Find takes scientists from cold sores to cancer

WCVM virologist Dr. Vikram Misra: “It’s funny how you start working on one thing and you end up doing something completely different.” Photo: David Stobbe.

A few years ago, Dr. Vikram Misra and his research team were studying how herpes simplex virus (HSV) can determine when their host is stressed. The virus responds by reactivating and causing cold sores to recur on or around the lips of people infected with HSV.

“As many already know from personal experience or observation, once someone gets a cold sore it never really goes away,” explains Misra, a virologist and head of the Western College of Veterinary Medicine’s Department of Veterinary Microbiology. “They go away for awhile, but then they come back — often during times of stress.”

After HSV replicates in skin cells, it infects the sensory nerve cells that deliver sensations of pain and heat to the face, thereby becoming latent and effectively “hiding” from the body’s immune system.

When a person becomes stressed from illness, emotional stress or something as simple as a sunburn, the virus reactivates, replicates and returns to the skin’s surface to create a cold sore.

“What we’ve been trying to figure out is how the virus actually senses when a host is stressed,” says Misra. “We know it’s to the virus’s benefit to desert a so-called sinking ship. But how does it know when the ship is sinking?”

To investigate this mystery, the team began looking for what could rouse the sleeping HSV in these nerve cells. That’s when they found the two unique proteins that were eventually named Zhangfei and Luman after two famous characters in Beijing opera.

“We were the first to discover these proteins so we got to name them,” says Misra. “They work at cross purposes to each other. Luman is a very powerful gene activator that turns on genes that help to alleviate stress. It also turns on HSV replication. Zhangfei, on the other hand, turns off stress genes when they are no longer needed, and it also suppresses HSV replication — soothing the virus into a ‘sleeping’ state.”

What’s interesting is that Zhangfei can also suppress the growth of many cancer cells.

“The discovery illustrates really nicely how science is not linear,” says Misra. “It’s funny how you start working on one thing and you end up doing something completely different.”

Over the years, the WCVM research group has studied Zhangfei more intensely and determined that it has several different functions, many of which may be useful for controlling cancer.

“It suppresses cell division in many tumour cells,” explains Misra, adding that the protein also shuts down the stress response. And Zhangfei has no effect on healthy, normal cells – making it ideal as a potential cancer therapy.

Very few cells produce Zhangfei naturally. According to Misra, it’s only present in mature neurons – cells that have been instructed by various signalling mechanisms to become nerve cells.

“But you can induce other cells to make Zhangfei by delivering the gene to them,” he explains. In the lab, an inactivated virus is used as a vector to introduce the Zhangfei gene into tumour cells.

“It works extremely well at turning off the growth of cancer cells, rendering them more susceptible to chemotherapy and radiation treatment,” says Misra. And, in some cases, Zhangfei can even induce death of the cancer cells.

Oncology research has gradually become a staple for Misra’s team. Besides work being done by oncology resident Dr. Kirsty Elliot, PhD student Rupali is working on a side project that looks at the reliance of certain breast cancers on estrogen for growth. Estrogen binds to a receptor within the cell, allowing it to enter the nucleus. There it can turn on cell division, causing the tumour to grow.

In retaliation, breast cancer patients take tamoxifen, a drug that acts as a substitute for estrogen and results in cell growth arrest. Unfortunately, over a period of time, the cancer cells become resistant to the drug. That’s where Zhangfei enters the picture.

“Zhangfei also shuts down responses to nuclear receptors — the gene activator that binds estrogen is one of them,” Misra says. “So our hypothesis is that if we deliver Zhangfei to the estrogen-dependent breast cancer cells or to the tamoxifen-resistant cells, it will not only turn off the primary tumour, but it will also negate any resistance.”

So far, the work with Zhangfei has been confined to the laboratory setting and it’s unknown when the protein will be used to treat a live animal.

“The use of viral vectors for laboratory analysis is acceptable, but may be problematic for clinical therapy,” says Misra. He adds that future studies will look at determining other methods to get cells to make Zhangfei.

“We plan to find out the cell signals required to turn on the expression of this protein and hopefully figure out ways to manipulate these mechanisms so Zhangfei may be used in the live patient.”

Robyn Thrasher of Edmonton, Alta., is a third-year veterinary student at the WCVM. Robyn is a WCVM research communications intern as well as a summer student in the WCVM Veterinary Medical Centre during the summer of 2012.