Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis

Abstract

The incidence of brain metastasis is increasing, however, little is known about molecular mechanism responsible for lung cancer-derived brain metastasis and their development in the brain. In the present study, brain pathology was examined in an experimental model system of brain metastasis as well as in human brain with lung cancer metastasis. In an experimental model, after 3–6 weeks of intracardiac inoculation of human lung cancer-derived (HARA-B) cells in nude mice, wide range of brain metastases were observed. The brain sections showed significant increase in glial fibrillary acidic protein (GFAP)-positive astrocytes around metastatic lesions. To elucidate the role of astrocytes in lung cancer proliferation, the interaction between primary cultured mouse astrocytes and HARA-B cells was analyzed in vitro. Co-cultures and insert-cultures demonstrated that astrocytes were activated by tumor cell-oriented factors; macrophage migration inhibitory factor (MIF), interleukin-8 (IL-8) and plasminogen activator inhibitor-1 (PAI-1). Activated astrocytes produced interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1 β (IL-1β), which in turn promoted tumor cell proliferation. Semi-quantitative immunocytochemistry showed that increased expression of receptors for IL-6 and its subunits gp130 on HARA-B cells. Receptors for TNF-α and IL-1β were also detected on HARA-B cells but down-regulated after co-culture with astrocytes. Insert-culture with astrocytes also stimulated the proliferation of other lung cancer-derived cell lines (PC-9, QG56, and EBC-1). These results suggest that tumor cells and astrocytes stimulate each other and these mutual relationships may be important to understand how lung cancer cells metastasize and develop in the brain.Electronic supplementary materialThe online version of this article (doi:10.1007/s10585-010-9354-8) contains supplementary material, which is available to authorized users.

Cisplatin-induced CCL5 secretion from CAFs promotes cisplatin-resistance in ovarian cancer via regulation of the STAT3 and PI3K/Akt signaling pathways

“…2A and B, a series of factors were secreted and increased in CM* compared with the control medium. Many of these factors were associated with tumor cell malignant phenotype, including chemotherapy resistance and tumor progression, migration and invasion (27)(28)(29). CCL5 was significantly increased up to ~72-fold compared with the control medium.…”

Blood-brain Barrier Remodeling during Brain Metastasis Formation

“…Characterizing in detail the process of tumor cell migration through the BBB and the interactions ECM-degrading enzyme heparanase (72). The production of cytokines by astrocytes may also stimulate brain metastatic tumor growth by paracrine signaling (73). On the other hand, it was reported that that plasmin can convert membrane-bound astrocytic FasL into a paracrine death signal for extravasated lung and breast cancer cells.…”

The Role of Astrocytes in Tumor Growth and Progression

“…In between these two extremes, other phenotypic changes that occur include hypertrophy of the cell body and processes, a vast array of gene expression changes, and varying degrees of proliferation up to the point of scar formation. Some of the chemical activators of astrocytes known to be secreted by or induced by tumor cells include EGF (glioblastoma and medulloblastoma), TGF-α (medulloblastoma), receptor activator of nuclear factor kappa-B (NFκB) ligand (RANKL) (glioma), macrophage migration inhibitory factor (MIF), interleukin-8 (IL-8), and plasminogen activator inhibitor-1 (PAI-1) (lung cancer metastases) [11,[157][158][159][160].…”

“…As we know, astrocytes are capable of signaling to trigger tumor cell (breast, lung, skin, and brain) migration, invasion and metastasis in vivo [88,95,127,160]. There are many targets in the brain microenvironment that provide effective intervention strategies for metastasis, and is reviewed elsewhere [164].…”