Hypoxic tumor cell death and modulation of endothelial adhesion molecules in the regression of granulocyte colony-stimulating factor-transduced tumors

Mario P. Colombo, Luciano Lombardi, Cecilia Melani, Mariella Parenza, Carlo Baroni, Luigi Ruco, Antonella Stoppacciaro

Research output: Contribution to journalArticle

Abstract

C-26 colon adenocarcinoma cells transduced with the granulocyte colony- stimulating factor (G-CSF) gene form large tumors when injected into sublethally irradiated mice. These tumors regress when leukocyte function is reconstituted. Electron microscopy and immunocytochemical analysis of regressing C-26/G-CSF nodules indicates that tumor destruction is due mainly to hypoxia resulting from the functional loss of tumor vasculature and is only marginally due to direct cytolysis. Desegregation of basal lamina, cell swelling, and loss of junctions characterized the vessels within regressing tumors. Tumor cells were necrotic or filled with lipid vacuoles regardless of the distance from nearby vessels. Damage of tumor vasculature was dependent on the infiltrating leukocytes and the cytotoxic cytokines they produced. Locally produced interleukin-1 and tumor necrosis factor-α (TNF-α) induced vascular cellular adhesion molecule-1 (VCAM-1) and E-selectin on tumor vessels. Treatment with monoclonal antibodies to interferon-γ (IFN-γ) or TNF-α blocked tumor regression by inhibiting VCAM-1 and E-selectin expression on tumor-associated endothelial cells resulting in a reduced number of infiltrating leukocytes. Thus, C-26/G-CSF tumor regression presents features typical of hemorrhagic necrosis that occurs through the cytokines produced by infiltrating leukocytes in response to G-CSF.

Original languageEnglish
Pages (from-to)473-483
Number of pages11
JournalAmerican Journal of Pathology
Volume148
Issue number2
Publication statusPublished - Feb 1996

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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