Canadian researchers have identified brain cancer stem cells that, even at extremely low levels, can propel tumor growth. Reporting in the November 18 Nature, Dr. Peter B. Dirks and colleagues from Toronto's Hospital for Sick Children and University of Toronto found that, in a xenograft mouse model, brain tumor cells from both pediatric and adult brain cancers that expressed the cell surface marker CD133 (CD133+) could initiate the development and growth of tumors. The architecture and cellular makeup of the tumors that developed in the mice closely resembled the human tumors from which the CD133+ cells were derived, the researchers said.

In comparison, when the researchers injected anywhere from 50,000 to 100,000 cells from these same human tumors in the mice that lacked the CD133 surface marker, they reported, "Human cells could be found in small clusters near the original injection site, but these cells did not form a nodule or mass." To confirm that the tumor-forming cells were cancer stem cells - that is, that they had the ability to self-renew - the research team performed serial transplantation, taking CD133+ cells from the tumors that developed in the first set of mice and injecting them into a second set of xenograft mice. These mice also developed tumors that closely resembled the original human tumors from which they came, as well as the tumors in the primary mice.

"The identification of cancer stem cells is a significant step in the fight against [cancer]," wrote Dr. Michael F. Clarke, of the University of Michigan in Ann Arbor, in a related commentary. "Because self-renewal is essential if tumors are to grow, agents that target such cells may be effective treatments."

Efficiency of Targeted Clinical Trials Evaluated

Targeted clinical trials can be a more efficient way to study the effectiveness of certain cancer drugs, according to a paper by NCI researchers in the October 15 Clinical Cancer Research. "Most tumors at a given site are heterogeneous with regard to their underlying molecular and genomic signatures," said Dr. Richard Simon of the Division of Cancer Treatment and Diagnosis (DCTD). "It is not reasonable to expect such tumors to have equal sensitivities to a drug that inhibits a particular target." As a result, the potential of many drugs may be hidden in standard clinical trials that use broad eligibility criteria.

Dr. Simon and colleagues developed a model to compare the efficiency of targeted versus untargeted trials for a cancer drug that primarily benefits a specific subset of the population. They found that in most cases a targeted trial would require fewer participants to reach the same end point than a generalized trial, even when including enough patients to screen for the desired subpopulation. A targeted trial would be less efficient in cases where the drug would also be fairly effective in the general population.

Dr. Simon also noted that beyond understanding the mechanisms of drug action, being able to easily screen patients who may respond to these drugs is critical. As understanding in both areas increases, clinical trials tailored to population subsets may become more prominent for finding new therapies.

Smokeless Tobacco Causes Oral and Pancreatic Cancer; Nitrosamines Classified as Human Carcinogens

The International Agency for Research on Cancer (IARC) recently reported that smokeless tobacco, including snuff and chewing tobacco, causes oral and pancreatic cancer in humans. In a separate report, two tobacco-specific N-nitrosamines (TSNA), N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were together classified as human carcinogens. The chemicals occur in all smokeless tobacco products and are formed during the curing and processing of tobacco and during storage of manufactured smokeless tobacco products. Many studies in animals have shown that different routes of exposure to NNN and NNK cause benign and malignant tumors. Results of epidemiological studies of smokeless tobacco users and studies of the mechanisms of action of TSNA plausibly associate NNN and NNK with cancer in humans.

"The working group reaffirmed that smokeless tobacco use causes oral cancer in humans, and concluded that it causes pancreatic cancer as well. These findings reinforce that tobacco use is not safe in any form," said Dr. Deborah Winn of NCI's Division of Cancer Control and Population Sciences. Dr. Winn served on the IARC working group. Conclusions will appear at http://monographs.iarc.fr. A summary of the scientific evidence will be published in the December 2004 Lancet.