Keynote: J Cell Sci Ther
W e have developed a single breast cancer stem cell (CSC) model system based on the MMTV-PyMT transgenic mouse that is used to show potential diff erentiation therapy of breast cancer by blocking expression of the stemness gene Bmi-1 Th e feasibility of a single-cell model of tumor initiation and metastasis for solid tumors remains controversial. We report here mu ltiple lines of experimental evidence that validate a single-cell CSC tumor initiation model for solid tumors in immunocompetent hosts . Using a FACS protocol for a defi ned set of cell surface markers, we characterized distinct tumor cell populations derived from transgenic MMTV-PyMT mice. Two tumor derived cell cultures, epithelilal cancer stem cells and tumor derived mesenchymal stem cells, were able to diff erentiate into several specialized lineages when cultured in selective media. When epithelial cells cultured from MMTV-PyMT breast cancers were tested by transplantion to syngeneic hosts for tumor initiation potential, the minimum number of cells to initiate tumors varied 1000-fold. Th e number of epithelial tumors cells required to initiate tumors was signifi cantly reduced when the tumor cells were co-transplanted with tumor derived mesenchymal cells, but not with mesenchymal cells from other sources. Expression of the Bmi-1 gene and the presence of mesenchymal stem cells are necessary for reproducible single-cell tum or initiation. Blocking of expression of the Bmi-1 gene in either the epithelial cancer cells or the tumor derived mesenchymal cel ls by shRNA1 signifi cantly reduced tumor initiation by the epithelial cells. Our experiments highlight the practical utility and potential translational signifi cance of a single-cell CSC model to identify genetic and microenvironmental requirements for maintenance of a breast CSC phenotype and provide a pre-clinical model for diff erentiation therapy.
Dr. Sell received an MD from the University of Pittsburgh in 1960, residency in pathology at Massachusetts General Hospital, an d fellowship training at NIH and U. Birmingham in England. He served on the faculty at Pitt; USCD; UT Houston; and Albany Medical College. He has published 265 research papers, 83 invited papers, 36 book chapters and 14 books. He has a paper listed as a ?Ci tation Classic? by Current Contents and another as a ?Scienti fi c Landmark? by AACR. Awards include: Distinguished Scientist Award, IATMO; Virchow Award, LeadershipMedica; Legacy Laureate, Pitt (Highest Award for Alumni); and the Abbott Award of ISOBM