Prostate cancer (PCa) is the most common male urological malignancy, and it is not curable at its advanced stages. It is proposed that a rare population of functionally distinct cancer cells possess the extensive proliferative and self-renewal potential necessary to create a tumor;these are the cancer stem cells (CSCs). Progress in identification of CSCs in solid tumors including those in the breast and brain has prompted strong belief that PCa is a stem cell disease. However, definitive evidence of the existence of CSCs in PCa is lacking. Our long-term objective is to identify, isolate, and characterize a pure population of CSCs from PCa. To achieve this goal, we will first identify certain phenotypic features of cancer cells that co-segregate with functional attributes of sternness, most importantly self-renewal. We will stratify cells using fluorescenceactivated cell sorting based on three criteria: 1) the expression of cell surface markers that have been shown to be expressed by normal prostate stem cells or CSCs in other tissues;2) the ability to actively efflux a fluorescent dye, Hoechst 33342, a characteristic of stem cells in other tissues;and 3) the expression of genes involved in stem cell renewal including Wnt and Hedgehog pathways using reporter genes. We will then test the relative ability of cell populations with or without these properties to form tumors in immunodeficient mice. Methods to grow and expand enriched """"""""stem"""""""" populations will be developed. Finally, we will identify new markers for CSCs by comparing gene expression profiles of cell populations enriched for CSCs to more differentiated cells and generating antibody libraries against cell surface antigens on enriched """"""""stem"""""""" populations. Relevance: Cancer stem cell theory suggests that only a minority of cells, the cancer stem cells (CSCs), within a tumor are truly malignant and capable of driving tumor growth and metastasis, whereas the bulk of a tumor is actually made up of differentiated non-tumorigenic cells. Standard therapies shrink tumors by eradicating the sensitive non-tumorgenic cells, but the tumors recur because the resistant stem cells repopulate the cancer. Our results will help the design of new therapies targeting prostate cancer CSCs that effectively kill the CSCs, rendering the tumors unable to maintain themselves or grow, thus effecting a cure.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA123532-05
Application #
7880635
Study Section
Special Emphasis Panel (ZCA1-RTRB-A (M1))
Program Officer
Lohrey, Nancy
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
5
Fiscal Year
2010
Total Cost
$137,870
Indirect Cost
Name
Stanford University
Department
Urology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Zhao, Hongjuan; Nolley, Rosalie; Chen, Zuxiong et al. (2010) Tissue slice grafts: an in vivo model of human prostate androgen signaling. Am J Pathol 177:229-39
Flamand, Vincent; Zhao, Hongjuan; Peehl, Donna M (2010) Targeting monoamine oxidase A in advanced prostate cancer. J Cancer Res Clin Oncol 136:1761-71
Zhao, Hongjuan; Peehl, Donna M (2009) Tumor-promoting phenotype of CD90hi prostate cancer-associated fibroblasts. Prostate 69:991-1000
Zhao, Hongjuan; Flamand, Vincent; Peehl, Donna M (2009) Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics 2:55
Zhao, Hongjuan; Zongming Ma; Tibshirani, Robert et al. (2009) Alteration of gene expression signatures of cortical differentiation and wound response in lethal clear cell renal cell carcinomas. PLoS One 4:e6039
Peehl, Donna M; Coram, Marc; Khine, Htet et al. (2008) The significance of monoamine oxidase-A expression in high grade prostate cancer. J Urol 180:2206-11
Zhao, Hongjuan; Nolley, Rosalie; Chen, Zuxiong et al. (2008) Inhibition of monoamine oxidase A promotes secretory differentiation in basal prostatic epithelial cells. Differentiation 76:820-30
Zhao, Hongjuan; Ramos, Cristiane F; Brooks, James D et al. (2007) Distinctive gene expression of prostatic stromal cells cultured from diseased versus normal tissues. J Cell Physiol 210:111-21
Zhao, Hongjuan; Brooks, James D (2007) Selenomethionine induced transcriptional programs in human prostate cancer cells. J Urol 177:743-50
Li, Tzu-Huey; Zhao, Hongjuan; Peng, Yue et al. (2007) A promoting role of androgen receptor in androgen-sensitive and -insensitive prostate cancer cells. Nucleic Acids Res 35:2767-76