Prospective Identification, Tracking And Targeting Of Cancer-initiating Cells In Breast Cancer And Glioma Via Low Proteosome Activity

Identification of cancer stem cells remains a challenge at the microscopic level, but researchers have concluded that low proteosome activity can be an effective marker to isolate these cells from the wider population and track their response to treatment in vitro and in vivo.


"These cells are relatively resistant to radiation and chemotherapy, and their complete elimination from the tumor mass determines therapeutic success," said lead investigator Frank Pajonk, M.D., Ph.D., an assistant professor at the University of California, Los Angeles. "Therefore, prospective identification of this cell population is key to developing therapies."


Pajonk said current methods of identification, which closely rely on the detection of cell surface proteins, are inadequate to track these cells in vivo.


For the current study, Vlashi and colleagues identified stem cells in breast cancer and glioma, a cancer of the central nervous system, by a unique biochemical method and specifically measured the capacity for self-renewal and the likelihood the cells would form tumors.


Researchers determined that cells with low proteosome function, a protease responsible for the regulated destruction of most proteins in cells, exhibited a five-fold increase in self-renewal capacity and an almost 100-fold increase in tumor production capacity.


Further cellular examination found that these certain subclasses of cells responded to sublethal doses of radiation treatment proliferating and repopulating the tumors, while specific elimination of these cells led to tumor control in vivo.


"This unique feature of cancer initiating cells can be exploited as a specific target for selective elimination, and lead to improved tumor control," Pajonk said.


Molecular profiling reveals heterogeneity of active self-renewal pathways in bladder cancer stem cells: Abstract 4998
Chan KS, et al.


Researchers from Stanford University Medical Center have identified a distinct subpopulation of bladder cancer stem cells with properties similar to progenitor basal cells, one of the most common forms of cancer.


Keith Chan, Ph.D., a researcher at Stanford University, analyzed more than 300 bladder transitional cell carcinomas. Approximately 40 percent of them contained CD44+ cells that showed self-renewal patterns that distinguished them as stem cells.


"In addition to these markers, we found that the cells were small and round in shape, suggesting that these cells have properties similar to that seen in progenitor basal cells," Chan said.


Researchers also examined the self-renewal proteins in these bladder cancer stem cells and found further stem cell distinguishing characteristics. Approximately 10 percent had active Bmi1, 30 percent had active Stat3, 5 percent had active ОІ-catenin and 85 percent had active Gli1; no cells showed active Oct4 or Nanog.















With Gli1 identified as the most prevalent protein, researchers tested the potential effects of inhibiting Gli1 with cyclopamine. Chan reports that treatment in culture resulted in a reduction in tumor volume in four out of six samples.


"Further experiments are ongoing to determine what role Gli1 plays, but these diverse self-renewal proteins likely contribute to tumorigenic properties of cancer stem cells in this subset of bladder cancer," Chan said.


Prospective identification, tracking and targeting of cancer-initiating cells in breast cancer and glioma via low proteosome activity
Vlashi E, et al.

Abstract 4997


This was presented at the 2008 Annual Meeting of the American Association for Cancer Research.


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