Study first step toward novel therapy

dog and technician in kennel

Dr. Kirsty Elliot: “If we can learn more things about the UPR and how to manipulate it, we hope to improve cancer treatment not only in dogs, but in people as well.” Photo: Michael Raine.

Cancer — it’s a diagnosis that no pet owner wants to hear and no veterinarian wants to make. What can be even tougher is coming up with a prognosis and an appropriate treatment plan for oncology patients.

Dr. Kirsty Elliot hopes she can help to improve the odds for pets with cancer. As the oncology resident explains, her research may help to pave the way to discovering novel methods of treating and predicting the outcome of certain cancers.

Under the direction of virologist Dr. Vikram Misra, Elliot has been collaborating with a team of researchers to test the hypothesis that the unfolded protein response (UPR) is upregulated in spontaneous canine solid tumours, and that suppression of the UPR in these tumours will prevent their growth, spread and development of resistance to anti-cancer drugs.

With WCVM oncologist Dr. Valerie MacDonald as her supervisor, Elliot has begun to characterize the expression and activity of the UPR in various tumour cells in comparison to normal, healthy tissue – a first step that’s vital to this complex study.

“The UPR is a conserved cellular response to stress,” explains Elliot. “Stressors to the cell, such as lack of oxygen or nutrients, results in the accumulation of unfolded or misfolded proteins within the cell. That turns on the UPR – a response that helps the cell survive in these adverse conditions.”

This response is beneficial for normal cells that need to survive transient changes in their microenvironment. However, in cancer cells, research has shown that upregulation of the UPR in human cancers is associated in many cases with increased aggressiveness (higher rates of metastasis, recurrence and resistance to chemotherapy).

This mechanism has been one of the more recently recognized pathways in tumour biology. Most solid tumours are characterized by regions of hypoxia (low oxygen) and lack of nutrients as they outgrow their blood supply.

The WCVM team is the first to look at the UPR and its association with tumours in dogs.

Elliot’s project, which began in the fall of 2010, involves collecting tumour samples from cancer patients at the WCVM’s Veterinary Medical Centre (VMC). The study includes dogs with any type of solid tumour that are undergoing surgery.

After WCVM surgeon Dr. Kathleen Linn removes the tumours, Elliot takes tissue samples from within the tumour as well as from the surrounding normal tissue.

Each sample is divided into three smaller pieces: one for histologic examination, one for cell culture and one for extraction of RNA (molecules that control gene expression and play a role in protein synthesis).

WCVM veterinary pathologist Dr. Elemir Simko performed histologic tissue analysis to confirm that the samples were taken from tumour or non-tumour sites. The cultured cells are used in an additional project in Misra’s lab. These cells are exposed to Zhangfei – a unique protein that has been shown to suppress the UPR, preventing tumour growth.

Elliot runs polymerase chain reaction (PCR) tests on the RNA extracted from the samples. To detect upregulation of the UPR, she measures RNA levels of four different UPR genes in the tumour samples and compares them to normal surrounding tissue as a control.

Since the sample size is small, results of the study aren’t definitive. Elliot hopes to continue collecting more samples to provide support for their preliminary findings. However, there does appear to be a connection between the UPR and selected tumour types.

“It certainly looks like there may be some upregulation of a few of the different UPR genes in some of the tumour types examined,” says Elliot. “The most exciting results we’ve had were from a metastatic hemangiosarcoma that had hugely elevated UPR genes compared to normal surrounding tissue.”

She adds that Zhangfei was also used successfully in this sample to shut down tumour cell growth in culture while having no effect on the growth of normal cells.

Hemangiosarcoma, a common and fatal canine cancer, is a highly malignant tumour of endothelial cells (cells found throughout the body lining the blood vessels). The research team has hypothesized that upregulation of the UPR is more drastic in metastatic, aggressive tumours as compared to primary or non-aggressive tumours.

This information may prove useful as a prognostic factor and may help guide treatment decisions, but Elliot points out that greater sample numbers are required to prove this association.


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