Abstract
Treating human breast cancer xenografts in mice with bevacizumab or sunitinib has increased the population of cancer stem cells found in the tumors.
Treating human breast cancer xenografts in mice using 2 antiangiogenic drugs has increased the population of cancer stem cells (CSC) found in the tumors. The finding, recently reported in PNAS, might help to explain the increased tumor invasiveness and metastasis seen in response to VEGF inhibitors or vegf inactivation in other mouse models.
A team led by Max S. Wicha, MD, director of the University of Michigan Comprehensive Cancer Center in Ann Arbor, grew human breast cancer xenografts in mice and generated hypoxia in the tumors by treating with either bevacizumab (Avastin; Genentech) or sunitinib (Sutent; Pfizer). Both agents delayed tumor onset and decreased tumor size.
But when the researchers analyzed the tumors using markers specific to CSCs, they found the percentage of CSCs had risen between 2- and 4- fold in treated versus control tumors. To make sure the increase represented a boost in the absolute number of CSCs rather than only the proportion, the team assessed cell viability and found no significant difference between viability in the control and treated tumors.
Importantly, Wicha and his colleagues also tested the residual cancer cells for the ability to initiate tumors in secondary animals. “When we did this, cells from the treated animals formed tumors much quicker, and they grew faster,” Wicha says. “It was surprising to me how aggressive the tumors became after treatment with these agents—that's very worrisome.”
Using both in vivo and in vitro assays, the researchers showed the hypoxia within the tumors generated by the antiangiogenic agents served to boost the population of CSCs. More specifically, the effect was driven by hypoxia-inducible factor-1α, and the team also saw activation of the downstream Akt/β-catenin CSC regulatory pathway.
Recent trials indicating that bevacizumab does not increase survival time in patients with advanced breast cancer led to the U.S. Food and Drug Administration's November 2011 revocation of its approval of bevacizumab in combination with paclitaxel for the treatment of metastatic breast cancer.
Wicha believes that his findings, along with related studies, indicate oncologists need to combine antiangiogenic treatments with agents that specifically target CSCs. Several such agents are already in clinical trials, and he hopes that combination trials begin within the next year.
