Myc overexpression that may be a useful platform for
further investigation of preventive and target therapy for human OS. Stem Cells
Translational Medicine 2017;6:512-526.