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-alpha (TNF-alpha), 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-alpha 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.
Highlights
The brain is an important organ in the metastasis of lung cancer cells [1,2,3] and one of the major sites of distant relapse in patients with lung cancer and other cancers [4]
Immunohistochemistry The mass of metastatic cancer cells in the brain could be clearly identified as a neurofilament heavy subunit (NFH)-negative region because neurons and their processes positively stained with anti-NFH antibody were evenly distributed in the normal brain parenchyma; no positive staining could be observed within the region with cancer cell aggregation (Figure 1A)
The current study has provided evidence that both ionized calcium binding adaptor molecule 1 (Iba-1)–positive microglia and glial fibril acidic protein (GFAP)-positive astrocytes are activated in the vicinity of metastatic lung cancer cells in the brain
Summary
The brain is an important organ in the metastasis of lung cancer cells [1,2,3] and one of the major sites of distant relapse in patients with lung cancer and other cancers [4]. The successful homing in and growth of metastatic lung cancer cells in the brain parenchyma appears to suggest failure of the immune defense in the brain environment. The impermeability of the BBB could prevent entrance of immunoglobulins and invasion of leukocytes from the blood [5] and limit the delivery of most cytotoxic agents into the brain [6,7], thereby resulting in ineffective chemotherapy in the treatment of brain metastases and hindrance of immune reactions against metastatic lung cancer cells. The BBB has failed to block the invasion of metastatic lung cancer cells into brain parenchyma in many patients, suggesting the presence of some mechanisms that facilitate invasion of cancer cells into the brain parenchyma through the BBB. It is likely that cell–cell interactions play a crucial role in this mechanism; inter-
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