Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity.

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE
    • Publication Information:
      Publication: New York Ny : Nature Publishing Company
      Original Publication: New York, NY : Nature Pub. Co., [1995-
    • Subject Terms:
    • Abstract:
      Conventional anticancer drug screening is typically performed in the absence of accessory cells of the tumor microenvironment, which can profoundly alter antitumor drug activity. To address this limitation, we developed the tumor cell-specific in vitro bioluminescence imaging (CS-BLI) assay. Tumor cells (for example, myeloma, leukemia and solid tumors) stably expressing luciferase are cultured with nonmalignant accessory cells (for example, stromal cells) for selective quantification of tumor cell viability, in presence versus absence of stromal cells or drug treatment. CS-BLI is high-throughput scalable and identifies stroma-induced chemoresistance in diverse malignancies, including imatinib resistance in leukemic cells. A stroma-induced signature in tumor cells correlates with adverse clinical prognosis and includes signatures for activated Akt, Ras, NF-kappaB, HIF-1alpha, myc, hTERT and IRF4; for biological aggressiveness; and for self-renewal. Unlike conventional screening, CS-BLI can also identify agents with increased activity against tumor cells interacting with stroma. One such compound, reversine, shows more potent activity in an orthotopic model of diffuse myeloma bone lesions than in conventional subcutaneous xenografts. Use of CS-BLI, therefore, enables refined screening of candidate anticancer agents to enrich preclinical pipelines with potential therapeutics that overcome stroma-mediated drug resistance and can act in a synthetic lethal manner in the context of tumor-stroma interactions.
    • Comments:
      Erratum in: Nat Med. 2024 Feb 14;:. (PMID: 38355975)
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    • Grant Information:
      P01 CA078378 United States CA NCI NIH HHS; P01 CA155258 United States CA NCI NIH HHS; R01 CA050947 United States CA NCI NIH HHS; R01 CA124929 United States CA NCI NIH HHS; P50 CA100707 United States CA NCI NIH HHS; R01 CA050947-17A1 United States CA NCI NIH HHS
    • Accession Number:
      0 (Antineoplastic Agents)
      0 (Morpholines)
      0 (Purines)
      Z499CLJ023 (2-(4-morpholinoanilino)-6-cyclohexylaminopurine)
    • Publication Date:
      Date Created: 20100316 Date Completed: 20100423 Latest Revision: 20240215
    • Publication Date:
      20240215
    • Accession Number:
      PMC3786785
    • Accession Number:
      10.1038/nm.2112
    • Accession Number:
      20228816