Stopping Cancer's Spread

Blocking a key enzyme could put brakes on metastasis, experts say

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By E.J. Mundell
HealthDay Reporter

WEDNESDAY, April 26, 2006 (HealthDay News) -- Before local tumors can begin to spread throughout the body, they need a road on which to travel.

Now, new research reveals how that road gets built.

A key enzyme called lysyl oxidase (LOX) allows oxygen-poor, localized tumors to gain access to other sites throughout the body, "making a sort of highway for metastasis to spread," explained lead researcher Amato Giaccia, director of the department of cancer and radiation biology at Stanford University.

He called the finding exciting for two reasons: First, it helps explain how cancers make the switch from a localized to a metastatic state; and second, it points to LOX as a potent new target for drugs or vaccines aimed at arresting that lethal change.

"Based on our animal studies, it looks like it could be a very useful weapon in our arsenal against cancer," Giaccia said.

The findings appear in the April 27 issue of Nature.

Over the past few decades, science has made great inroads in the fight against localized tumors -- that's why early detection is so important to long-term survival. However, once a cancer leaves its site of origin, the challenge for doctors gets much tougher.

"In a fair number of solid tumors, metastasis is still the major problem," Giaccia said. For breast, prostate, pancreatic and other cancers, "those that are locally controlled do very well, but those that have metastatic spread do very poorly," he said.

Up until recently, however, scientists have known little about the mechanisms that get cancers moving.

"In other words, those things that make a tumor highly aggressive. We're finding that it's a function not only of the tumor, but also of the 'microenvironment' of the host," explained David Cheresh, a professor of pathology at the University of California, San Diego, and a leading expert in the field of metastatic cancer research.

One of these microenvironmental changes relies on an undersupply of oxygen -- a state called hypoxia -- in tumor cells.

"Solid tumors have a very ill-defined and poorly developed blood supply," Giaccia explained. In fact, many tumors become hypoxic, and experts have long noticed that hypoxic tumors are much more aggressive and prone to metastasis than more oxygen-rich cancers.

The Stanford group discovered that the hypoxic state triggers a very high expression of the gene that produces the LOX enzyme. That's important, because LOX aids metastasis by building the collagen "matrix tracks" that cancer cells travel on as they migrate to other sites.

But would inhibiting LOX curtail this migration? To find out, Giaccia's team created a human breast cancer cell line that was genetically unable to produce LOX, even under hypoxic conditions.

They then implanted these cells into mice, along with normal breast cancer cell lines.

"We showed that just by altering this single gene we could rather remarkably reduce the amount of metastatic [disease] that formed," Giaccia said. While mice with normal cancer lines went on to develop metastatic cancer, mice with LOX-disabled tumors showed no such spread.

Furthermore, antibodies aimed at LOX also inhibited cancer spread, suggesting that vaccines might someday keep the body "on guard" against the threat of metastatic disease. LOX-inhibiting drugs might do the same, Giaccia said.

Cheresh agreed that the findings show great promise. "This work provides a target that one can use to pharmacologically interfere with, and thereby suppress, the metastatic properties of cancer," he said.

But he cautioned that these remain preliminary findings in mice. "The big question will be how this will translate in a clinical setting."

Giaccia stressed that LOX inhibition, if it works, won't be an outright cure for cancer. "But we know nowadays that there is no 'magic bullet,' anyway," he said. Instead, he and Cheresh believe the future of cancer care lies in combination therapies that will attack and suppress the disease on multiple fronts.

"In many ways, I think of treating cancer like we treat AIDS," Cheresh said. "You don't cure the person, but you give them a cocktail of drugs that treats the biological properties of the disease, allowing them to live a relatively healthy and disease-free life."

More information

For more on cancer metastasis, head to the American Cancer Society.

SOURCES: Amato Giaccia, Ph.D., professor and director, department of cancer and radiation biology, Stanford University, Stanford, Calif.; David Cheresh, Ph.D., professor, pathology, cancer biology program, Moores Cancer Center, University of California, San Diego; April 27, 2006, Nature

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