Abstract
Brain metastases are resistant to chemotherapy and carry a poor prognosis. Studies have shown that tumor cells are surrounded by activated astrocytes, whose cytoprotective properties they exploit for protection from chemotherapy-induced apoptosis. The mechanism of such astrocytic protection is poorly understood. A non-mutational mechanism of resistance to chemotherapy that is receiving increased attention is the regulation of gene translation mediated by small noncoding RNAs (sRNAs), and particularly microRNAs (miRNAs). With the aim of examining the role of astrocytic sRNAs in promoting resistance of human lung tumor PC14 cells to chemotherapy-induced apoptosis, here we used a miRNA microarray to compare sRNA profiles of human lung tumor cells cultured with and without astrocytes. We found that sRNAs are transferred from astrocytes to PC14 cells in a contact-dependent manner. Transfer was rapid, reaching a plateau after only 6 hours in culture. The sRNA transfer was inhibited by the broad-spectrum gap-junction antagonist carbenoxolone, indicating that transfer occurs via gap junctions. Among the transferred sRNAs were several that are implicated in survival pathways. Enforced expression of these sRNAs in PC14 cells increased their resistance to the chemotherapeutic agent paclitaxel. These novel findings might be of clinical relevance for the treatment of patients with brain metastases.
Highlights
According to the American Cancer Society, approximately 1.6 million new cases of cancer are reported each year in the United States, and up to 40% of those patients will develop brain metastases [1, 2]
We focused on the transfer of small noncoding RNAs (sRNAs) from astrocytes to PC14 cells, a cell line of aggressive human lung adenocarcinoma, and to MDA-MB-231, an aggressive human breast adenocarcinoma cell line
Our results showed that sRNAs are transferred from astrocytes to these cancer cells, that the transfer is contact-dependent and most probably occurs through gap junctions, and that the combined expression of selected transferred sRNAs in PC14 cells was found to increases their resistance to chemotherapy
Summary
According to the American Cancer Society, approximately 1.6 million new cases of cancer are reported each year in the United States, and up to 40% of those patients will develop brain metastases [1, 2]. Current therapies for brain metastases include surgery, radiotherapy and in a limited manner, chemotherapy [3]. Stromal cells modify the neoplastic properties of the tumor cells and contribute to their proliferation [5,6,7]. The brain cells that correspond to stromal cells are the astrocytes, which are the most abundant of all cell types in the human brain and perform a variety of functions in the central nervous system (CNS) [8]. The communication between tumor cells and the CNS cells is crucial for tumor cells thriving and survival, and can impact their sensitivity to chemotherapy [9,10,11]
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