U-M researchers discover first tumor-inducing cells within solid tumors

Muhammad Al-Hajj and Michael Clarke Photo: Martin Vloet

Of all the neoplastic cells in human breast cancers, only a small minority — perhaps as few as one in 100 — appears to be capable of forming new malignant tumors, according to research by scientists in the University of Michigan Comprehensive Cancer Center. Their discovery could help researchers zero in on the most dangerous cancer cells to develop new, more effective treatments.

“These tumor-inducing cells have many of the properties of stem cells,” says Michael Clarke, M.D., professor of internal medicine, who directed the study. “They make copies of themselves — a process called self-renewal — and produce all the other kinds of cells in the original tumor.”

Although similar cells have been identified in human leukemia, these are the first to be found in solid tumors, Clarke adds. The cells were isolated from primary or metastatic breast cancers removed from nine women treated for cancer at the U-M’s Cancer Center.

The discovery, reported recently in the Proceedings of the National Academy of Sciences, may also explain why current treatments for metastatic breast cancer often fail, says Max S. Wicha, M.D., an oncologist and director of the U-M Comprehensive Cancer Center.

“The goal of all our existing therapies has been to kill as many cells within the tumor as possible,” Wicha says. “This study suggests that the current model may not be getting us anywhere, because we have been targeting the wrong cells with the wrong treatments. Instead, we need to develop drugs targeted at the tumor’s stem cells.”

All cancer cells have a unique pattern of proteins, similar to a fingerprint, on their surface membranes, explains Muhammad Al-Hajj, Ph.D., a U-M post-doctoral fellow and first author of the National Academy of Sciences paper. “We used specific antibodies and flow cytometry technology to segregate the cancer cells within a tumor into isolated populations based on their surface protein markers,” Al-Hajj says. These isolated cell populations were then individually injected into immune-deficient mice and the mice were examined for tumor growth every week for up to six months. Al-Hajj found only one small group of cells was capable of forming new cancers in mice.

“As few as 100 to 200 of these tumor-inducing cells, islated from eight of nine tumors in the study, formed tumors in mice, while tens of thousands of the other cancer cells from the original tumor failed to do so,” Clarke says.

Given that tumor-inducing cells now have been identified in breast and blood cancers, Wicha and Clarke believe it is likely that similar cells drive the development of other types of cancer, as well. The Center is establishing a new research program to identify stem cells in other cancers and develop new therapies to destroy them.

“This is not a cure for cancer,” Clarke emphasizes. “But it is a very promising lead, which will focus our efforts to try to find a cure for cancer.”

The U-M study was funded by the National Cancer Institute. Sean J. Morrison, Ph.D., a Howard Hughes Medical Institute assistant investigator and U-M assistant professor of internal medicine, was a collaborator in the research study.

—SFP

For an expanded version of the story and a video clip:
www.med.umich.edu/opm/newspage/2003/tumorsc.htm
For more about breast cancer:
www.cancer.med.umich.edu