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Study finds inhibiting inflammatory pathway could be brain metastasis target

Researchers have revealed a key inflammation mechanism that contributes to melanoma brain metastasis and could be a therapeutic target.

A new study has discovered that melanoma brain metastasis occurs when tumour cells take control of an inflammatory pathway in the brain. According to the researchers, from Tel Aviv University in Israel, blocking this route could prevent these metastases from developing.

“Patients used to die from metastases in other places before brain metastases were clinically evident. Treatments have improved and patients are living longer, so the incidence of diagnosed brain metastases is increasing. Understanding how and why brain metastasis occurs is an urgent challenge facing cancer researchers today,” said Professor Neta Erez, the lead author of the study.

…blocking this signalling pathway may prevent brain metastasis”

Using a mouse model of spontaneous melanoma brain metastasis, the team investigated the interactions of melanoma tumours within the brain microenvironment. They discovered that metastasis is facilitated by the manipulation of a physiological inflammatory pathway by astrocytes, the brain cells that maintain a protected environment. Astrocytes respond to tissue damage in the brain by instigating an inflammatory and tissue repair response to contain damage, secreting inflammatory factors that recruit immune cells.

“We discovered that tumour cells recruit these inflammatory factors to hijack their way to the brain,” added Professor Erez. “We identified a specific factor that mediates their attraction to the brain and showed that brain metastasising melanoma cells express the receptor for the inflammatory factor, which is how they respond to this signal.”

When the researchers used genetic tools to inhibit the expression of the receptor on melanoma cells, they successfully blocked the ability of tumour cells to respond to astrocyte signalling. This also reduced the development of brain metastases.

After their initial research in a pre-clinical mouse model, the team confirmed their findings in the brain metastases of patients who had undergone brain surgery. The discovered that astrocytes express the same inflammatory factor, CXCL10, and that the tumour cells express the same receptor, CXCR3, as the mouse model. This suggests an identical mechanism is operative in humans.

“Our findings suggest that blocking this signalling pathway may prevent brain metastasis,” concluded Professor Erez. “The CXCL10-CXCR3 axis may be a potential therapeutic target for prevention of melanoma brain metastasis.”

The team are currently researching the trigger that instigates inflammation in the brain, which promotes metastasis.

The findings were published in Cell Reports.

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