Proinflammatory mediators and genetic background in oncogene mediated tumor progression.
RET/PTC3 (RP3) is an oncogenic fusion protein which is frequently expressed in papillary thyroid carcinomas and has been detected in thyroid tissue from patients diagnosed with Hashimoto's thyroiditis. The constitutive activation of the tyrosine kinase domain in the carboxyl-terminal end of RP3 induces signaling pathways within thyrocytes and causes cellular transformation. One of the signaling pathways activated in RP3-expressing cells involves the activity of the transcription factor NF-kappaB and the production of downstream targets including GM-CSF and macrophage chemotactic protein 1. These factors are known to be immunostimulatory, making RP3 a molecular adjuvant and potentially promoting tissue-specific immunity. However compelling, these in vitro data do not reliably predict gene function in vivo or the cumulative effects of time-dependent processes such as angiogenesis, inflammation, or the influence of genetic background. To address these issues, we analyzed the production of proinflammatory mediators in mouse thyroid organs and demonstrate consistency with in vitro studies performed previously that Il1alpha, Il1beta, Il6, and Tnfalpha and the enzyme Cox2 are produced by RP3-transgenic thyroid tissue, but absent from nontransgenic thyroids. Furthermore, we find that that the genetic background of the host is important in the observed RP3-induced inflammation and tumor progression. These findings provide support for the notion that oncogene-induced cytokine secretion is important for the development and progression of thyroid carcinomas in genetically permissive hosts.
Russell
John P
JP
Department of Microbiology/Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Engiles
Julie B
JB
Rothstein
Jay L
JL
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002291:Carcinoma, Papillary / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D007962:Leukocytes / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000502:physiology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012313:RNA / Q000096:biosynthesis; D013961:Thyroid Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D033921:Vesicular Transport Proteins
D016207:Cytokines; D018836:Inflammation Mediators; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D011506:Proteins; D012313:RNA; D014157:Transcription Factors; C111382:NCOA4 protein, human; C484335:Tfg protein, mouse; D033921:Vesicular Transport Proteins