Kelly, Stephen Arthur;
(1991)
Investigations into the modulation of metastatic potential by cytokines.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Tumours are comprised of diverse populations of cells with different metastatic abilities. Although this can be due to alterations of genotype, there is evidence that metastatic potential may also be affected by transient modulations in the local environment. Thus pretreatment of colon 26 - an undifferentiated murine colon carcinoma - with interferon-γ (IFN-γ) but not interferon-α (IFN-α) leads to a significant increase in experimental pulmonary metastases in syngeneic B ALB/c, and T cell deficient nude mice. A 1 hour incubation with 1 unit/ml of IFN-γ is sufficient to produce the enhancement, which persists for at least 72 hours following removal of the cytokine. IFN-γ exerts its effects by increasing the pulmonary retention of cells during the first 6 hours following tumour cell injection. During this period the cells are trapped in pulmonary capillaries. Thereafter the rate of loss of cells pretreated with control diluent, IFN-α, or IFN-γ is similar. The enhancement is not due to modulations in class I MHC antigen expression since a 1 hour incubation with IFN-γ or IFN-α does produce any significant alteration, and a 24 hour incubation with both interferons produces an equal enhancement. In vivo colon 26 are sensitive to natural killer cell (NK) mediated lysis. Pretreatment of mice with anti-asialo GM1 serum abrogates splenic NK cell activity leading to increased pulmonary retention of radiolabelled cells and enhancement of metastases in NK cell depleted mice compared with immunocompetent controls. It is not possible to determine whether pretreatment with IFN-γ alters the sensitivity of colon 26 to NK cell mediated lysis since in vitro colon 26 are completely resistant to NK cell mediated lysis. The enhancement of metastases is not due to alterations in cell size, adhesion to components of the extracellular matrix, homotypic adhesion, sensitivity to lysis by pulmonary or activated peritoneal macrophages, osmotic fragility, or enhancement of either surface Class II MHC antigen expression or ICAM-1. Pretreatment with TGF-β significantly reduces the metastatic potential of colon 26 and abrogates the IFN-γ-induced enhancement. Interleukin-1, tumour necrosis factor, epidermal growth factor, and platelet derived growth factor have no effect on metastatic potential. 2 dimensional gel electrophoresis has identified two proteins which are induced by IFN-γ and not by IFN-α, TGF-β, or the combination of IFN-γ and TGF-β which are good candidates for further study.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigations into the modulation of metastatic potential by cytokines |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. |
| Keywords: | Health and environmental sciences; Cytokines |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10114190 |
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