The Globalist

By Eric Sauter

Junli Luo, the recently named assistant professor in the Department of Cancer Biology at Scripps Florida, is an excellent example of the benefits and realities of the globalization of science. Born in China, where he earned his medical degree, Luo moved to Germany, spent time in France, worked for several years at the University of California, San Diego (UCSD) School of Medicine, and finally landed at Scripps Florida, a division of The Scripps Research Institute, in March of this year.

"Actually I talked with my friends about all this," he said. "I have gone from China to Europe and to the United States—and moved twice while living here. So maybe next time I'll go to Africa."

Luo is the one of the most recent recruits to Scripps Florida, and for good reason.

Four years ago, while at UCSD, Luo and a few others came up with a novel strategy to fight cancer, turning the body's inflammatory response, which under normal circumstances actually encourages tumor growth, into a cancer-killing machine. He was the first author of the paper, which appeared in the September 20, 2004 issue of journal Cancer Cell, that drew clear molecular connections among colon cancer, breast cancer, and inflammation and showed that those connections, at least in animal models, could be played to benefit the patient, instead of the malignancy.

That study, and much of what Luo has been doing ever since, focused on the nuclear factor-kappa beta (NF-κβ) and an enzyme called I-kappa-B kinase beta (IKKβ) that is needed to activate NF-κβ. NF-κβ in turn, ignites an inflammatory response that sets off a whirl of reactions that ends in cancer.

At the time of that study, Luo was quoted as saying that it might be "possible to use NF-κβ or TNFα [tumor necrosis factor alpha, an inflammatory mediator] inhibitors to prevent inflammation-induced tumor growth, thus destroying their advantage, and allowing TRAIL [a cancer killing ligand] to tip the balance in its favor."

That possibility of a novel cancer treatment has become a little more probable in the intervening years and Luo has come to Scripps Florida to nail it down.

A Long and Winding Road

Luo was born in a small town of around 10,000 in Hunan, a province in south central China. Located in the middle of the Yangtze River valley, Hunan lies south of Lake Dongting, the second largest freshwater lake in China; Hunan basically means south of the lake. Hunan is known for its elaborate and fiery style of cooking and for the fact that its capitol, Changsha, was the place where Mao Zedong went to school and then decided to become a revolutionary.

Born the same year that the Cultural Revolution was launched and the country thrown into turmoil for nearly a decade, Luo was one of four brothers and two sisters. He has memories of that turbulent time but, like children everywhere, the memories consist largely of the talking heads of adults.

"When I was in school, we were in the middle of the Cultural Revolution," he said. "I didn't know anything about politics. We just attended the meetings and it was just really boring. There would be someone talking about something in front of us. That's all we knew about it."

China passed through the crucible and, by the time Luo was ready for higher education, educational opportunities were opening up in China.

 "In the 1980s there was a national examination for students to see who would go to college," he said. "Only very few people could go to college, so if you passed the exam you could look forward to a good future. At that moment, I decided to study hard and pass the exam. I had no idea about studying medicine. I was 17 at the time—I didn't even know which school I would go to."

Luo's teacher, however, thought he should go to medical school and sent him off to Hunan Medical University in Changsha, a well-regarded joint project of the Hunan Yuqun Society and the Yale-in-China Association, and one of the earliest schools of Western medicine in China. Luo started there in 1984 and graduated as a doctor in 1989. In China, you don't need a bachelor's degree to go to medical school.

"I wanted to be a surgeon because my parents thought I was very skillful with my hands," Luo remembered. "Of course, when I got there, a colleague said my fingers were too short. My teachers said it didn't matter, but as it turned out, it did."

Still, he ended up doing some surgery in Hunan on patients with head and neck cancers, something he took to. When he graduated, he stayed on in Hunan for nearly a decade, first as a resident, then as a physician. He got a Ph.D. in oncology and cancer biology from the university in 1997, and was a lecturer in head and neck cancers until 2002, when he landed at UCSD.

He liked working with patients and still does.

"Even now, I like to deal with patients," he said. "In talking with patients, you gain a lot of knowledge. You can observe how the disease develops and how the cancer metastasizes, and this is what we're focused on in our research."

