Astrocytes Upregulate Survival Genes in Tumor Cells and Induce Protection from Chemotherapy

Abstract

In the United States, more than 40% of cancer patients develop brain metastasis. The median survival for untreated patients is 1 to 2 months, which may be extended to 6 months with conventional radiotherapy and chemotherapy. The growth and survival of metastasis depend on the interaction of tumor cells with host factors in the organ microenvironment. Brain metastases are surrounded and infiltrated by activated astrocytes and are highly resistant to chemotherapy. We report here that coculture of human breast cancer cells or lung cancer cells with murine astrocytes (but not murine fibroblasts) led to the up-regulation of survival genes, including GSTA5, BCL2L1, and TWIST1, in the tumor cells. The degree of up-regulation directly correlated with increased resistance to all tested chemotherapeutic agents. We further show that the up-regulation of the survival genes and consequent resistance are dependent on the direct contact between the astrocytes and tumor cells through gap junctions and are therefore transient. Knocking down these genes with specific small interfering RNA rendered the tumor cells sensitive to chemotherapeutic agents. These data clearly demonstrate that host cells in the microenvironment influence the biologic behavior of tumor cells and reinforce the contention that the organ microenvironment must be taken into consideration during the design of therapy.

Closing the gap: astrocytes and brain metastasis

“…show that this occurs via the formation of gap junctions between activated astrocytes and cancer cells. The observation that cancer cells and astrocytes communicate through gap junctions is consistent with other findings on the exchange of pro-survival signals and ions through gap junctions as a potential mechanism of resistance to chemotherapy in breast, melanoma, and lung cancer cells [7,8]. BM progression is also facilitated via downregulation of tumor PTEN by miRNA-containing exosomes secreted by astrocytes [9].…”

Orchestration of the crosstalk between astrocytes and cancer cells affects the treatment and prognosis of lung cancer sufferers with brain metastasis

“…The direct cell-to-cell interaction between astrocytes and cancer cells altered the pattern of gene expression in both cancer cells and astrocytes, including BCL2L1, GSTA5, and TWIST1. We further discovered that the up-regulation of the survival genes and consequent resistance are transient owing to the direct contact between the astrocytes and cancer cells through gap junctions (12).…”

“…The contact with astrocytes leads to up-regulated expression of multiple genes in the cancer cells (15), including several survival genes that are in charge of the increased resistance of cancer cells to cytotoxic drugs (12). Better therapeutic strategies need to be raised urgently.…”

The Role of Astrocytes in Tumor Growth and Progression

“…In metastatic brain tumors, reactive astrocytes protect melanoma cells from chemotherapy induced cell death by sequestering intracellular calcium through gap junctions [64]. In the brain, metastases from breast and lung cancer show upregulation of many survival genes which is dependent on the direct contact through gap junctions between the astrocytes and tumor cells, which was found to be causal for developing resistance [65]. These data suggest that reactive astrocytes participate in tumor progression and chemo-resistance by their direct physical contacts and gap junctional communication with tumor cells in the brain.…”

“…Astrocytes are co-opted to up-regulate survival genes in tumor cells and induce protection from chemotherapy [65]. Downregulation of the astrocyte-initiated survival gene expression in tumor cells will render tumor cells sensitive to chemotherapy [65].…”