Cancer Stem Cells (CSC) represent a very small population within in vitro cell lines and in situ tumors. Currently, isolation can only be appropriately done with FLOW Cytometry cell sorting capabilities. Additionally, tissue culture methods have been devised to maintain stem cell characteristics to prevent differentiation into progeny cells. We have been able to characterize CSC from various epithelial carcinoma cell lines.1) We have identified the CSC phenotype of prostate cancer cell lines, which agrees with clinical tissue observation, as a CD44+, 24- subpopulation, these cells are genomically distinct from other populations and uniquely develop tumors in murine xenograft models. 2) We have developed in vitro methods to study how CSC differentiate into progeny cells, a phenomenon which occurs in situ. We have tentatively identified the extrinsic substance which induces differentiation and are developing methods to block this pathway in vitro and in CSC xenografts.3) Identification of immunosuppressive/toleragenic markers on cancer stem cells. We have found that almost all CSC found in melanoma, prostate, breast, and renal cell carcinomas have an immunosuppressive surface antigen called CD200, suggesting that the immune system may recognize or not CSC differently from the progeny cells.4) The effects phytochemicals on CSC viability. Because of the historical research regarding the effects of certain phytonutrients on cancer prevent, we screened a highly selected library for induction of apoptosis in CSC compared to normal stem cells. WE have found two that kill CSC, their progeny, but have little effects on normal stem cells. We have discovered three phytochemicals that block CSC growth in xenografts and determining the mechanism(s) by which the phytochemicals work.5) We have identified novel characteristics in polycomb gene expression which controls docetaxel sensitivity in prostate cancer.Also findings that highly invasive pancreatic cancer cells exhibit increased expression of DNA repair genes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010794-06
Application #
8552833
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2012
Total Cost
$490,842
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Crea, F; Fornaro, L; Paolicchi, E et al. (2012) An EZH2 polymorphism is associated with clinical outcome in metastatic colorectal cancer patients. Ann Oncol 23:1207-13
Cho, Yong Mee; Kim, Young Seok; Kang, Mun Jung et al. (2012) Long-term recovery of irradiated prostate cancer increases cancer stem cells. Prostate 72:1746-56
Mathews, Lesley A; Cabarcas, Stephanie M; Hurt, Elaine M et al. (2011) Increased expression of DNA repair genes in invasive human pancreatic cancer cells. Pancreas 40:730-9
Crea, Francesco; Duhagon, Maria Ana; Farrar, William L et al. (2011) Pharmacogenomics and cancer stem cells: a changing landscape? Trends Pharmacol Sci 32:487-94
Crea, Francesco; Duhagon Serrat, Maria A; Hurt, Elaine M et al. (2011) BMI1 silencing enhances docetaxel activity and impairs antioxidant response in prostate cancer. Int J Cancer 128:1946-54
Cabarcas, Stephanie M; Mathews, Lesley A; Farrar, William L (2011) The cancer stem cell niche--there goes the neighborhood? Int J Cancer 129:2315-27
Crea, Francesco; Hurt, Elaine M; Mathews, Lesley A et al. (2011) Pharmacologic disruption of Polycomb Repressive Complex 2 inhibits tumorigenicity and tumor progression in prostate cancer. Mol Cancer 10:40
Crea, Francesco; Hurt, Elaine M; Farrar, William L (2010) Clinical significance of Polycomb gene expression in brain tumors. Mol Cancer 9:265
Duhagon, Maria Ana; Hurt, Elaine M; Sotelo-Silveira, Jose R et al. (2010) Genomic profiling of tumor initiating prostatospheres. BMC Genomics 11:324
Mathews, Lesley A; Hurt, Elaine M; Zhang, Xiaohu et al. (2010) Epigenetic regulation of CpG promoter methylation in invasive prostate cancer cells. Mol Cancer 9:267

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