Changes in endogenous cytokines, adhesion molecules and platelets during cytokine-induced tumour necrosis.
The aim of this study was to investigate mechanisms of anti-tumour activity and necrosis induced by combinations of tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma). In a breast cancer xenograft model, locally injected recombinant human TNF-alpha arrested growth of established tumours in the absence of overt necrosis. Macroscopic necrosis occurred when rat IFN-gamma, which had no anti-tumour activity as a single agent, was given systemically. Treatment with TNF-alpha and IFN-gamma caused focal engorgement of tumour capillaries with erythrocytes, intravascular recruitment of polymorphonuclear cells and platelet adherence to the tumour vascular endothelium 4 h after the combined treatment. This was followed by destruction of tumour vascular endothelium and both necrosis and apoptosis of tumour cells. Concomitant with these changes, semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed the increase of stromal (murine) mRNA levels for TNF-alpha, TNF receptor 55 kDa, TNF receptor 75 kDa, intracellular adhesion molecule 1, vascular cell adhesion molecule 1, P-selectin and interleukin 6 (IL-6). Thus, the effect of the combined TNF-alpha and IFN-gamma therapy involved the selective destruction of the tumour vasculature, death of tumour cells and increased expression of a series of stromal cytokines, cytokine receptors and adhesion molecules, which could be implicated in the observed events.
de Kossodo
S
S
Biological Therapies Laboratory, Imperial Cancer Research Fund, London, UK.
Moore
R
R
Gschmeissner
S
S
East
N
N
Upton
C
C
Balkwill
F R
FR
D002288:Adenocarcinoma, Mucinous / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003238:Connective Tissue / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006470:Hemorrhage / Q000139:chemically induced / Q000473:pathology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000187:drug effects; D008969:Molecular Sequence Data; D009336:Necrosis; D009368:Neoplasm Transplantation; D010973:Platelet Adhesiveness / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use
D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D016207:Cytokines; D007155:Immunologic Factors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma