Melanoma brain metastasis occurs when tumor cells hijack an inflammatory pathway in the brain


Brain metastases are among the deadliest tumor metastases, with a median survival period of less than one year, and the incidence of brain metastasis is rising.

A new Tel Aviv University study finds that melanoma brain metastasis occurs when tumor cells “hijack” an inflammatory pathway in the brain.

Blocking this pathway could prevent these metastases from developing, according to the research.

“The prognosis of patients with brain metastases is very grim,” explains Prof. Neta Erez of the Department of Pathology at TAU’s Sackler Faculty of Medicine, the lead author of the study.

“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.”

The research was published in Cell Reports on August 13.

It was conducted by TAU graduate students Dr. Hila Doron and Malak Amer, in collaboration with Prof. Ronit Satchi-Fainaro, also of TAU’s Sackler Faculty of Medicine.

The new research focuses on melanoma brain metastasis because “melanoma is the deadliest skin cancer due to its high rate of metastasis, frequently to the brain,” says Prof. Erez.

The scientists utilized a mouse model of spontaneous melanoma brain metastasis to study the interactions of melanoma tumors within the brain microenvironment.

They discovered that melanoma brain metastasis is facilitated by the takeover of a physiological inflammatory pathway by astrocytes, the brain cells that maintain a protected environment in the brain.

In addition, astrocytes respond to tissue damage in the brain by instigating an inflammatory and tissue repair response to contain the damage, secreting inflammatory factors that recruit immune cells.

“We discovered that tumor cells recruit these inflammatory factors to hijack their way to the brain,” says Prof. 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.”

Significantly, when the researchers used genetic tools to inhibit the expression of the receptor on melanoma cells, they successfully blocked the ability of tumor cells to respond to astrocyte signalling – and the development of brain metastases was significantly inhibited.

After the initial research was performed in a pre-clinical mouse model, the scientists validated their results in the brain metastases of patients who had undergone brain surgery, finding that astrocytes express the same inflammatory factor (CXCL10) and that the tumor cells express the same receptor (CXCR3) as the mouse model.

This suggests that the identical mechanism is operative in humans.

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

The researchers are currently investigating the trigger that instigates inflammation in the brain, which promotes metastasis.

Brain metastases are one of the deadliest forms of tumor metastasis. Arising in 10-30% of adult patients with systemic malignancies (1), brain metastases confer dismal prognosis, with a median survival of less than one year (Figure 1A) (2,3).

The main cancer types that frequently metastasize to the brain are lung, breast, melanoma, renal and colorectal cancers (2).

Different studies suggest that the incidence of brain metastasis is twice to ten times higher than primary central nervous system (CNS) malignancies (e.g. glioma) (4,5).

Interestingly, post-mortem studies suggest higher incidence of brain metastases compared with clinically diagnosed incidence (6).

Moreover, the incidence of brain metastasis appears to be on the rise (7).

Possible explanations for this apparent increase include better diagnosis of smaller, asymptomatic brain metastasis by MRI, and improved control of extracranial disease by systemic therapy, enabling the emergence of otherwise not clinically manifested metastasis (1,6).

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Figure 1
A. Epidemiology of brain metastases. Summary of main epidemiological findings from various primary tumor types that metastasize to brain (%: percentage of brain metastasis cases diagnosed, m=months) (1,2,170172). B. The brain microenvironment: Illustration of different cell types in normal brain. The physiological roles of different brain cells are detailed in Box 1.

When discussing brain metastases, it is important to keep in mind that they are not a single clinical entity: major differences in the diagnosis, treatment and prognosis depend on various parameters including the primary tumor from which metastases developed, suitability for targeted therapies, number of metastases, stage of extra-cranial disease etc.

Brain metastasis from different primary tumors can occur early in the clinical course of the disease, at the time of initial diagnosis (synchronous), or sometimes months or years after surgical removal of the primary tumor (metachronous).

The currently used diagnosis-specific graded prognostic assessment (DS-GPA) of patients with brain metastases are associated with tumor-specific parameters:

The DS-GPA for non small cell lung carcinoma (NSCLC), breast cancer and malignant melanoma includes molecular predictive markers, such as EGFR, Her2 and B-Raf, respectively, to identify subgroups with a significantly improved overall survival (OS) (810).

For example, patients with the best melanoma molecular markers (mol-GPA) score have an estimated OS of 34.1 months compared with 7.1 months in the past (8).

In addition to molecular subgroups, the OS of patients with brain metastasis also correlates with the infiltration pattern of macrometastases at the brain parenchyma/metastatic interface: while metastases of renal cell cancer are mainly non-infiltrative and are additionally protected by a highly vascularized collagen capsule, the majority of NSCLC brain metastases infiltrate into the adjacent brain parenchyma with tumor cell cohorts, and malignant melanoma cells favor an angio-cooptive infiltration (11).

In general, an infiltrative phenotype is associated with a poor prognostic outcome (11). However, the underlying mechanisms that differentiate patterns of brain metastatic infiltration are poorly understood.

In brain metastasis, earlier studies identified gene signatures in primary breast cancer cells that were associated with brain tropism (12), while a more recent study demonstrated branched evolution that distinguishes the mutation landscape in the primary tumor from its brain metastases (13).

Thus, additional co-evolution with the brain microenvironment may be required to enable brain colonization by disseminated metastatic cells.

There is a growing understanding that the metastatic microenvironment plays a crucial role in enabling brain tropism and colonization of disseminated tumor cells.

Herein, we summarize the main findings of recent pre-clinical studies focused on the biology of the brain metastatic microenvironment, with emphasis on the role of neuroinflammation.

More information: Hila Doron et al, Inflammatory Activation of Astrocytes Facilitates Melanoma Brain Tropism via the CXCL10-CXCR3 Signaling Axis, Cell Reports (2019). DOI: 10.1016/j.celrep.2019.07.033.

Journal information: Cell Reports
Provided by Tel Aviv University


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