Spontaneous Expression of Embryonic Factors and p53 Point Mutations in Aged Mesenchymal Stem Cells: A Model of Age-Related Tumorigenesis In Mice

Abstract

Aging is the single most common risk factor for cancer. Peripheral and marrow-derived stem cells are long lived and are candidate cells for the cancer-initiating cell. Repeated rounds of replication are likely required for accumulation of the necessary genetic mutations. Based on the facts that mesenchymal stem cells (MSC) transform with higher frequency than other cell types, and tumors in aged C57BL/6 mice are frequently fibrosarcomas, we used a genetically tagged bone marrow (BM) transplant model to show that aged mice develop MSC-derived fibrosarcomas. We further show that, with aging, MSCs spontaneously transform in culture and, when placed into our mouse model, recapitulated the naturally occurring fibrosarcomas of the aged mice with gene expression changes and p53 mutation similar to the in vivo model. Spontaneously transformed MSCs contribute directly to the tumor, tumor vasculature, and tumor adipose tissue, recruit additional host BM-derived cells (BMDC) to the area, and fuse with the host BMDC. Unfused transformed MSCs act as the cancer stem cell and are able to form tumors in successive mice, whereas fusion restores a nonmalignant phenotype. These data suggest that MSCs may play a key role in age-related tumors, and fusion with host cells restores a nonmalignant phenotype, thereby providing a mechanism for regulating tumor cell activity. [Cancer Res 2007;67(22):10889-98]

Morphological, molecular and functional differences of adult bone marrow- and adipose-derived stem cells isolated from rats of different ages

“…The level of the expression of p53 protein appears to be slightly increased in both differentiated ASC and MSC compared to the undifferentiated cells. Mutations in p53 have been implicated in age-related mesenchymal stem cell transformation and in the self-renewal and differentiation of neural stem cells [53,54]. The activity of p53 protein was initially thought to be limited to the nucleus, although recently it became apparent that p53 also regulates mitochondrial response to stress stimuli [55,56].…”

Modeling sarcomagenesis using multipotent mesenchymal stem cells

“…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]. In these reports, the transformation of mMSCs was associated with the accumulation of chromosome instability [16][17][18][19], p53 mutations [15] or loss of CDKN2A/p16 [17], highlighting the importance of a tight cell cycle control in MSC homeostasis.…”

“…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].…”

Controversial issue: Is it safe to employ mesenchymal stem cells in cell-based therapies?

“…It is also thought that similar problems may arise, when MSC derived from aged donors are employed in cell therapy (Li et al, 2007). This conclusion however is based on extrapolations from studies performed on murine MSC.…”