About 20 years ago, Claudia Bagni and her team made a curious discovery: FMR1, the gene underlying most cases of Fragile X Syndrome, was highly expressed in human cancer tissue.
At first, Bagni dismissed it as a stroke of luck. FMR1 had no known role in cancer-related processes such as B. cell proliferation. But over time, she began to see evidence of a connection. From their own findings and those of other scientists, as well as a handful of smaller epidemiological studies and case reports, it appeared that people with fragile X, the most common form of inherited intellectual disability, could be protected from cancer.
“These first clinical reports marked the beginning of a new, completely unexplored one for our group [research] Field that connects neuroscience and cancer biology,” says Bagni, now director of fundamental neuroscience at the University of Lausanne in Switzerland.
Over the past decade, Bagni and others have shown that several different types of cancer — including colon cancer, liver cancer, pancreatic cancer, and melanoma — are associated with elevated levels of FMRP, the protein encoded by FMR1. In a mouse model of breast cancer, high levels of FMRP in tumors are linked to the spread of the cancer to other areas of the body, including the lungs, according to a 2013 report. And the list keeps getting longer.
Bagni’s latest study, published in last month Cell Death & Disease, identified high levels of FMRP in tumors of people with glioblastoma, an aggressive cancer of the brain or spinal cord. Patients’ FMRP levels were tracked not only with tumor growth but also with their overall survival. Furthermore, overexpression of FMRP in glioblastoma stem cells, which are thought to be involved in tumorigenesis, also promoted cell proliferation in a laboratory dish.
The new results bolster FMRP’s link to cancer and the notion that people with fragile X syndrome may be at unusually low risk for it, says Randi Hagerman, medical director of the MIND Institute at the University of California, Davis, who is not a graduate student Study involved work. People with Fragile X, who often also have autism, have mutations that silence FMR1 and prevent cells throughout the body from producing FMRP.
“[The new work] also proposes a new treatment for glioblastoma, a terrible type of cancer,” says Hagerman.
But research into exactly how FMRP levels might affect a person’s cancer risk is still in its infancy — and studying the link to fragile X isn’t easy, says Nien-Pei Tsai, associate professor of molecular and cell biology at the University of Illinois Urbana-Champaign.
“A lot more work is needed to say that people with fragile X syndrome have a lower risk of developing cancer,” Tsai says, noting that FMRP is lost during development and its long-term absence has to be compensated for later effects.
“If compensatory effects are present, the correlation between FMRP levels and cancer progression may no longer be the same,” he adds. “There is no easy way to test how [fragile X syndrome] may reduce cancer risk.”
Eepidemiological studies seem to be the most direct way to establish the cancer-sensitive X-connection. National registries like those in Sweden, Denmark and Finland track the condition as well as newly diagnosed malignancies, says Sven Sandin, a biostatistician at Karolinska Institutet in Stockholm, Sweden. With that information, he says, “it’s not that difficult to do a direct analysis.”
However, he notes that there are numerous potential confounds: “If we have an increase in Fragil X diagnoses due to increasing awareness and testing, and at the same time we diagnose more children with cancer, that alone would create a false association,” he says says.
It is also difficult to definitely connect the dots by FMR1. The FMRP protein binds to hundreds of RNA molecules in the brain and other tissues and affects numerous signaling pathways – some of which help regulate brain development and are also involved in cancer development.
The cancer connection is not unique to FMR1. More than 40 genes associated with autism, including PTEN, TSC1 and TSC2, have links to cancer. Studies suggest that some autistic people have a lower risk of developing cancer, although people with co-occurring intellectual disabilities or birth defects are at higher risk of developing cancer early in life than non-autistic people, according to a report from April.
“If cancer genes weren’t involved in autism, it would be a miracle: they’re everywhere… they’re involved in virtually every aspect of signaling that occurs in the organism,” says Michael Wigler, professor of cancer research at Cold Spring Harbor Laboratory in New York. “There is no simple story here.”
“If cancer genes weren’t involved in autism, it would be a miracle: they’re everywhere.” Michael Wigler
Still, the connection to Fragile X appears to be particularly robust, based on reports collected over the past 20 years. Out of 223 Danes with fragile X syndrome, only three had cancer, according to a 2001 study. This proportion is about 70 percent below what is expected in the general population. Another study conducted in Finland found that 11 out of 302 people with fragile X had cancer – about 20 percent less than expected in the general population.
A third report described the case of a boy with fragile X who developed an inoperable form of glioblastoma but survived at least eight years after cancer diagnosis, with the tumor growing more slowly than expected. Children with glioblastoma typically survive one to six years after diagnosis, and less than 20 percent survive five years after diagnosis.
A number of mechanisms may play a role: two genes overexpressed in people with fragile X are linked to tumor suppressors, a 2010 study found. And among the genes whose levels were reduced in more than half of the people with the syndrome in this study, one encodes a component of the Wnt/beta-catenin pathway. This pathway regulates cell growth and has been linked to both cancer and neurodevelopmental disorders such as autism. Bagni’s recent work on glioblastoma also suggests Wnt involvement: She and her colleagues found that reducing FMRP levels dampens Wnt signaling.
“If you’re trying to identify converging signaling pathways, Wnt signaling could be one of them,” says Peng Jin, professor of human genetics at Emory University in Atlanta, Georgia.
But FMRP also targets vimentin, a protein associated with increased metastatic potential, Hagerman says. “Vimentin allows the cancer to invade tissues, and when FMRP is high, it suggests that metastasis may also be present.”
Another FMRP target is MDM2, a protein that impedes neuron maturation and is overexpressed in people with Fragile X syndrome. A compound being tested in cancer clinical trials, Nutlin-3, inhibits MDM2 and increases the number of mature neurons in a fragile X mouse model. It can also reverse cognitive and behavioral difficulties in the model, according to a study published in May.
“We looked for molecular signaling pathways that could be modulated to correct what is dysregulated in mice,” says study leader Xinyu Zhao, professor of neuroscience at the University of Wisconsin-Madison. “It turns out that some of them are actually targets for cancer drugs.”
It might prove difficult to single out one of these potential contributors. FMRP appears to have specific functions in some cell types and not others, says Ethan Greenblatt, an assistant professor of biochemistry and molecular biology at the University of British Columbia in Canada. It may also have cell-type specific roles in cancer and only affects some types of cancer.
And whether children with certain neurodevelopmental disorders have a higher or lower risk of malignancy may depend on the type of molecules involved, Jin says.
“FMRP acts as a brake to suppress protein translation while other molecules might be involved in gene activation,” he says. “Different molecules can play different roles in regulating neuronal function as well as cell proliferation.”
Ultimately, Wigler says, there may be a link between FMRP and just some malignancies, with no direct link between cancer and Fragile X syndrome or other neurodevelopmental conditions.
Notwithstanding, consideration of this compound could lead to new therapeutic targets for several diseases. “Something that down-regulates FMRP could help in glioblastoma… and down-regulating FMRP can be really helpful in a lot of other cancers,” says Hagerman. And, Bagni adds, identifying downstream FMRP molecular signaling pathways that are dysregulated in cancer cells could also lead to more targeted treatments for fragile X.
Cite this article: https://doi.org/10.53053/XLXD4405
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