Editors' ChoiceCancer

Rogue tumor cells use SEMAntics to infiltrate the brain

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Science Translational Medicine  06 Nov 2019:
Vol. 11, Issue 517, eaaz9748
DOI: 10.1126/scitranslmed.aaz9748

Abstract

Semaphorins promote breast cancer metastasis to brain.

Although earlier diagnosis and improved treatments for breast cancer during the last two decades have led to a substantial decline in mortality, the rate of breast to brain metastasis (BBM) occurrence has increased in recent years. The median survival of brain metastatic patients ranges from 2 to 25.3 months after diagnosis despite treatment. Metastasis is initiated by cells that leave primary or metastatic tumors into the vascular pipeline, which are called circulating tumor cells (CTCs). Because the brain is structurally and functionally isolated from the rest of the body by an intricate blood-brain barrier (BBB), it takes longer for CTCs to successfully invade the CNS compared with other organs. Improved control of extracranial systemic disease and the limited ability of current therapeutics to cross the BBB also contribute to the rise in incidence of brain metastases, as CTCs find refuge in the brain. Previously it has been shown that BBMs can be conceptualized as a progressive injury similar to that seen in traumatic brain injury. It is during this critical stage when metastatic cells will likely commandeer the brain’s microenvironment to either form crosstalk or escape native neural cells in order to gain a proliferative advantage.

Now Klotz et al. show that prior to becoming BBMs, their CTC predecessors express semaphorins, which are part of a large family of transmembrane proteins involved in both axonal guidance and the immune system. Specifically, CTCs established from patients with breast cancer up-regulated semaphorin 4D (SEMA4D) and were then able to cross the BBB after injection into mice. Interestingly, survival data showed patients who had higher expression of SEMA4D had the worse brain metastasis outcomes, whereas no difference was seen in bone or lung metastases. Once they entered the brain, a sanctuary site, tumor cells expressing the oncogene MYC were able to adapt to their new brain microenvironment by extenuating the oxidative stress produced by activated microglia.

Although these findings indicate that a subset of CTCs can express both neural guidance genes and oncogenes, which can promote their adaptation into a sanctuary neural niche for brain metastases, they also raise several biological questions. Additional tumor microenvironment studies need to be conducted to determine whether these CTCs are from the original primary tumor or progeny from other metastatic sites such as liver or bone. It also remains to be determined whether CTCs from other solid metastatic tumors—such as lung, melanoma, or colon—or leptomeningeal cells utilize similar pathways to adapt to the neural niche.

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