Aging-US: PAM (PIK3/AKT/mTOR) signaling in glia: potential contributions to brain tumors

January 25, 2021

Aging-US Issue 1 Volume 13 features "PAM (PIK3/AKT/mTOR) signaling in glia: potential contributions to brain tumors in aging" which reported that despite a growing proportion of aged individuals at risk for developing cancer in the brain, the prognosis for these conditions remains abnormally poor due to limited knowledge of underlying mechanisms and minimal treatment options.

While cancer metabolism in other organs is commonly associated with upregulated glycolysis and hyperactivation of PIK3/AKT/mTOR pathways, the unique bioenergetic demands of the central nervous system may interact with these oncogenic processes to promote tumor progression in aging. Specifically, constitutive glycolysis and PIK3/AKT/mTOR signaling in glia may be dysregulated by age-dependent alterations in neurometabolic demands, ultimately contributing to pathological processes otherwise associated with PIK3/AKT/mTOR induction.

Although several limitations to this theoretical model exist, the consideration of aberrant PIK3/AKT/mTOR signaling in glia during aging elucidates several therapeutic opportunities for brain tumors, including non-pharmacological interventions.

Dr. Kamel Khalili from Temple University said, "Cancer in the brain is significantly less common than in other organs, but disproportionately contributes to higher rates of mortality"

Since metabolic syndrome is an independent risk factor for worse prognosis in patients with certain CNS tumors, bioenergetic processes in particular are emerging as important variables in tumor neuropathology.

Among primary cell types implicated in tumor pathogenesis, minimal contributions are observed from non-glia; less than 10% of all tumors manifest as lymphomas, meningiomas, embryonal tumors, or choroid plexus carcinomas, among others.

As tumors of glial origin account for the vast majority of all CNS cancers, age-dependent variation in glial functioning may particularly contribute to tumor pathology in the brain.

Within the CNS, astrocytes in particular have long been associated with metabolic homeostasis and are the most common cell type associated with tumor pathology.

Given that glia are responsible for maintaining energy homeostasis of the CNS by utilizing similar metabolic pathways of cancer cells, chronic alterations in bioenergetic demands during aging.

The Khalili Research Team concluded in their Aging-USReview Article that in particular, the inhibition of PI3K's downstream effectors, AKT and mTOR, may prove to reliably mitigate proliferation, motility and viability in glioma cells.

Additionally, PI3K inhibitors are emerging as potent antagonistic agents in various types of cancer, including gliomas.

While cancer cells have been shown to overcome this inhibition, evidence from preclinical models suggest the combination of dietary manipulations as well as PI3K inhibitors can augment the inhibition of PAM signaling and increase therapeutic efficacy.

Compared to mice treated with PI3K inhibitors alone, mice maintained on a ketogenic diet during treatment display significantly decreased mortality rates following intracranial implantation of aggressive human gliomas.

Although further validation of these targets is required, the modulation of PAM signaling to mitigate glioma progression in the aging CNS may prove efficacious and merits consideration.
Full Text -

Correspondence to: Kamel Khalili

Keywords:glioma, aging, bioenergetics

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways.

To learn more about Aging-US, please visit or connect with @AgingJrnl

Aging-US is published by Impact Journals, LLC please visit or connect with @ImpactJrnls

Media Contact


Impact Journals LLC

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to