When he went to Germany to study in 1997, the plan was to learn some basic techniques and then return to China. But once there, someone told him that he had to go to the United States because of the good laboratories and technologies available.

After he finished up a research project in Germany, Luo interviewed with USCD's Michael Karin, a professor of pharmacology, packed up with his family, and moved to San Diego

"Moving from Germany to the U.S. was a big decision but I went because of the science," he said. "I married in China—my wife is a nurse—and had a baby there. We now have two daughters."

After six years at UCSD as a postdoctoral fellow, Luo heard that Scripps Florida was recruiting.

"I was looking for a position and went to the website," he said. "I saw they were recruiting people for cancer biology and sent a letter to Dr. John Cleveland. He liked my application and offered me a job. I like this department because the science is very good and because the researchers help each other—all the people here are very kind."

Luo's interest in cancer has been a constant in his peripatetic life and is now spurred on by events close to home; his brother and several relatives have developed cancer.

The Inflammatory Option

A year after their groundbreaking paper in Cancer Cell, Luo, Hideaki Kamata, and Michael Karin published a review paper in The Journal of Clinical Investigation. The paper, "IKK/NF-κβ Signaling: Balancing Life And Death – A New Approach To Cancer Therapy," presented a broad overview of how the IKK/NF-κβ signal pathway could be used as a new strategy in the treatment of different malignancies, flipping the entire immune system on its head—forcing the regression of tumors instead of their growth.

As it turns out, the linkage between NF-κβ activation and inflammation-associated tumor promotion, progression, and metastasis is well documented and was demonstrated in several mouse models in Luo's earlier studies and in others. The IKKβ-dependent NF-κβ activation pathway was also established as a critical molecular link between inflammation and colon cancer in mice. Activation of IKKβ in certain intestinal cells gives rise to the malignant component of this tumor and suppresses apoptosis of pre-cancerous cells; its activation in white blood cells promotes production of various cytokines that act as growth factors for those same white blood cells.

While there are some specific IKKβ inhibitors being developed, and some publications have documented their efficacy in triggering apoptosis or programmed cell death in cancer cells in combination with other drugs, there are still drawbacks.

As the Luo himself said in the review paper, "An important advantage of IKKβ /NF-κβ inhibitors over conventional therapeutics is their ability to block NF-κβ activation also in infiltrating inflammatory cells, which are an important source of tumor growth and survival factors. It should be noted, however, that, given the critical role of NF-κβ in innate and adaptive immune responses, there may be a certain amount of risk due to induced immunodeficiency caused by long-term use of IKKβ/NF-κβ inhibitors. Hence, alternative approaches should be considered. For instance, an approach based on selective inhibition of anti-apoptotic targets of NF-κβ, without affecting target genes required for immune responses, would be particularly attractive."

Luo has already established a new link between IKKα  activation and the spread of prostate cancer. In a 2007 study, published in Nature, Luo and his colleagues shows that a ligand binding to NF-κβ increased metastases in mice by activating IKKα, which then enters the cancer cell and suppresses the expression of the gene maspin, a known inhibitor of metastasis in prostate and breast cancers—two cancers that are hormonally driven. That ligand, known by the unappetizing name of RANK, may, in fact, turn out to promote the growth of prostate cancer by inhibiting an endogenous cancer killer.

Of course, the primary culprit in all these cancers remains inflammation, which is looming ever larger as cancer's all around helpmate, potentially even when it comes to something as routine as a biopsy, a procedure long associated with cancer treatment.

Perhaps not anymore.

"A biopsy can stimulate the inflammation that helps the cancer," Luo said. "When I was a doctor in China if we saw a cancer in patients we would do a biopsy just before the surgery. It was standard procedure. This is a better way because if the biopsy is done much earlier, it could help trigger metastasis unless the doctor uses anti-inflammatory treatments at the same time."

Luo has gotten some interesting feedback on this particular hypothesis.

"Because of what we said in our Nature paper in 2007, some patients have even refused to have biopsies," he said.

But Luo is working toward a more powerful approach, harnessing inflammation for the body's fight against cancer.

Send comments to: mikaono[at]scripps.edu

Assistant Professor Jun-Li Luo is working to harness inflammation in the body's fight against cancer.