Spontaneous expression of embryonic factors and p53 point mutations in aged mesenchymal stem cells: a model of age-related tumorigenesis in mice
Authors
Li, HanchenFan, Xueli
Kovi, Ramesh C.
Jo, YunJu
Moquin, Brian
Konz, Richard
Stoicov, Calin
Kurt-Jones, Evelyn A.
Grossman, Steven R.
Lyle, Stephen
Rogers, Arlin B.
Montrose, Marshall
Houghton, JeanMarie
Student Authors
Ramesh C. Kovi; Calin StoicovUMass Chan Affiliations
Department of Medicine, Division of Hematology/OncologyDepartment of Medicine, Division of Gastroenterology
Department of Cancer Biology
Document Type
Journal ArticlePublication Date
2007-11-17Keywords
Adipocytes; Animals; Bone Marrow Transplantation; Cell Line, Transformed; Cell Transformation, Neoplastic; Endothelial Cells; Fibrosarcoma; *Gene Expression Regulation, Neoplastic; *Genes, p53; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; *Point Mutation; Time FactorsCancer Biology
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
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.Source
Cancer Res. 2007 Nov 15;67(22):10889-98. Link to article on publisher's siteDOI
10.1158/0008-5472.CAN-07-2665Permanent Link to this Item
http://hdl.handle.net/20.500.14038/33723PubMed ID
18006834Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1158/0008-5472.CAN-07-2665