Home > Newsroom > News Archive

U-M CCC - Progress Newsletter Winter 2004 Online

Discovering a New World

U-M stem cell discovery "not a cancer cure, but a promising lead." A tale of finding a finding.

Most tales of exploration and discovery recount adventure and challenge, risk and reward, and heroes larger than life. This tale of a breakthrough discovery in cancer research is no exception. It was a voyage to uncharted territory, requiring vision and perseverance, and it too produced heroes, but of a very different kind.

Michael Clarke, M.D., Professor of Internal Medicine, and his team of scientists at the U-M Comprehensive Cancer Center, had a theory: Not all cells in a cancerous tumor are equally lethal. Only some were cast in the role of "stem cells," capable of forming new malignant tumors.

If true, the theory could reset the compass for cancer researchers, pointing them in a dramatically new direction -- to focus on understanding, and ultimately defeating, just those stem cells.

Quite a provocative notion waited just across the sea. But proving or disproving it meant first traveling there, and no model existed to test the theory.

discussion in the lab

Enter the boat-builder. Muhammed Al-Hajj, Ph.D. A post-doctoral fellow whose previous research focused on DNA repair pathways in fruit flies, Al-Hajj was looking for a new challenge, a project "closer to a human application."

As Al-Hajj describes his recruitment to Clarke's team, it's easy to be disarmed by his nonchalance. But even though he seems bent on understatement, there”s something about the lure of the science that he can't quite mask. "He (Clarke) made it clear that the hypothesis might not work -- but that was part of what made it appealing -- the notion that it just might. It was different than a traditional research assignment -- where you pursue a step, record the outcome, publish a paper, proceed to the next step . . . in most cases you're working on a theory based on common belief." This approach wasn”t common at all. There wasn't widespread agreement that cancer could be a stem cell disease. It would be Al-Hajj's job to create the model to test the theory -- to "build the boat" to sail to that new place.

Building the Boat

Experiments "under the hood"
Above: Repeating the ordinary looking for the extraordinary. Al-Hajj conducts one of hundreds of laboratory steps "under the hood."

Below: Sample cells are prepared for a trip through the flow cytometer.

Sample cells are prepared for a trip through the flow cytometer

The process of determining the model was tedious and took more than a year to perfect. Simply put, the model involves taking tumor tissue removed from a breast cancer patient, extracting single cells from it and injecting those cells into immune-deficient laboratory mice within which new tumors will "regrow." Prior to Al-Hajj”s work, no straightforward protocol existed for creating such a viable mouse model. This in itself, although not the final destination, was a remarkable milepost along the way. Scientists from institutions as far away as Cambridge England and the University of Dusseldorf Germany, as well as other U-M colleagues researching breast, prostate and head and neck cancers have already visited the Clarke lab to learn Al-Hajj”s mouse model technique. So on the journey to discovery, there is discovery. According to Al-Hajj, there”s also drudgery and monotony, leaving very little time for resting on laurels. "Sure, it was great to get to that point. But it was more exciting to put the model to work testing the theory."

Proving the theory meant successfully separating the cells that can produce new tumors (those that behave like stem cells) from other cells. Like the development of the model, this meant more patience and thoroughness. ÒIt was one big process of elimination,Ó says Al-Hajj. Cancer cells have unique patterns of proteins, called markers, on their surface membranes. There are hundreds of markers to consider. Even after categorizing the markers into similar populations, the team was still left with about 50 possibilities to test to look for the group or groups that might include stem cells. Fortunately, technology lent a big hand in the form of flow cytometry, a relatively recent advancement that analyzes fluorescent labeled cells and allows scientists to isolate cells of interest, one by one. This laser-powered device, refined in recent years, accurately analyzes and isolates thousands of specially-selected cells in minutes. Utilizing flow cytometry, Al-Hajj and others segregated and analyzed the different marker populations. Of the approximately 50 identified, they eventually determined that, in eight of the nine human breast tumors used in the study, the cells all expressed a protein marker called CD44, and all had very low levels or no presence of another marker called CD24. ÒThat became the prime marker pattern to test,Ó recalls Al-Hajj.

