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Newswise BOSTON Ever since it was first identified more than 15 years ago, the PTEN gene has been known to play an integral role in preventing the onset and progression of numerous cancers. Consequently, when PTEN is either lost or mutated, malignant cells can grow unchecked and cancer can develop.

Now a team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) helps explain more precisely how PTEN exerts its anti-cancer effects and how its loss or alteration can set cells on a cancerous course. The new study, which reveals that PTEN loss and PTEN mutations are not synonymous, not only provides key insights into basic tumor biology but also offers a potential new direction in the pursuit of new cancer therapies.

The findings are reported online in the April 24 issue of the journal Cell.

By characterizing the ways that two specific PTEN mutations regulate the tumor suppressor function of the normal PTEN protein, our findings suggest that different PTEN mutations contribute to tumorigenesis by regulating different aspects of PTEN biology, explains senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center at BIDMC and George C. Reisman Professor of Medicine at Harvard Medical School. It has been suggested that cancer patients harboring mutations in PTEN had poorer outcomes than cancer patients with PTEN loss. Now, using mouse modeling, we are able to demonstrate that this is indeed the case. Because PTEN mutations are extremely frequent in various types of tumors, this discovery could help pave the way for a new level of personalized cancer treatment.

The PTEN gene encodes a protein, which acts as a phosphatase, an enzyme that removes phosphates from other substrates. Several of the proteins that PTEN acts upon, both lipids and proteins, are known to promote cancer when bound to a phosphate. Consequently, when PTEN removes their phosphates, it is acting as a tumor suppressor to prevent cancer. When PTEN is mutated, it loses this suppressive ability, and the cancer-promoting proteins are left intact and uninhibited. This new study unexpectedly shows that the PTEN mutant protein is not only functionally impaired (losing its enzymatic function) it additionally acquires the ability to affect the function of the normal PTEN proteins, thereby gaining a pro-tumorigenic function.

We sought to compare PTEN loss with PTEN mutations, explains first author Antonella Papa, PhD, an investigator in the Pandolfi laboratory. We wanted to know, would outcomes differ in cases when PTEN was not expressed compared with cases when PTEN was expressed, but encoded a mutation within its sequence? It turned out the answer was yes.

The scientific team created several genetically modified strains of mice to mimic the PTEN mutations found in human cancer patients. All mice [and humans] have two copies of the PTEN gene, Papa explains. The genetically modified mice in our study had one copy of the PTEN gene that contained a cancer-associated mutation [either PTENC124S or PTENG129E] and one normal copy of PTEN. Other mice in the study had only one copy of the normal PTEN gene, and the second copy was removed.

The researchers found that the mice with a single mutated copy of PTEN were more tumor-prone than the mice with a deleted copy of PTEN. They also discovered that the mutated protein that was produced by PTENC124S or PTENG129E was binding to and inhibiting the PTEN protein made from the normal copy of the PTEN gene.

More:
Surprising New Insights Into PTEN Tumor Suppressor Gene

Image Caption: This shows regenerated auditory nerves after gene therapy (top) compared with no treatment (below). Credit: UNSW Translational Neuroscience Facility

[ Watch The Video: Bionic Ear Delivers DNA To Regrow Auditory Nerve Cells ]

University of New South Wales

Researchers at UNSW Australia have for the first time used electrical pulses delivered from a cochlear implant to deliver gene therapy, thereby successfully regrowing auditory nerves.

The research also heralds a possible new way of treating a range of neurological disorders, including Parkinsons disease, and psychiatric conditions such as depression through this novel way of delivering gene therapy.

The research is published today (Thursday 24 April) in the prestigious journal Science Translational Medicine.

People with cochlear implants do well with understanding speech, but their perception of pitch can be poor, so they often miss out on the joy of music, says UNSW Professor Gary Housley, who is the senior author of the research paper.

Ultimately, we hope that after further research, people who depend on cochlear implant devices will be able to enjoy a broader dynamic and tonal range of sound, which is particularly important for our sense of the auditory world around us and for music appreciation, says Professor Housley, who is also the Director of the Translational Neuroscience Facility at UNSW Medicine.

The research, which has the support of Cochlear Limited through an Australian Research Council Linkage Project grant, has been five years in development.

[ Watch The Video: Regenerated Auditory Nerves ]

Read more:
Existing Cochlear Technology Used To Re-grow Auditory Nerves

Australian researchers are trying a novel way to boost the power of cochlear implants: They used the technology to beam gene therapy into the ears of deaf animals and found the combination improved hearing.

The approach reported Wednesday isn't ready for human testing, but it's part of growing research into ways to let users of cochlear implants experience richer, more normal sound.

Normally, microscopic hair cells in a part of the inner ear called the cochlea detect vibrations and convert them to electrical impulses that the brain recognizes as sound. Hearing loss typically occurs as those hair cells are lost, whether from aging, exposure to loud noises or other factors.

Cochlear implants substitute for the missing hair cells, sending electrical impulses to directly activate auditory nerves in the brain. They've been implanted in more than 300,000 people. While highly successful, they don't restore hearing to normal, missing out on musical tone, for instance.

The idea behind the project: Perhaps a closer connection between the implant and the auditory nerves would improve hearing. Those nerves' bush-like endings can regrow if exposed to nerve-nourishing proteins called neurotrophins. Usually, the hair cells would provide those.

Researchers at Australia's University of New South Wales figured out a new way to deliver one of those growth factors.

They injected a growth factor-producing gene into the ears of deafened guinea pigs, animals commonly used as a model for human hearing. Then they adapted an electrode from a cochlear implant to beam in a few stronger-than-normal electrical pulses.

That made the membranes of nearby cells temporarily permeable, so the gene could slip inside. Those cells began producing the growth factor, which in turn stimulated regrowth of the nerve fibers - closing some of the space between the nerves and the cochlear implant, the team reported in the journal Science Translational Medicine.

The animals still needed a cochlear implant to detect sound - but those given the gene therapy had twice the improvement, they concluded.

Senior author Gary Housley estimated small studies in people could begin in two or three years.

Excerpt from:
Gene therapy may boost power of cochlear implants, study says