Editor's note: This is part one of a two-part series on cancer metastasis. Part two will run in Wednesday's issue.

What cancer patients need to be worried about is most often not the primary tumor - it's metastasis.

Cancer metastases are a bad combination of deadly characteristics, because they take up residence in organs and cause organ damage through their growth, and they're hard to get a handle on. Once cancer metastasizes, "it has usually developed a number of mutations that make it very complex to treat," William Harbour, professor of medicine and molecular oncology at Washington University in St. Louis, told BioWorld Today.

Harbour said there's not likely to be a magic bullet targeting a generic metastasis. The reason is that the molecular characteristics of a metastasis depend very strongly on those of the original tumor - only worse, because of the extra mutations.

Indeed, Harbour said that a molecular classification is a more accurate way of thinking about cancers than a simple classification by the gross localization of the primary tumor. "What's important . . . is the molecular type of cancer."

Some disagree. Biotechnology company Epeius Biosciences has a compound in Phase I/II clinical trials that the company believes will be essentially a broad-spectrum antimetastatic agent.

But the prevailing current opinion appears to be more aptly summarized by scientists such as Robert Mayer, medical oncologist at the Dana-Farber Cancer Institute: "Metastasis isn't a generic condition or finding," he told BioWorld Today.

Still, despite the sometimes bewildering array of mutations that can underlie cancer, certain themes are evident in attempts to prevent it. Probably none has received more attention recently than the cancer stem cell, the idea that there is a subpopulation of tumor-initiating cells that is responsible for replenishing tumors and possibly initiating cancer recurrence and metastasis.

Putative cancer stem cells have been identified for a number of cancers, though their existence is not undisputed. (See BioWorld Today, March 13, 2007.)

At the 2007 American Association for Cancer Research Annual Meeting, researchers from Biogen Idec presented data suggesting that the cell surface protein CD44 may be a marker of cancer-initiating cells for colon cancer. First author Peter Chu (who noted that he prefers the term "cancer initiating cell" because it is unclear whether the cells have all the properties of a true stem cell) told BioWorld Today that there is no direct evidence that stem cells contribute to metastasis, though the idea makes intuitive sense and is "strongly supported" by animal models.

Chu, a researcher at Biogen Idec, cautioned that the company still is getting a handle on identifying markers and isolating the putative stem cells, let alone developing targeted therapies against them. "It's still the early days," he said.

But the company does have big plans. "Our goal is to improve cancer survival rates by identifying these cancer stem cells in order to pave the way for therapeutics to prevent the relapse or metastasis of cancer."

Somewhat ironically, if the idea that stem cells are behind metastases and recurrence proves correct, it would mean that current cancer therapies, which by and large target fully differentiated and rapidly dividing cells, are the opposite of what would be optimal; stem cells neither divide rapidly, nor are they differentiated.

Better ways to identify stem cells could lead not only to new targets, but also to a second lease on life for an old method. "Now that we're starting to understand stem cell antigens, we can maybe go back to immunotherapies," Harbour said. Cancer vaccines have had a decidedly mixed history in the clinic to date, but more accurate targeting could change their fortunes for the better.

Harbour's lab also is taking the idea that there are many different types of cancer into a different direction. His team is working to find gene expression signatures that predict a tumor is likely to metastasize.

The idea that gene expression signatures can be used to predict metastases may seem hard to reconcile with the concept of a cancer stem cell at first blush, since cancer stem cells are by definition rare tumor denizens with a different program of gene expression than regular tumor cells.

Biogen Idec's Chu noted that early attempts to predict metastasis through gene expression signatures of the whole tumor "didn't really lead to much." But recent technological advances have allowed scientists to study the gene expression profiles, specifically of likely cancer stem cells, and such more specific investigations might lead to more predictive answers.