Calling off the invasion
Of every million tumor cells that embark on a metastatic journey, only one will successfully colonize a new site. The cells' genetic "knapsacks" hold tools necessary for the trip—enabling them to dislodge from surrounding tissue, survive in the normally inhospitable blood and lymph channels, and settle elsewhere. Proteins secreted from their membranes "soften up" nearby barriers, helping the cells burrow through tissue and enter and exit the circulatory system. These activities, collectively known as "invasion," are in many respects the defining features of metastatic cells.
Alan Lader, PhD, (left) and David Kwiatkowski, MD, PhD, are seeking genes that enable metastatic cells to invade distant tissue.
That explains why Dana-Farber's David Kwiatkowski, MD, PhD, and Alan Lader, PhD, have chosen to make them the focus of their research. "Our goal is to identify the genes responsible for the invasive ability of metastatic cells," Kwiatkowski says. "This will not only provide clues to the causes of invasion, but also potentially help select gene targets for therapy."
For Kwiatkowski and Lader, the hunt began with 22 sets of lung cancer cells that varied in their degree of invasiveness. The investigators obtained gene profiles for each set, then analyzed the data to see if there was a link between the cells' aggressiveness and their patterns of gene activity.
Nine genes stood out as prime candidates, their activity levels changing in sync with the cells' ability to invade. "In the past, molecular research has focused primarily on single genes," Kwiatkowski notes. "With metastasis, however, it's likely that multiple genes are altered. The ones we're focusing on are the first that have been identified as potentially important to this process."
"If we can show that certain patterns of gene expression are associated with invasive tumors, doctors will have a new tool for determining which patients are likely to relapse and could benefit from additioal therapy."
— Alan Lader, PhD
Lader and Kwiatkowski reasoned that if abnormalities in these genes indeed play a role in invasion, then modifying them might have a beneficial effect. If a particular gene is overactive, or "overexpressed," investigators would try to restrain it; if it is underactive, they would attempt to rev it up.
Their goal is to accomplish this modulation for each of the nine genes individually and in various combinations. Answers won't come quickly, however, because the task of inserting bits of DNA into cells and seeing if they have the desired effect on gene activity is time-consuming as well as technically challenging. But it will help researchers determine if these genes hold the key to cell invasivenes—first in laboratory experiments, then in animal studies. "If we can reduce this ability, we'd expect it would diminish their potential to metastasize as well," Lader says.
"In the short term, this work may lead to better prognosic tests," he continues. "Patients with early-stage lung cancer generally receive surgery, followed by a waiting period to see if the cancer returns. If we can show that certain patterns of gene expression are associated with invasive tumors, doctors will have a new tool for determining which patients are likely to relapse and could benefit from additional therapy."
Like other investigators, Lader became interested in metastasis out of a sense that scientists had barely scratched its potential as a therapy target. "Most treatments focus on cancer cells' formation, survival, and proliferation," he remarks. "Once a cancer diagnosis has been made, though, all those processes have already taken place. At that point, blocking metastasis makes sense as a treatment strategy."
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