Setting Sail

Proving the theory meant successfully separating the cells that can produce new tumors (those that behave like stem cells) from other cells. Like the development of the model, this meant more patience and thoroughness. "It was one big process of elimination," says Al-Hajj. Cancer cells have unique patterns of proteins, called markers, on their surface membranes. There are hundreds of markers to consider. Even after categorizing the markers into similar populations, the team was still left with about 50 possibilities to test to look for the group or groups that might include stem cells. Fortunately, technology lent a big hand in the form of flow cytometry, a relatively recent advancement that analyzes fluorescent labeled cells and allows scientists to isolate cells of interest, one by one. This laser-powered device, refined in recent years, accurately analyzes and isolates thousands of specially-selected cells in minutes. Utilizing flow cytometry, Al-Hajj and others segregated and analyzed the different marker populations. Of the approximately 50 identified, they eventually determined that, in eight of the nine human breast tumors used in the study, the cells all expressed a protein marker called CD44, and all had very low levels or no presence of another marker called CD24. "That became the prime marker pattern to test,"recalls Al-Hajj.

Land Ho

They now put the model to the test, injecting mice with cells bearing the suspicious marker patterns to see which, if any, would indeed "grow tumors." One would think that by this time (nearly three years had elapsed), the anticipation would be palpable, but to hear Al-Hajj tell it, the actual moment of discovery was something akin to another day at the office:

Al-Hajj: "So Mike, you want to go check the mice?"

Clarke: "Sure."

At the facility, they observed that a tumor had formed on one breast of a mouse that had been injected with less than 200 of one group of cells, while thousands of cells injected from another group had failed to produce a tumor in the other breast. The first group was indeed stem cells. The theory was proven.

What does Al-Hajj remember of that actual moment? "I think we said 'Wow, this is so cool!'."

He doesn't dwell on the accomplishment, nor does he relish the attention that has followed. He's quick to deflect any credit -- a common trait on Clarke's team. For him, it was a good day, but only one of many. Immediately after came the need to replicate the finding. Which they did. Four times. Al-Hajj removed the tumor they had "grown," again used flow cytometry to isolate another 200 stem cells from it, injected them into another mouse, produced another tumor, and then repeated the process (called a passage) two additional times, proving the stem cell's ability to regenerate the original tumor.

The impact of confirming stem cells in breast tumors can't be gauged by Al-Hajj's characteristic low-key recap of the story. Commenting for the press after publishing the finding, lead investigator Clarke framed the discovery this way: "It's not a cure for cancer, but it is a very promising lead which will focus our efforts to try to find a cure." Max Wicha, M.D., director of the U-M Cancer Center added, "for the first time, we can define what we believe are the important cells. If we are to have any real cures in advanced breast cancer, it will be absolutely necessary to eliminate these cells. Before this, we didn”t even know there were such cells."

The next leg of the journey has already been charted: to learn more about these cells -- what drives them, and how to shut them off. Will Al-Hajj sign on for that voyage, too? He already has. "We have some exciting things in the works now -- hopefully we'll have an outcome to talk about soon." He's not being evasive, just cautious. For Al-Hajj, understatement seems to be a studied protection against disappointment. "When you take on a project, you know the odds are against you. So you focus on the work and try not to invest too much of yourself in the outcome. For every one idea that works, there may be ten that don”t. Welcome to science."

Welcome to the new world.

 

image of a non-tumorigenic cell
 
image of a tumorigenic cell

Top left: Non-tumorigenic cells. On their own, these cells lack the ability to form new tumors.
Top right: Tumorigenic cells. These "cancer stem cells" are capable of replicating themselves, as well as producing the heterogeneous populations of cells in malignant tumors.

Photo credit: Muhammad Al-Hajj, University of Michigan,
courtesy of the Proceedings of the National Academy of Sciences

The proof is in under the microscope 

The research conducted in the Clarke lab at teh U-M Cancer Center confirmed that only a small fraction of the cells that make up a human breast cancer tumor -- maybe as few as one in 100 -- are able to form new cancerous tumors. Studies are underway at Michigan to learn more about these "stem cells," and to determine whether they are also found in other solid tumors types.

 

To read more about this discovery, log on to view the press release.

 

Return to top


Speak with a Cancer nurse: 1-800-865-1125
Please Note:

This article is part of the Cancer Center's News Archive, and is listed here for historical purposes.

The information and links may no longer be up-to-date.

Small Text SizeMedium Text SizeLarge Text Size
Adjust text size