Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy

Sun Jin Kim, Jang Seong Kim, Eun Sung Park, Ju Seog Lee, Qingtang Lin, Robert R. Langley, Marva Maya, Junqin He, Seung Wook Kim, Zhang Weihua, Krishnakumar Balasubramanian, Dominic Fan, Gordon B. Mills, Mien Chie Hung, Isaiah J. Fidler

    Research output: Contribution to journalArticle

    147 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)286-298
    Number of pages13
    JournalNeoplasia
    Volume13
    Issue number3
    DOIs
    StatePublished - Mar 2011

    ASJC Scopus subject areas

    • Cancer Research

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  • Cite this

    Kim, S. J., Kim, J. S., Park, E. S., Lee, J. S., Lin, Q., Langley, R. R., Maya, M., He, J., Kim, S. W., Weihua, Z., Balasubramanian, K., Fan, D., Mills, G. B., Hung, M. C., & Fidler, I. J. (2011). Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy. Neoplasia, 13(3), 286-298. https://doi.org/10.1593/neo.11112