A Pre-clinical Breast Cancer Stem Cell Model Based On MMTV-PyMT Mice For Testing Nanoparticle Directed Therapy | 15799
Journal of Cancer Science & Therapy
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The stem cell model of cancer predicts that cancer treatment failure can be overcome if treatment is directed to the self-renewing
cancer stem cell (CSC). Most therapeutic approaches are directed to the proliferating cells of the tumor and not the tumor
stem cells. In order to advance therapy to tumor stem cells, we need models of cancer in which the stem cells can be identified,
targeted and treated. Cells comprising the micro environment (stem cell niche) of CSCs also play a defining role in optimal tumor
initiation potential and are a second target for treatment. We used the MMTV-PyMT transgenic mouse model of spontaneous
breast cancer to identify both CSCs and tumor supporting mesenchymal cells. Female mouse mammary cancer (FFMC) cell lines
consisting of two major populations were generated from primary breast cancers: CD24
tumor-derived mesenchymal stem cells (TDMSCs). CD24
419II cells at 1x10
consistently initiated mammary gland
tumors, whereas the CD24
TDMSCs failed to initiate such tumors at 1x10
cells. Co-transplantation of TDMSCs and CD24+
TICs resulted in a significant increase in TI to the level of a single CSC. Knock-down of Bmi-1, a polycomb group protein and
stem cell transcriptional promoter, by shRNA prevented 419II cells from initiating tumors. TI was restored when Bmi-1 was
reintroduced via an expression vector. We now propose to use anti-CD49f coated nanoparticles containing shRNA to inhibit
Bmi-1 and/or docetaxol to target therapy to the CSCs. Future experiments are planned to direct therapy to the TDMSCs as well
as the CSCs.
Stewart Sell began research as a medical student at the University of Pittsburgh, in the Department of Pathology. After a pathology residency at
Massachusetts General Hospital, and post doctoral fellowships at NIH and Birmingham England he returned to the University of Pittsburgh for 5
years before moving to the University of California at San Diego. After 12 years at UCSD, Sell became Chair of Pathology and Laboratory Medicine at
the University of Texas (UT) at Houston for 14 years before moving to Albany Medical College as Director of the Division of Experimental Pathology.
As of February 2003 he has been a senior scientist at Wadsworth Center. Awards received: Rudolph L. K. Virchow Award; Legacy Laureate of the
University of Pittsburgh; Abbott Award of the ISOBM.
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