Hypoxic tumor cell death and modulation of endothelial adhesion molecules in the regression of granulocyte colony-stimulating factor-transduced tumors.
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-alpha (TNF-alpha) induced vascular cellular adhesion molecule-1 (VCAM-1) and E-selectin on tumor vessels. Treatment with monoclonal antibodies to interferon-gamma (IFN-gamma) or TNF-alpha 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.
Colombo
M P
MP
Division of Experimental Oncology D, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy.
Lombardi
L
L
Melani
C
C
Parenza
M
M
Baroni
C
C
Ruco
L
L
Stoppacciaro
A
A
D000230:Adenocarcinoma / Q000098:blood supply / Q000473:pathology* / Q000648:ultrastructure; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D016923:Cell Death; D015687:Cell Hypoxia; D003110:Colonic Neoplasms / Q000098:blood supply / Q000473:pathology* / Q000648:ultrastructure; D019040:E-Selectin / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics*; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D009336:Necrosis / Q000473:pathology; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000096:biosynthesis; D012074:Remission Induction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D015815:Cell Adhesion Molecules; D019040:E-Selectin; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor