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NEW IDEAS ABOUT METASTASIS:
Cancer begins its spread much earlier than thought // hijacks healthy cells to help it proliferate // activates a dormant embryonic program that gives it license to travel.

Metastasis: The Killing Fields

By Anita Slomski // Illustrations by Jon Han // Fall 2009
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metastasis

Jon Han

For cancer cells, it’s a make-or-break journey. To do their worst, the cells have to depart from a tumor in the breast, prostate or other site of origin and set up a colony in another part of the body. In nine out of 10 cases, it’s these metastases that kill patients. In short order, they pop up in multiple places, too many to yield to the surgeon’s scalpel and with genetic alterations that make them more resistant to chemotherapy and radiation than the original tumor ever was.

Yet very, very few cancer cells survive the trip. Just 0.01% of the millions of cells shed daily from a primary tumor will avoid being torn apart in the bloodstream, take hold in a new organ’s tissues and then recruit normal cells to aid in their lethal endeavor. “To metastasize, a tumor cell has to complete many steps, and if it misses even one, it’s out of the game,” says Isaiah J. Fidler, professor and chairman of cancer biology and director of the Metastasis Research Center at the University of Texas M.D. Anderson Cancer Center in Houston.

The long, uncertain nature of this process should, theoretically, provide ample opportunity for therapies that would disrupt a tumor cell, and much research has focused on comprehending exactly what occurs during each stage of the so-called metastasis-invasion cascade to pinpoint the cell’s vulnerabilities. Still, researchers are dealing with a vast ecosystem of genetically unstable cancer cells and normal cells, each with their own biological characteristics. Until recently, progress was slow. “The biology of metastatic cells has been bewildering, because there are so many genes and proteins involved,” says Robert Weinberg, director of the Massachusetts Institute of Technology Ludwig Center for Cancer Research.

During the past few years, however, work on metastasis has advanced quickly, with scientists first identifying, then deciphering many of the genes and cellular functions important to cancer’s spread. That has led to new ideas about how and when the process might be short-circuited. One theory sees cancer as an inflammatory disease that subverts immune-
system cells, such as macrophages, to assist in its spread, so disrupting the activities of these noncancerous cells could avert metastasis. According to another theory, metastatic cells may exploit a normal embryonic process to break free from the primary tumor and migrate, acquiring the properties of indestructible stem cells along the way. New research has taken aim at these cancer stem cells, searching for a compound that would arrest their ability to metastasize. A third theory is focused on the timing of cancer’s spread.

“We used to think metastasis was triggered very late in the evolution of the primary tumor, because that’s when we could physically detect the secondary tumors at distant sites,” says Sridhar Ramaswamy, an oncologist and researcher at the Massachusetts General Hospital Cancer Center. “Now it seems more likely that rare metastatic cells leave some tumors when they are still very small and that many genes that trigger a metastasis are actually active early during the formation of the primary tumors.” The evidence for early metastasis, Ramaswamy says, is the detection of individual cancer cells in the blood of many patients with early-stage cancers, made possible by new technologies such as a silicon chip etched with thousands of tiny, antibody-coated, cancer-cell-attracting pegs.

If confirmed, this controversial theory could open the door to a remarkable idea—that cancer-screening tests could detect disseminated cells even before symptoms of the primary tumor appear. That would permit therapies targeting the migrating cells and their mutations to be delivered much earlier than happens now. This clashes with some other ideas about metastasis, and much more experimentation lies ahead. But all these emerging theories are part of a sudden, hopeful acceleration in the battle against cancer’s lethal colonization.

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Illness Illustrated

Proto cover artists Jon Han and Stuart Bradford discuss the process of translating words into images.

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hed-dossier

1. “Focus on Migration and Metastasis,” Nature Reviews Cancer, April 2009. This compilation of 14 articles by top experts reflects the latest research on the complex biology of metastatic tumors and offers new theories on how cancer’s deadly spread might be thwarted.

2. “The ‘Seed and Soil’ Hypothesis Revisited,” by Isaiah J. Fidler and George Poste, The Lancet Oncology, August 2008. The authors pay tribute to British surgeon Stephen Paget, whose 120-year-old idea—that metastasizing cancer cells can thrive only in the “rich soil” of certain organs—was only recently vindicated.

3. “The Epithelial-Mesenchymal Transition Generates Cells With Properties of Stem Cells,” by Sendurai A. Mani et al., Cell, May 16, 2008. The article describes how Robert Weinberg’s discovery that cancer cells take on properties of self-rejuvenating stem cells dispels the mystery of how disseminated cells can colonize a distant organ.

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