One Gene, Many Consequences

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CDH4 affects many features in osteosarcoma that are related to its aggressive nature.
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Osteosarcoma—the kind of cancer Terry Fox had—is an aggressive form of bone cancer that affects those under 20. It most commonly occurs where bones are growing, particularly near the knees.

Osteosarcoma is the most common bone cancer in young people. It is an aggressive cancer that commonly spreads from the bone to the lungs. Once it spreads, only one in five people survive past five years.

Dr. Rama Khokha recognized the need to better understand the genes that drive this aggressive disease, and focused her lab’s efforts on studying the CDH4 gene, which has been implicated in other cancers.

The team explored whether the levels of the CDH4 gene correlate with the aggressiveness of the cancer.

First, they looked in osteosarcoma cell lines. These cells are derived from patient cancers, but are kept alive in the laboratory, where they are used to study the disease. The researchers found that CDH4 levels were higher in cell lines from more aggressive types of osteosarcoma.

Next, they measured CDH4 levels in tumour samples from 64 patients and classified them as either high or low. The samples that were classified as high were more likely to come from patients with aggressive cancers—those that were more likely to spread to the lungs and that were associated with lower patient survival.

While higher levels of CDH4 were observed in more aggressive osteosarcomas, the researchers wanted to see whether CDH4 was an active player in determining cancer aggression. They did this by using different genetic techniques to artificially increase or decrease the expression of CDH4 in osteosarcoma cells.

The results revealed that CDH4 affects the ability of the cells to grow and develop, as well as their ability to spread into neighbouring tissue—a hallmark of more aggressive cancer. Importantly, when levels of CDH4 were reduced, the ability of the tumour to grow and spread was also reduced.

“CDH4 has an important role to play in osteosarcoma,” concludes Dr. Khokha. “Our findings are particularly interesting because CDH4 has been implicated as serving the opposite role—one that is protective or ‘tumour suppressing’—in other cancers. By identifying CDH4 as a factor of aggressive cancers of the bone, this work lays the foundation for the development of new therapeutics that target CDH4.”

This work was supported by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, International Science & Technology Cooperation Program of Guangzhou, Graduate Student Overseas Study Program of China Scholarship Council, National Natural Science Foundation of China, the Chinese National Postdoctoral Program for Innovative Talents, and The Princess Margaret Cancer Foundation.

Tang Q, Lu J, Zou C, Shao Y, Chen Y, Narala S, Fang H, Xu H, Wang J, Shen J, Khokha R. CDH4 is a novel determinant of osteosarcoma tumorigenesis and metastasis. Oncogene. 2018 Apr 3. doi: 10.1038/s41388-018-0231-2.