title: Lymphokines modulate the growth and survival of thymic tumor cells containing a novel feline leukemia virus/Notch2 variant.
abstract: Tumorigenesis occurs through a multistep process initiated by genetic lesions and facilitated by endogenous and external growth/survival signals. In many malignancies, specific oncogenic mutations correlate with phenotypic characteristics, inferring lineage-specific pathogenic mechanisms. To characterize these relationships in a unique feline tumor, we studied primary cells and two-cell lines independently-derived from a thymic lymphoma that contained and actively expressed a novel feline leukemia virus (FeLV) recombinant with transduced host Notch2 sequences. All three tumor cell populations contained similar FeLV/Notch2 proviral variants and phenotypically resembled mature thymocytes. Multiple Notch2 transcripts were expressed in the cell lines, including species that correspond to viral genomes and spliced subgenomic viral mRNA. Tumor cell line FeLV/Notch2 virus was packaged into virions; however, the variant was not efficiently transmitted to feline cells in vitro. Primary tumor cells constitutively expressed mRNA for interleukin-4 (IL-4), IL-6 and the p40 subunit of IL-12. Lymphokine mRNA was not detected in established tumor cell lines nor was T-cell growth-promoting activity found in culture supernatants. Exogenous IL-4 enhanced primary tumor cell survival, but inhibited proliferation of the cell lines. Interleukin-4 abrogated hydrocortisone-induced apoptosis in all three populations and had divergent effects on cell line clonogenic colony formation. Exogenous IL-7 and, to a lesser degree, IL-6 also had variable positive effects on the growth and viability of the tumor cell populations. Collectively, these data suggest that thymocytes are susceptible to the transforming potential of dysregulated Notch2 and that thymopoietic factors could, through overlapping and distinct mechanisms, promote the survival and outgrowth of FeLV/Notch2-containing neoplastic cells.
authors.affiliation: Department of Medicine, University of Washington, Seattle 98195, USA. linen@u.washington.edu
authors.forename: M L
authors.initials: ML
authors.lastname: Linenberger
authors.forename: J L
authors.initials: JL
authors.lastname: Rohn
authors.forename: T
authors.initials: T
authors.lastname: Deng
authors.forename: S
authors.initials: S
authors.lastname: Ellis-Smith
authors.forename: R
authors.initials: R
authors.lastname: Ingber
authors.forename: J
authors.initials: J
authors.lastname: Overbaugh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002371:Cat Diseases / Q000473:pathology / Q000821:virology*; D002415:Cats; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D006854:Hydrocortisone / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D005256:Leukemia Virus, Feline; D008222:Lymphokines / Q000494:pharmacology*; D010641:Phenotype; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface / Q000032:analysis*; D012192:Retroviridae Infections / Q000473:pathology / Q000662:veterinary* / Q000821:virology; D013953:Thymus Neoplasms / Q000473:pathology / Q000662:veterinary* / Q000821:virology; D014407:Tumor Cells, Cultured; D014412:Tumor Virus Infections / Q000473:pathology / Q000662:veterinary* / Q000821:virology
chemical_list: D015850:Interleukin-6; D015851:Interleukin-7; D008222:Lymphokines; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface; D015847:Interleukin-4; D006854:Hydrocortisone