May 7, 2009 Traditionally, cancer biologists have embraced a simple and direct model of the disease process: The tumor -- the "seed" -- was seen as bearing total responsibility for the spread of cancer to distant tissues -- the "soil" in which the seed embedded itself, grew, and reproduced. The result was a seed-dominant model that determined the way doctors treated cancer, using strategies targeting the tumor seed but neglecting the role of the soil.
Recently, however, some researchers have been focusing on the permissive microenvironment, or the metastatic niche, that forms in particular tissues located far from the primary tumor, well before full metastasis takes hold.
"In cancer, it is metastatic disease that causes morbidity and mortality," says Dr. David Lyden, co-author of an article in the April 2009 issue of Nature Reviews Cancer.
"At our lab, we're developing a strategic approach to studying metastasis. Our goal is ultimately to be able to predict and pre-empt the process -- early, if possible, but even in advanced metastasis," adds Dr. Lyden, the Stavros S. Niarchos Associate Professor in Pediatric Cardiology, an investigator in the Division of Pediatric Hematology and Oncology, and associate professor of cell and development biology at Weill Cornell Medical College.
Led by Dr. Lyden, a team of researchers is looking at the molecular and cellular players that mediate changes at future sites of metastasis such as liver, lung, brain or bone, and thereby direct the migration patterns of tumor cells.
The group has zeroed in on several of these essential players, including bone marrow-derived cells and growth factors secreted by the tumor itself. These, Dr. Lyden explains, instruct the pre-metastatic niche to get ready for a long visit, one that will require comfortable accommodations for a rapidly growing population of permanent guests.
If the pre-metastatic niche does the tumor's bidding and boosts production of inflammatory chemokines and fibronectin, among other cancer-friendly proteins, a secondary tumor has a good chance of forming -- and thriving.
Dr. Lyden believes his lab's discoveries could open doors leading to the development of new cancer treatments that target each step along the metastatic pathway. "We can envision a time in the not-too-distant future when we'll be able to prevent metastasis through a new approach for early detection and treatment," he says. "That's why we're studying the earliest changes in the pre-metastatic niche in such depth.
"At the same time," he continues, "the challenge is to understand metastasis in its entirety by familiarizing ourselves with the shifting molecular and cellular microenvironment at each step along the way. The ramifications of this approach for cancer treatment, we believe, are inestimable."
The Lyden lab at Weill Cornell was one of seven to be represented in the current issue of Nature Reviews, which is devoted exclusively to the subject of cancer metastasis in a special issue. In their article titled "The Metastatic Niche: Adapting the Foreign Soil," Dr. Lyden and lead author Dr. Bethan Psaila, a Fulbright Fellow in the Lyden lab, summarize the discoveries and insights they've gleaned over the past decade.
"The 'seed and soil' hypothesis is considered one of the most important among cancer biologists, but our lab -- especially in collaboration with Dr. Rosandra Kaplan and the lab of Dr. Shahin Rafii -- was actually first to address it in real terms," Dr. Lyden says. "Now, many other labs are moving in this direction, and all of them are opening up highly promising new avenues for inquiry."
Preventing and treating cancerous tumors will continue to be central to cancer treatment strategy, he adds. But soon, we may begin to see new strategies aimed at disarming the real killer: metastatic disease.
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