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Studies of cytokines in the biology and treatment of cancer

Miles, David William; (1995) Studies of cytokines in the biology and treatment of cancer. Doctoral thesis (M.D), UCL (University College London). Green open access

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Abstract

While cytokines produced by infiltrating mononuclear cells in primary breast cancer might mediate a host immune response to tumour, they have other properties which could promote tumour development. The first part of the thesis describes the site and extent of tumour necrosis factor (TNF-[alpha]) expression in human breast tissue. Cells expressing TNF mRNA were rarely noted in normal breast tissue. Greater levels were noted in invasive breast cancer but expression was focal, scanty and found in the stroma adjacent to tumour islands. The presence of TNF-[alpha] protein was assessed and its production by cells of the monocyte lineage was confirmed. The number of infiltrating macrophages did not vary with tumour grade, but the proportion of them expressing TNF-[alpha] correlated with increasing tumour grade. This finding, coupled with the observation that TNF-receptors were not detected on tumour cells but rather on other infiltrating mononuclear cells and vascular endothelium, led to the hypothesis that the net effect of TNF-[alpha] expression in breast cancer could be to promote tumour progression. Further studies investigated expression of the TNF-[alpha] inducible enzyme, nitric oxide (NO) synthase which, by generating the vasoactive agent NO, may modulate tumour blood flow and promote angiogenesis. Biochemical assays demonstrated raised levels of activity of calcium dependent and independent isoforms of NO synthase in malignant compared with benign breast tissue. A correlation between NO synthase activity and tumour grade was noted and histochemical studies localised expression to macrophages, endothelium and myoepithelium. TNF-[alpha] may also regulate production and activation of the type IV collagenases. Zymography of breast tumour tissue demonstrated that the proportion of the 72kDa isoform of the enzyme in the activated state correlated with tumour grade and that expression of the 92kDa isoform was significantly raised in high grade tumours. In the second part of the thesis the clinical and biological effects of prolonged infusions of interleukin-2, given in an attempt to augment the host immune response to tumour, were studied. Mechanisms of toxicity were investigated, with particular respect to induction of cytokines and nitric oxide, and comparison of lymphocyte trafficking to tumour and normal tissue in response to therapy were made. At the level of primary tumour and in metastatic disease in response to systemic therapy, any anti-tumour effects of cytokines may be offset by those which promote tumour progression or cause treatment toxicity.

Type: Thesis (Doctoral)
Qualification: M.D
Title: Studies of cytokines in the biology and treatment of cancer
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
URI: https://discovery.ucl.ac.uk/id/eprint/10104268
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