Am J Cancer Res 2012;2(6):745-751
Original Article
Stromal modulation of bladder cancer-initiating cells in
a subcutaneous tumor model
Elizabeth M Peek*, David R Li*, Hanwei Zhang, Hyun Pyo Kim, Baohui Zhang, Isla P Garraway,
Arnold I Chin
UCLA Department of Urology, Los Angeles, California; Eli & Edythe Broad Center of Regenerative Medicine &
Stem Cell Research, UCLA, Los Angeles, California; Molecular Biology Institute at UCLA, Los Angeles, California;
Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California. *Elizabeth M Peek and David R Li contributed
equally to this work.
Received October 24, 2012; Accepted November 19, 2012; Epub November 20, 2012; Published November 30, 2012
Abstract: The development of new cancer therapeutics would benefit from incorporating efficient tumor models that
mimic human disease. We have developed a subcutaneous bladder tumor regeneration system that recapitulates
primary human bladder tumor architecture by recombining benign human fetal bladder stromal cells with SW780
bladder carcinoma cells. As a first step, SW780 cells were seeded in ultra low attachment cultures in order to select
for sphere-forming cells, the putative cancer stem cell (CSC) phenotype. Spheroids were combined with primary human
fetal stromal cells or vehicle control and injected subcutaneously with Matrigel into NSG mice. SW780 bladder
tumors that formed in the presence of stroma showed accelerated growth, muscle invasion, epithelial to mesenchymal
transition (EMT), decreased differentiation, and greater activation of growth pathways compared to tumors
formed in the absence of fetal stroma. Tumors grown with stroma also demonstrated a greater similarity to typical
malignant bladder architecture, including the formation of papillary structures. In an effort to determine if cancer
cells from primary tumors could form similar structures in vivo using this recombinatorial approach, putative CSCs,
sorted based on the CD44+CD49f+ antigenic profile, were collected and recombined with fetal bladder stromal cells
and Matrigel prior to subcutaneous implantation. Retrieved grafts contained tumors that exhibited the same structure
as the original primary human tumor. Primary bladder tumor regeneration using human fetal bladder stroma
may help elucidate the influences of stroma on tumor growth and development, as well as provide an efficient and
accessible system for therapeutic testing. (ajcr0000156).
Keywords: Bladder cancer, cancer stem cell (CSC), subcutaneous tumor model, stroma, sphere
Address all correspondence to:
Dr. Arnold I Chin
Department of Urology
University of California at Los Angeles
10833 Le Conte Avenue, P.O. Box 951738
Los Angeles, CA 90095-1738, USA.
Phone: 310-206-4022; Fax: 310-206-5343
E-mail: aichin@ucla.edu
Original Article
Stromal modulation of bladder cancer-initiating cells in
a subcutaneous tumor model
Elizabeth M Peek*, David R Li*, Hanwei Zhang, Hyun Pyo Kim, Baohui Zhang, Isla P Garraway,
Arnold I Chin
UCLA Department of Urology, Los Angeles, California; Eli & Edythe Broad Center of Regenerative Medicine &
Stem Cell Research, UCLA, Los Angeles, California; Molecular Biology Institute at UCLA, Los Angeles, California;
Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California. *Elizabeth M Peek and David R Li contributed
equally to this work.
Received October 24, 2012; Accepted November 19, 2012; Epub November 20, 2012; Published November 30, 2012
Abstract: The development of new cancer therapeutics would benefit from incorporating efficient tumor models that
mimic human disease. We have developed a subcutaneous bladder tumor regeneration system that recapitulates
primary human bladder tumor architecture by recombining benign human fetal bladder stromal cells with SW780
bladder carcinoma cells. As a first step, SW780 cells were seeded in ultra low attachment cultures in order to select
for sphere-forming cells, the putative cancer stem cell (CSC) phenotype. Spheroids were combined with primary human
fetal stromal cells or vehicle control and injected subcutaneously with Matrigel into NSG mice. SW780 bladder
tumors that formed in the presence of stroma showed accelerated growth, muscle invasion, epithelial to mesenchymal
transition (EMT), decreased differentiation, and greater activation of growth pathways compared to tumors
formed in the absence of fetal stroma. Tumors grown with stroma also demonstrated a greater similarity to typical
malignant bladder architecture, including the formation of papillary structures. In an effort to determine if cancer
cells from primary tumors could form similar structures in vivo using this recombinatorial approach, putative CSCs,
sorted based on the CD44+CD49f+ antigenic profile, were collected and recombined with fetal bladder stromal cells
and Matrigel prior to subcutaneous implantation. Retrieved grafts contained tumors that exhibited the same structure
as the original primary human tumor. Primary bladder tumor regeneration using human fetal bladder stroma
may help elucidate the influences of stroma on tumor growth and development, as well as provide an efficient and
accessible system for therapeutic testing. (ajcr0000156).
Keywords: Bladder cancer, cancer stem cell (CSC), subcutaneous tumor model, stroma, sphere
Address all correspondence to:
Dr. Arnold I Chin
Department of Urology
University of California at Los Angeles
10833 Le Conte Avenue, P.O. Box 951738
Los Angeles, CA 90095-1738, USA.
Phone: 310-206-4022; Fax: 310-206-5343
E-mail: aichin@ucla.edu
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American Journal of Cancer Research
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