This text is part of the special notebook Innovating for better care
Researchers at the University of Montreal recently made a discovery that would make it possible to better predict the aggressiveness of ovarian cancer and patients’ chances of survival. The team of experts identified a potential new marker for this disease through an innovative approach to hypoxia, which occurs when the body or brain is partially deprived of oxygen, over the long term.
Hypoxia is a common pathology in many solid tumors, making malignant cells particularly resistant to treatment. To better understand this phenomenon, the team from the laboratory of Étienne Gagnon, research director of the cancer immunology unit at the Institute for Research in Immunology and Cancer (IRIC) affiliated with the University of Montreal, developed point a cell culture protocol. Called “ Long-term hypoxia » (LTHY), it imitates the transition between the different stages of hypoxia.
“Existing methods for studying hypoxia in the laboratory do not accurately reproduce the conditions seen in primary tumors. Our protocol, on the other hand, makes it possible to mimic the progressive development of severe hypoxia observed in vivo,” explains the professor.
The work, published in the journal Cancer Gene Therapythus reveal that cells subjected to the LTHY protocol undergo a transition which allows them to move to other places in the body, while making them invasive and likely to form metastases.
After isolating the cells to determine what was generating this transition, the researchers made a surprising discovery regarding a truncated form of the Wilms Tumor 1 (WT1) gene. In a healthy state, this gene encodes a protein that allows the development of organs of the urogenital system. Alteration of this protein causes cells to multiply to form a cancerous tumor.
A new marker to predict aggression
Postdoctoral researcher Jordan Quenneville played a key role in this discovery by observing the effect of prolonged hypoxia on malignant cells. “At specific times during oxygenation, they changed from a static cobblestone appearance to a more elongated shape. This new form of the WT1 gene is a prognostic indicator in the progression of cancer, since this morphological change is a precursor to cell mobility and metastases,” he explains.
Another surprising fact, adds the researcher, “we identified this phenomenon in both humans and mice, even if the mechanism of evolution was different,” he points out. This means that the cancer is still trying to adapt and grow, by expressing this truncated form of the WT1 gene.
This revelation suggests that this marker could be used to assess the aggressiveness of ovarian cancer. “We discovered that this new form of the protein encoded by WT1 is associated with poor long-term survival for patients with ovarian cancer,” indicates Étienne Gagnon.
Although this gene variant has been observed in different types of cancer, it is mainly present in that which affects the ovaries, the researchers point out. “This is a cancer that had an over-representation of the expression of this new fragmented gene. About a quarter of people who suffer from it will have this type of truncated variation,” specifies Mr. Gagnon.
Promising prospects
Researchers are now continuing to explore the implications of this discovery, particularly to determine whether other types of cancers could have this truncated variant of the WT1 gene. “We believe that there are many more cancers, especially solid tumors, that will express this truncated variant. But, for this, we will need deeper sequencing databases,” specifies Mr. Gagnon.
Work continues, with the aim of developing screening tests sensitive to this truncated form of the WT1 gene and developing more effective therapies for patients. “This marker clearly demonstrates a reduction in survival potential in patients with ovarian cancer,” emphasizes Étienne Gagnon.
In the longer term, this discovery could well open a new era in the care provided to women suffering from ovarian cancer and other hypoxic tumors. “It’s more about treatment than prevention. If a patient has ovarian cancer and we detect the emergence of this new form of WT1, which is associated with a more aggressive form, we may be tempted to increase the intensity of treatments as well. It’s up to the doctors to see that,” says Mr. Gagnon.
This discovery is proof that scientific research remains crucial for the possible development of therapy or new screening markers.
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