Analysis of tumor-initiating cells in engrafted patient-derived human bladder carcinomas may direct precise cancer therapy

Onyi Balogun1†, Jukes Namm2†, Michael Beckett1, Mitchell C Posner2, Gary Steinberg2, Ralph R Weichselbaum1

1Department of Radiation and Cellular Oncology, 2Department of Surgery, University of Chicago, Chicago, IL†Co-first authors

Background• Volkmer et al* proposed three bladder tumor-

initiating cells (TICs) populations.• Human tumor engraftment into immune-

deficient mice is mediated by TICs and has been associated with a poor prognosis.

• TICs have also been implicated in radiation resistance but this has yet to be investigated in bladder cancer.

Purpose• We investigated the distribution of TIC

populations in patient-derived xenografts (PDXs) from bladder cancer patients as well as the effect of radiation on TIC populations.

Basal Intermediate Differentiated

*Volkmer JP et al. Three differentiation states risk-stratify bladder cancer into distinct subtypes. Proc Natl Acad Sci U S A 2012;109(6):2078-83.

33% of Stage 0-I tumors engrafted in NOD/SCID mice.57% of Stage II-IV tumors engrafted in NOD/SCID mice.

T3aN1 rhabdomyosarcoma.Increase in basal TICs after irradiation.Control vs. +20Gy: 0.4% vs. 29.9% basal TICs

T4bN1 urothelial carcinoma. Increase in basal TICs after irradiation.Control vs. +20Gy: 6.2% vs. 25.7% basal TICs

Results

Conclusions• All bladder tumors contain TICs.• Heterogeneity exists with regard to the distribution of the TIC populations.• Our preliminary results suggest radioresistant TICs may exist in human bladder

tumors.• Specifically, CD90+ TICs may mediate radioresistance.• PDXs may identify patients with radioresistant TIC populations.• Patients whose tumors harbor significant numbers of radioresistant TICs may

be better suited for cystectomy.

Future Directions• Molecular analysis of the different TIC populations• Definition of the relationship between growth in NOD/SCID mice and clinical

outcome