Malignant Messengers

from Science Magazine by Jocelyn Kaiser –

Tumor cells may send out tiny vesicles that prime organs for cancer to spread

One day, while poring over slides of mouse lung tissue for signs of cancer, David Lyden noticed some odd red specks. They were so small under an electron microscope that he first thought of viruses. But the animals had skin tumors that were prone to spread to the lungs, and the skin tumors had been dyed red. Lyden eventually concluded that the specks were tiny vesicles that had budded off from the skin tumors and found their way to the lungs—and that they functioned as the cancer’s advance guard.

That observation 10 years ago sent Lyden’s career in a new and controversial direction. The physician-scientist at Weill Cornell Medicine in New York City has since become convinced that a primary tumor—the first to grow in a person’s body—spews protein- and RNA-packed vesicles known as exosomes into the blood that have a powerful impact in distant tissues. Far from being passive trash bags, as some have thought, the exosomes help cells from the primary tumor take root in other organs, or metastasize, the process that ultimately kills 90% of cancer patients.

In a series of provocative papers, he and his colleagues have injected exosomes from cultured tumor cells into mice and observed striking effects on metastasis. They conclude that exosomes “prime” certain organs by making them more hospitable to primary tumor cells and “educate” other, nontumor cells to help the new cancer flourish.

Lyden’s ideas run counter to the traditional view of metastasis, which is that cells shed from the primary tumor simply take root in distant organs and grow. “Most cancer biologists think the tumor cell dictates every part of the metastastic cascade,” Lyden notes. But he believes that exosomes prepare metastatic sites by changing tissue so it can nourish tumor growth long before cancer cells arrive.

“Tumor cells are pretty much an innocent bystander. They go to organs where premetastatic niches are already established by tumor-secreted factors including exosomes,” he maintains.

If Lyden is correct, tests for blood-borne tumor exosomes might provide a warning that a cancer is about to metastasize. His work also raises the prospect that targeting these vesicles with drugs could thwart the growth of metastatic tumors.

Lyden’s ideas are “very interesting,” says cancer biologist Raghu Kalluri of MD Anderson Cancer Center in Houston, Texas, who also studies the vesicles. But in his view, “It’s an open book still. Nothing is completely proven about exosomes and metastasis”—much less the relevance to human disease and treatments. Indeed, some biologists say Lyden has stretched his conclusions beyond what his data support. They question his work on several grounds—for example, that injecting mice with a large number of exosomes from cultured cancer cells may not entirely reflect what happens in a living animal.

One Lyden collaborator says skepticism is a natural reaction. His proposal “is mind-boggling,” says cancer biologist Mina Bissell of Lawrence Berkeley National Laboratory in Berkeley, California. “When someone is brave enough to make observations that are turning the field on its head, that’s where the uncomfortableness comes in,” she says. “People start bashing it.”

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