Inhibitor blocks 'siren call' of metastatic breast tumors

New laboratory models show that scientists have blocked production of a chemical that acts as a “siren call” to aggressive cancers such as glioblastoma and metastatic breast cancer. The call beckons the bone marrow to send whatever tumors need to survive and thrive.

In research published in the International Journal of Molecular Sciences, Ali S. Arbab, PhD, MD, leader of the Tumor Angiogenesis Initiative at the Georgia Cancer Center, Augusta, GA, and colleagues have successfully used an inhibitor of the chemical 20-HETE to control the growth and spread of human glioblastoma and breast cancer in laboratory models.

“Our idea is that the most aggressive tumors have the same basic mechanisms of growth and spread,” said Dr. Arbab, who is also professor in the Department of Biochemistry and Molecular Biology at the Medical College of Georgia (MCG) at Augusta University. “We have good evidence that blocking 20-HETE production is a good way to inhibit that growth.”

The 20-HETE chemical is essential for a healthy body and for tumors. Also known as 20-Hydroxyeicosatetraenoic acid, the chemical is a metabolite of arachidonic acid, a fatty acid that has a variety of functions such as assisting in the production of lipids for cell membranes.

The normal functions of 20-HETE also include helping to regulate blood pressure and blood flow. It is a known mediator of inflammation, which under healthy conditions can help fight infection and protect from cancer and other invaders.

However, when tumors express too much 20-HETE the chemical begins to activate immune cells to send the cytokines that become the siren call to our bone marrow, says B.R. Achyut, PhD, cancer biologist in the MCG Department of Biochemistry and Molecular Biology and corresponding author of the paper on glioblastoma.

Once the bone marrow cells arrive, 20-HETE turns the cells’ usually lifesaving functions of making blood vessels and populating the immune system against us, Dr. Achyut says. This includes bolstering the primary tumor site. In breast cancer, this action helps prepare remote sites in places like the brain, lungs, and liver.

Dr. Arbab and his team have shown that 20-HETE aids activation of protein kinases, which can change the proteins’ function, location, and what cells they associate with, as well as growth factors which can make cells grow in size, proliferate, and differentiate. It can even help recruit cells that make blood vessels.

The chemical also activates signaling kinases that enable cell division. It encourages inflammation-promoting factors such as tumor necrosis factor alpha and several interleukins. These factors increase inflammation to support—not fight—cancer.

To reduce the many ill effects of excessive 20-HETE, the scientists used an inhibitor called HET0016 in combination with chemotherapy, according to Thaiz F. Borin, PhD, molecular biologist in the MCG Department of Biochemistry and Molecular Biology, and corresponding author of the paper on breast cancer metastasis. The authors expect HET0016 will be beneficial as an adjuvant therapy.

The team administered the drug alternately with temozolomide for 3 to 6 weeks. Rats with glioblastoma survived for at least 6 months before they were euthanized as part of the study. Typically, rats with this disease live for only a few weeks.

Hypoxia appears to be a survival tactic for both of these rapidly growing tumor types. When a glioblastoma tumor reaches a diameter of 0.1 inch, for example, the rapid growth and cell division makes the center of this very vascular tumor hypoxic, the scientists say. That activity initiates recruitment of a myriad of factors from the bone marrow such as vascular endothelial growth factor (VEGF), which 20-HETE enables.

Other bone marrow cells that the tumor cytokines recruit include endothelial progenitor cells that make the lining for the new blood vessels made by VEGF and myeloid cells. Myeloid cells are immature, multitasking cells that can drive protective inflammation, but in this case they help tumors suppress the usual immune response.

Increased numbers of these myeloid-derived suppressor cells (MDSCs) are recruited to both the main tumor and its metastatic sites. Higher rates of these cells are associated with higher rates of recurrence and metastasis.

One of the team’s many findings is that targeting the arachidonic acid pathway by inhibiting the production of 20-HETE reduced MDSCs in the sites of breast cancer metastases, such as the lungs, liver, brain, or bones. Less communication occurred between the tumor’s base camp and the deadly satellite locations.

When the investigators examined the lungs, they found fewer cytokines to summon the bone marrow cells and fewer enzymes to support invasiveness of the breast cancer cells. HET0016 was also able to decrease the amount of growth factors, cytokines, and metalloproteinases responsible for the aggressiveness and invasiveness of tumor cells, Dr. Borin said.

The primary tumors also shrank because they were no longer recruiting the factors that enable growth, Dr. Arbab stated. “They are becoming static,” he added, noting that the 20-HETE blocker does not kill tumor cells, but rather puts them “’on hold.’

The Georgia Cancer Center team pointed out that chemotherapy does kill tumor cells. However, when the tumors start dying they release more cytokines in an attempt at survival, which is another reason to target the call for assistance that tumors send.

“Cytokines are the point of action, and cancer releases a lot of them,” according to Dr. Borin.

Research support included funding from the American Cancer Society and the National Institutes of Health.

To read more about this study, click here.