SAN DIEGO – Recent discoveries about the role of stem cells in cancer have altered the landscape of cancer research. As scientists learn more their cancer-initiating properties, stem cells are emerging as potential therapeutic targets for many types of cancers. Studies presented at the 2008 Annual Meeting of the American Association for Cancer Research, April 12-16, report stem cell discoveries related to pancreatic, bladder, ovarian, and breast cancer, and glioma.
Rasheed ZA, et al. The functional stem cell marker aldehyde dehydrogenase enhances pancreatic cancer stem cell isolation and correlates with clinical prognosis: Abstract 5000
Researchers have identified aldehyde dehydrogenase as a new marker for the presence of pancreatic cancer stem cells, a finding with potential for the development of targeted therapy. Pancreatic cancer is highly aggressive and largely resistant to current therapies. Researchers believe that pancreatic cancer stem cells may be responsible for resistance to chemotherapy.
“Cancer stem cells have emerged as a potential therapeutic target, but the development of effective therapies requires the identification and isolation of highly purified cell populations,” said Zeshaan Rasheed, M.D., Ph.D., a researcher at Johns Hopkins University. Analyzing human pancreatic tumor samples, Rasheed and colleagues found that each contained a small population of cells that expressed aldehyde dehydrogenase, and that these cells showed a greater capacity for growth compared with the cells that did not express aldehyde dehydrogenase. Capacity for growth is among the definitive characteristics of stem cells.
Previous research identified CD24+ and CD44+ cells as pancreatic cancer stem cells, Rasheed says. Rasheed and colleagues found that cells that were CD24+, CD44+, and expressed aldehyde dehydrogenase had a significantly greater potential for reproduction, another definitive characteristic of stem cells, and may be responsible for pancreatic cancer metastasis.
The authors also found that the presence of cells positive for aldehyde dehydrogenase was significantly associated with poorer overall survival. Specifically, patients with these cells lived an average of 14 months after diagnosis compared with 18 months for those without the cells.
“These results suggest a direct link between cancer stem cells and patient outcomes,” said senior author William Matsui, M.D., of Johns Hopkins University.
Vlashi E, et al. Prospective identification, tracking and targeting of cancer-initiating cells in breast cancer and glioma via low proteosome activity: Abstract 4997
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.
Chan KS, et al. Molecular profiling reveals heterogeneity of active self-renewal pathways in bladder cancer stem cells: Abstract 4998
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 ß-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.
Mor G, et al. Identification and characterization of cancer stem cells in ovarian cancer: Abstract 2029
Researchers have identified stem cells in epithelial ovarian cancer that may play a role in the cancer’s resistance to chemotherapy. The findings hold potential for more effective targeting of one of the most lethal forms of cancer.
“Present chemotherapy modalities eliminate the bulk of the tumor but leave a core of these cancer stem cells with high capacity for repair and renewal,” said Gil Mor, M.D., Ph.D., associate professor of obstetrics, gynecology and reproductive sciences at Yale University School of Medicine. “Identification of these cells, as we have done here, is the first step in the development of therapeutic modalities.”
Mor and colleagues isolated cells from 80 human samples of either ascites or solid ovarian tumors. The cancer stem cells were identified by showing positive for traditional markers including CD44 and MyD88, and by showing a high capacity for repair.
In addition Mor and colleagues were able to clone and establish CD44+ cell lines. The cells in culture formed tumors 100 percent of the time. Within those tumors, 10 percent of the cells were CD44+ and 90 percent were CD44-.
Isolating the CD44+ and CD44- stem cells for analysis, the researchers found that the CD44+ cells were highly resistant to chemotherapy with paclitaxel and carboplatin, standard therapies for ovarian cancer, while CD44- cells from the same patient were responsive to chemotherapy.
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