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Alzheimer’s protein is used by skin cancer cells to undermine immune system of brain

by Pragati Singh

According to a recent study, the protein amyloid beta, which is known to accumulate in the brains of Alzheimer’s sufferers, also promotes the growth of skin cancer cells when they invade the brain.

The findings, which was proven to be true in melanoma, the most deadly type of skin cancer, cancer cells that have travelled to the brain need on amyloid beta to live there, was published online on March 9 in Cancer Discovery, a publication of the American Association for Cancer Research. Melanoma was the primary focus of the study since it has the greatest prevalence of brain metastasis (spread) among common cancer forms, occurring in 40% of patients with advanced (Stage IV) illness.

The metastatic melanoma cells recovered from human brain tissue and grown in tissue cultures produce approximately three times as much amyloid beta as cancer cells that have spread to other parts of the body, according to a study led by researchers from NYU Grossman School of Medicine and its Laura and Isaac Perlmutter Cancer Center.

The study team also discovered that the immune responses that would normally identify cancer cells as aberrant and fight them, similar to how they kill invasive germs, are suppressed by the amyloid beta released by cancer cells. According to the researchers, amyloid beta causes brain immune cells to change into a state that is observed when infections subside and tissues start to repair, which enables cancer cells to go unnoticed.

The scientists also demonstrated that the beta secretase inhibitor LY2886721, which is known to significantly lower amyloid beta levels, reduced the amount of brain melanoma metastases in study animals by around half.

According to senior study author Eva Hernando, PhD, professor in the Department of Pathology and assistant dean for Research Integration at NYU Langone Health, “our study reveals an unexpected role for tumor-secreted amyloid beta in promoting the survival of melanoma brain metastases and suggests a new way to counter it.”

The latest discovery deepens the riddle surrounding amyloid beta, which makes up the majority of the deposits in Alzheimer’s patients’ brains. According to Hernando, a member of the Perlmutter Cancer Center, despite several research, its functions in healthy function and Alzheimer’s disease are still debatable.

Cancer Cannot Spread

The latest research included improvements to conventional methods that provided a more precise picture of which proteins are produced in higher amounts in melanoma cells that had travelled to the brain. First, the study team cultured cells isolated from human metastatic brain tumours for a brief period of time to prevent them from genetically diverging from the original cancer cells.

The authors then used the first whole cell proteomics assay to analyse brain metastases, to their knowledge, by measuring the proteins the melanoma cells generated.

The research team was able to demonstrate that melanoma cells from the brain create proteins associated with Alzheimer’s, Parkinson’s, and Huntington’s disorders using 24 human brain and non-brain cancer metastases that had been developed in short-term cultures. The authors claim that the development of novel methods that allowed the study team to distinguish between proteins produced by surrounding brain cells and those produced by cancer cells enabled the identification of a link between brain cancer and neurodegenerative illnesses.

These findings led the researchers to the hypothesis that cancer cells in the brain create amyloid beta to aid in their survival. Using melanoma cells injected into the hearts of research mice, they examined the impact of silencing the gene that codes for amyloid precursor protein (APP), a protein that is converted into amyloid beta by secretase enzymes (beta and gamma). Imaging research showed that the number of cancer metastases that developed in the brain was significantly decreased when the APP gene was silenced, cutting off the cancer cells’ source of amyloid beta.

Other research showed that immune assault prevented melanoma cells deficient in amyloid beta from successfully growing (dividing and multiplying) at the stage where they are creating tiny cell colonies (micro-metastases), which are required for spreading cancer cells to “take root” in a new tissue.

Last but not least, the study discovered that amyloid beta secreted by melanoma cells alters gene expression in astrocytes, brain cells that feed neurons, causing the astrocytes to release proteins that suppress immune responses to malignancy. It is also known that astrocytes and the immune cell type microglia in the brain exchange messages. The researchers also showed that the production of amyloid beta by melanoma cells shields them from being eaten by microglia.

According to the scientists, it’s possible that amyloid beta secreted by melanoma cells is affecting microglia both directly and indirectly through astrocytes to prevent them from “swallowing” and obliterating melanoma cells.

According to first study author Kevin Kleffman, PhD, an MD-PhD student at NYU Langone and member of Hernando’s lab, “the field has already developed treatments that have been shown in clinical trials to potently and safely reduce amyloid beta levels, but that fail to counteract Alzheimer’s disease for reasons unknown.” “In light of this, our team is now analysing whether anti-amyloid beta antibodies that have been previously tested and repurposed may stop or lessen brain metastases in experiments on animals. Combining immunotherapies, like as checkpoint inhibitors, and anti-amyloid beta treatments is another next step to make sure they can be used in conjunction safely.”

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