Differential Reactions of Microglia to Brain Metastasis of Lung Cancer

Abstract

The brain is a common metastatic site for various types of cancers, especially lung cancer. Patients with brain metastases have a poor prognosis in spite of radiotherapy and/or chemotherapy. It is postulated that immune cells in the brain may play a major role in cancer metastasis, dormancy, and relapse. Although microglia may serve as a major component in the brain immune system, the interaction between metastatic cancer cells and microglia is still largely unknown and remains to be elucidated. In this study, we have investigated microglial reactions in brain tissues with metastatic lung cancer cells and evaluated the cytotoxic effects of lipopolysaccharide (LPS)-activated microglia on metastatic lung cancer cells in vitro. In the vicinity of metastatic lung cancer mass in the brain, microglia showed signs of significant activation. There was an obvious increase in the number of microglia labeled with ionized calcium binding adaptor molecule 1 (Iba-1) antibody, a specific marker of microglia. The microglia were observed to form a clear boundary between the tumor mass and normal brain tissue. In the region where the tumor mass was situated, only a few microglia expressed inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α), indicating differential activation in those microglia. The supernatant from LPS-activated microglia induced apoptosis of metastatic lung cancer cells in vitro in a dose-and time-dependent manner. However, at lower concentrations of activated microglial supernatant, trophic effects on cancer cells were observed, some lung cancer cells being insensitive to microglial cytotoxicity. Together with the observation that TNF-α alone induced proliferation of the tumor cells, the findings provide possible clues to the mechanism involved in metastasis of lung cancer cells to the brain.

Glial Activation in the Early Stages of Brain Metastasis: TSPO as a Diagnostic Biomarker

“…Moreover, coculture with astrocytes has been shown to induce reprogramming of the tumor cell transcriptome, mirroring transcriptional changes observed in vivo (25) and thus increasing both invasiveness (6) and chemoresistance (26,27). At the same time, microglial activation is also known to be a feature of the brain metastatic microenvironment (4,5,28,29) and, as with astrogliosis, studies suggest both anti-and protumorigenic roles for microglia. For example, microglial-induced tumor cytotoxicity has been demonstrated in vitro (30,31), but these cells have also been shown to facilitate metastatic colonization (29).…”

“…Astrocytes also actively respond to challenges such as infection and neurodegeneration, by changing their transcriptional profile and morphology in a characteristic process of reactive astrogliosis. Reactive astrocytes have been reported around brain metastases in human postmortem tissue (4,5), and there has been increasing interest in determining their significance in mouse models of brain metastasis (6)(7)(8)(9). Nevertheless, their contribution to the progression of brain metastases remains unclear, with both pro-and antitumorigenic roles being proposed (6,(10)(11)(12)(13)(14).…”

“…Nevertheless, their contribution to the progression of brain metastases remains unclear, with both pro-and antitumorigenic roles being proposed (6,(10)(11)(12)(13)(14). At the same time, activated microglia, the resident macrophages of the brain, have also been found at sites of brain metastases (4,5,9), and these findings suggest that these 2 glial populations may be intimately involved in tumor progression.…”

NK1 receptor antagonists and dexamethasone as anticancer agents in vitro and in a model of brain tumours secondary to breast cancer

“…It has been postulated that microglia secrete growth-stimulatory substances that aid metastatic brain tumour growth, as evidenced by the increase in MDA-MB-231 human breast cancer cells when cocultured with microglia in vitro [94]. Other tumour cells have been shown to differentially activate microglia so that subpopulations express inducible nitric oxide synthase and tumour necrosis factora [95]. Thus, with more investigation, glial regulation may provide a possible target for the manipulation of metastatic brain tumour growth.…”

Biological characteristics of a specific brain metastatic cell line derived from human lung adenocarcinoma

“…Whereas VEGF is a powerful enhancing factor of angiopoiesis in tumor growth and tumor metastasis. VEGF can also promote the secretion of MMP-9 [25]. It has important Fig.…”