Brain metastases are among the deadliest forms of cancers that spread (metastasize) in the body. They are two to 10 times more common than tumors of the central nervous system (CNS). Despite the progress achieved in recent years in the development of novel treatments for melanoma and breast cancer, brain metastasis remains highly lethal in many cases with very low survival rates of less than one year
The incidence of brain metastases has been increasing in recent years, probably as a result of improvements in diagnostic methods as well as progress in the treatment of metastases in other organs, so developing better therapeutic strategies for brain metastasis is an urgent need.
The central factor
The researchers were able to characterize the mechanism, identify the central factor and show that its inhibition using genetic tools significantly reduces the formation of brain metastases in mice.
The findings are relevant to patients with brain metastatic disease – high levels of the factor in patients' blood could predict metastatic recurrence in the brain and a worse prognosis.
In a new study from Tel Aviv University (TAU) published in the prestigious journal Nature Cancer, under the title “Reciprocal interactions between innate immune cells and astrocytes facilitate neuroinflammation and brain metastasis via lipocalin-2,” the researchers identified and characterized a new mechanism that facilitates the formation of brain metastases and found that impairing this mechanism significantly reduced the development of brain metastases in mice.
The research was led by Prof. Neta Erez, head of the biology of tumors lab in the pathology department of TAU’s Sackler Faculty of Medicine, and members of her team: they included Omer Adler, Yael Zeit and Noam Cohen in collaboration with Prof. Shlomit Yust Katz from the Rabin Medical Center-Beilinson Campus in Petah Tikva and Prof. Tobias Pukrop from Regensburg Hospital, Germany.
The study
IN THIS NEW STUDY, the researchers show that Lipocalin-2 (LCN2) is a key factor in inducing neuroinflammation in the brain. Moreover, the researchers found that high LCN2 levels in patients' blood and brain metastases from several types of cancer are associated with disease progression and reduced survival. LCN2 is a secreted protein that functions in the innate immune system and was originally discovered due to its ability to bind iron molecules and as part of the inflammatory process in fighting bacterial infection. It is produced by a large variety of cells and was shown to be involved in multiple cancer-related processes.
“Our findings reveal a previously unknown mechanism, mediated by LCN2, which reveals a central role for the mutual interactions between immune cells recruited to the brain (granulocytes) and brain glial cells (astrocytes) in promoting inflammation and in the formation of brain metastases,” Erez said. “The findings establish LCN2 as a new prognostic marker and a potential therapeutic target.”
The team used models of melanoma and breast cancer brain metastases to reveal the mechanism by which neuroinflammation is activated in the metastatic niche in the brain.
"The findings establish LCN2 as a new prognostic marker and a potential therapeutic target.”
Prof. Neta Erez
“We show that signals secreted into the blood from the primary tumor stimulate pro-inflammatory activation of astrocytes in the brain,” Erez added. “The astrocytes promote the recruitment of inflammatory cells from the bone marrow (granulocytes) into the brain, and they then become a main source of signaling by LCN2.
“We demonstrated the importance of LCN2 for the development of metastases by genetically inhibiting its expression in mice, which resulted in a significant decrease in neuroinflammation and reduced brain metastases. Moreover, in blood and tissue samples from patients with brain metastases from three types of cancer, blood LCN2 levels were correlated with disease progression and with shorter survival, which positions LCN2 as a potential prognostic marker for brain metastases.”
The researchers also examined whether LCN2 is elevated in the blood of melanoma patients at the time of initial diagnosis and if it can be a prognostic factor. The findings showed that patients with melanoma had significantly higher levels of LCN2 in their blood compared to samples from healthy individuals. Strikingly, patients who developed brain metastases displayed significantly higher levels of LCN2 even before the diagnosis of the metastases, and high levels of LCN2 in the blood correlated with worse survival.
“We have identified a new mechanism in which LCN2 mediates the communication between immune cells from the bone marrow and supporting cells in the brain, activates inflammatory mechanisms and thus helps the progression of metastatic disease in the brain and demonstrated its importance,” Erez concluded.
“The functional and prognostic aspects of LCN2 that we have identified in brain metastases in mouse models as well as in cancer patients suggest that targeting LCN2 could be an effective therapeutic strategy to delay or prevent the recurrence of brain metastases.”