When Cancer Treatments Backfire and Cause the Body to Defend Tumors

New Israeli research could prevent cancer from using the body’s natural defenses to protect itself from chemotherapy - and even put the body on the offensive.

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Chemotherapy is one of the main treatments for cancer, but it can also be self-defeating.

When a tumor is exposed to chemo, it sends out “SOS” signals to the body. Seeing the tumor as part of itself, the body foolishly rushes to help – in some cases, allowing the tumor to regrow.

Now, researchers at the Technion – Israel Institute of Technology have discovered how one of the SOS signals works and have managed to block it to keep tumors from regrowing in mice. The findings, published in the journal PLOS ONE in April, explain the efficacy of a new type of cancer drug and could lead to novel ways of treating and diagnosing tumors.

“My lab has pioneered the study of how cancer treatments backfire and cause the body to defend tumors,” said Professor Yuval Shaked of the Technion’s Department of Cell Biology and Cancer Research, who led the study. “Our latest work shows that the cancer actually calls for help from the body. Fortunately, we found that several relatively new cancer drugs can mute the call.”

Kill the messenger

In a previous study, Shaked showed that when cells in a tumor are exposed to chemo drugs, they release “messengers” – a type of micro-particles – that call other cells in the body for help. The micro-particles travel through the blood stream to the bone marrow, where they bind to specific cells and recruit them to return to the tumor.

Once in the tumor, the bone-marrow cells help promote the formation of new blood vessels, which enhance tumor growth by providing nutrients and oxygen.

Professor Benjamin Brenner and Dr. Anat Aharon of Rambam Hospital in Haifa collaborated on the research.

In the latest study, Shaked and his colleagues treated human and mouse tumor cells with an anti-angiogenesis drug, which inhibits the formation of new blood vessels. They then collected the micro-particles released from the treated tumor cells and injected them into mice that had been implanted with artificial tumors.

The mice injected with the “treated micro-particles” didn’t grow blood-vessel cells in their artificial tumors. Had the tumors been real, it’s safe to say they would have grown less than those in mice injected with “untreated micro-particles.”

Halting blood vessel formation

So the drug works – but how? The mice injected with the treated micro-particles had fewer bone-marrow cells in their blood and tumors than those injected with the untreated micro-particles. The results suggest that anti-angiogenesis drugs prevent the bone-marrow cells from receiving the micro-particles’ SOS message.

Without the SOS signal, the bone-marrow cells don't head out to help the tumor.  Based on previous research, the researchers speculate that the drugs load the micro-particles with an overriding message telling the bone-marrow cells to stay put.

Micro-particles have been shown to act similarly in mice and men, suggesting that the results may apply to humans as well.

“It turns out that anti-angiogenesis drugs act by several therapeutic pathways, some of which we never knew about,” said Shaked. “There is a lot of potential there.”

Flipping the script

Anti-angiogenesis drugs are already used to treat cancer, often in combination with chemo. They are known to work by directly inhibiting the growth of blood vessels in tumors. But it is news that they neutralize the bone-marrow cells that contribute to the process.

Understanding how tumors use micro-particles to signal the bone-marrow cells could enable development of new diagnostic methods and treatment methods for cancer.

Micro-particles are good candidates to be cancer “biomarkers” for two reasons. First, they are in many ways like mini-clones of the cells they come from, and so can provide a wealth of information about tumors. This information can then be used to treat the tumors with targeted therapies.

Second, micro-particles can be easily checked with a simple blood test, which is important because tumors change often and need to be monitored constantly. Biopsies, one of the current methods of checking on tumors, require an invasive procedure that can sometimes be dangerous.

When it comes to treatment, drugs could also be developed to prevent micro-particles from delivering signals that promote tumor growth. The researchers are currently working on such drugs based on their findings. In the future, they hope to turn micro-particles into “Trojan horses,” replacing their SOS messages with new “search and destroy” commands that will rally the body to kill tumors.

Yuval Shaked