In a discovery that may lead to a new treatment for breast cancer that has spread to the bone, a Princeton University research team has unraveled a mystery about how these tumors take root.
Cancer cells often travel throughout the body and cause new tumors in individuals with advanced breast cancer -- a process called metastasis -- commonly resulting in malignant bone tumors. What the Princeton research has uncovered is the exact mechanism that lets the traveling tumor cells disrupt normal bone growth. By zeroing in on the molecules involved, and particularly a protein called "Jagged1" that sends destructive signals to cells, the research team has opened the door to drug therapies that could block this disruptive process. Doctors at other medical centers who have reviewed the research have found it promising.
"Right now we don't have many treatments to offer these patients," said Yibin Kang, an associate professor of molecular biology at Princeton who led the research team. "Doctors can manage the symptoms of this bone cancer, but they can't do much more. Our findings suggest there could be a new way of treatment," one that could slow or halt these bone tumors.
Breast cancer spreads to the bone in 70 to 80 percent of patients with advanced breast cancer, and it can also spread to the brain, lung and liver. Metastatic bone cancer is also a frequent occurrence among patients with advanced prostate, lung and skin cancers. In findings that will be published online in the journal Cancer Cell on Feb. 3, the team's research shows that breast tumor cells are able to give bone cells the wrong instructions through a process known as cell signaling -- with disastrous effects for the patient.
While tumor cells lack the specialized tools that osteoclasts have to break down the bone, they are able to use the destructive Jagged1 molecule to disrupt the balanced activity of bone renewal, forcing the osteoclasts and osteoblasts to behave in a way that allows the tumor cells to invade the bone, Kang explained.
For example, by activating Notch signaling in osteoclasts, Jagged1 makes osteoclasts mature more quickly from their precursor cells, known as monocytes. A massive accumulation of these bone-scouring osteoclasts becomes the front line of the invasive force of tumor cells. That speeds up the breakdown of bone tissue and clears the way for tumor cells to expand into a malignant mass in the bone.
"Meanwhile, Jagged1 instructs the osteoblasts to secrete elevated levels of Interleukin-6, a tumor growth factor, so the cancer grows even faster," Kang said. "It's a one-two punch."
Creating further damage, the breakdown of the bone matrix releases a large quantity of another protein called TGF-beta, another signaling molecule that is embedded in the bone matrix during the bone-building process. In their earlier work published in 2009, Kang and colleagues showed that the TGF-beta protein derived from bones fuels the malignant growth of bone metastasis.
In the current study, some experiments conducted by Sethi established a surprising new link between TGF-beta and the Jagged1 molecule in bone metastasis.
"When tumor cells use the hijacked osteoclasts to break down the bone and release TGF-beta, it signals back to tumor cells to further stimulate the expression in Jagged1 in tumor cells," Sethi said. "The link between the Jagged1/Notch and TGF-beta pathways establishes a vicious cycle, essentially driving the unstoppable expansion of tumors and the destruction of skeletal tissues."
As a medical student, Sethi said he is acutely aware of the consequence of bone metastasis. "These patients suffer a lot. They have fractures, severe bone pain and debilitating nerve compression," he said. In addition, as the bone breaks down, calcium builds up in the blood, causing other life-threatening complications.
Blocking destructive pathway a potential treatment path
The key to stopping the process appears to be finding a way to neutralize the Jagged1 signaling molecule or its receptor Notch.
Kang has several ideas on how scientists may learn how to do just that. One way to interrupt the destructive process is to put a roadblock in the Notch pathway. There is a way to do that by halting the activity of gamma secretase -- an enzyme that plays a key role when the Notch pathway is activated -- because without it the delivery of instructions to bone cells cannot be completed. The pharmaceutical firm Merck & Co. has developed one such experimental drug that stops gamma secretase, known as a gamma secretase inhibitor or GSI, and the company has provided it to Kang's lab to support his team's work.
The drug has already shown promise treating metastatic bone cancer, Kang said. In animal experiments, the inhibitors have been proven to block the disease-causing signaling between tumor cells and bone cells, communication mediated by Jagged1 and Notch. Kang said GSI can reduce bone metastasis significantly, along with a dramatic reduction of bone destruction.
He hopes his team's new data showing that GSIs appear to work to halt the spread of cancer to the bone will result in clinicians starting a clinical trial of GSI to fight breast cancer metastases in the near future.
According to Kang, there are few drugs currently available to relieve symptoms associated with bone metastases, and none is able to completely stop the cancer. If Kang's findings lead to a drug that can halt or slow this process, it could affect the 200,000 patients that the NCI estimates are diagnosed every year with breast cancer. It might work for some other cancer patients as well, Kang said.
Sloan-Kettering's Bromberg said Kang's recent discovery "underlies the importance of targeting the environmental milieu" in which disease develops, in this case the activity of the Notch signaling pathway and specific interactions between cancer cells and the specialized cells that break down and rebuild bone.
Kang’s work was funded by the New Jersey Commission on Cancer Research, the San Francisco-based Brewster Foundation founded by 1969 Princeton alumnus Leonard Schaeffer, U.S. Department of Defense, American Cancer Society, Merck & Co., the National Institutes of Health and the Champalimaud Foundation in Lisbon, Portugal.