Bladder cancer is the second most common urological malignancy in the United States and is usually not curable at its advanced stage. However, basic research funding geared specifically to diseases in this organ site is relatively meager. It has long been observed that human tumors are heterogenous, as defined by histology or biological properties (i.e. anchorage independent growth property, proliferation and differentiation status). One model hypothesizes the existence of a hierarchy in tumors, which may explain the heterogeneity of tumor cell population within a tumor. This model proposes that rare tumor-initiating cells with stem cell-like properties (cancer stem cells) exist, which can self-renew and differentiate into phenotypically diverse tumor cells that reconstitute the heterogeneity of original tumor. In the current proposal, I describe for the first time the successful isolation and initial characterization of a rare CD44 positive, bladder cancer stem cells (CSCs) from patient tumor. I hypothesize that CSCs exist in all patient bladder tumors and therefore can be prospectively isolated based on their unique biological properties. The primary experimental approaches will be utilizing a combination of cell surface markers (Aim 1A, B&C) and constructs that report on self-renewal signaling pathways (Aim2A). Localization of bladder CSCs and the correlation of their expression level to disease progression will be determined by immunohistochemical analysis in tissue sections and high throughput tissue microarrays (Aim1 D). Further, in order to define a molecular signature"""""""" for bladder CSCs, two separate approaches will be taken (Aim3): (I) a small scale molecular screen to look at specific """"""""sternness genes"""""""" at mRNA level by quantitative RT-PCR (Aim3Ai), and utilization of cutting edge microfluidics western technologies to look at these candidates at protein level (Aim3Aii);(II) a genome wide screen using HEEBO microarrays (Aim 3B). Preclinical targeting of self- pathways unique to bladder CSCs (Aim2B) in comparison to the MARK pathway (Aim2C) will reveal drug targets in vivo. I hypothesize that these CSCs are in fact the """"""""roots"""""""", and therefore ideal targets for future anti-cancer therapies. My long term goal is to enrich for a highly purified population of bladder CSCs, further characterize their biological properties (e.g. ability to invade, and migrate to distal organs), and to develop specific strategies to target such CSCs in attempt to eradicate advanced stage bladder cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
5R00CA129640-05
Application #
8136484
Study Section
Special Emphasis Panel (ZCA1-RTRB-A (M1))
Program Officer
Watson, Joanna M
Project Start
2007-08-15
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$241,529
Indirect Cost
Name
Baylor College of Medicine
Department
Urology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Kurtova, Antonina V; Xiao, Jing; Mo, Qianxing et al. (2015) Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature 517:209-13
King, Katherine Y; Matatall, Katie A; Shen, Ching-Chieh et al. (2015) Comparative long-term effects of interferon ? and hydroxyurea on human hematopoietic progenitor cells. Exp Hematol 43:912-918.e2
Volkmer, Jens-Peter; Sahoo, Debashis; Chin, Robert K et al. (2012) Three differentiation states risk-stratify bladder cancer into distinct subtypes. Proc Natl Acad Sci U S A 109:2078-83
Ho, Philip Levy; Lay, Erica Julianne; Jian, Weiguo et al. (2012) Stat3 activation in urothelial stem cells leads to direct progression to invasive bladder cancer. Cancer Res 72:3135-42
Ho, Philip Levy; Kurtova, Antonina; Chan, Keith Syson (2012) Normal and neoplastic urothelial stem cells: getting to the root of the problem. Nat Rev Urol 9:583-94
Chan, Keith Syson; Volkmer, Jens-Peter; Weissman, Irving (2010) Cancer stem cells in bladder cancer: a revisited and evolving concept. Curr Opin Urol 20:393-7
Chan, Keith Syson; Espinosa, Inigo; Chao, Mark et al. (2009) Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Natl Acad Sci U S A 106:14016-21