Peritumoral TNF alpha administration influences tumour stroma structure and physiology independently of growth in DMBA-induced mammary tumours

• Background. Systemic treatment of malignancies with high doses of tumour necrosis factor-alpha (TNF alpha) has an anticancer effect, but also serious side effects. The aim of the present study was to elucidate the effects of local TNF alpha administration alone or in combination with chemotherapy on tumour stroma structure and physiology in di-methyl-benz-anthracene (DMBA)-induced mammary carcinomas in rats. Methods. TNF alpha (500 ng/mL in a volume of 5 mu L) was given s.c. around the carcinoma and 5-fluorouracil (5-FU) (1.5 mg/kg, volume of 0.2 mL) was given i.p on days 1, 4, 7 and 10. Results. Treatment with TNF alpha resulted in a significant reduction of tumour interstitial fluid pressure (TIFP: 75-87 %, p<0.02-0.001), as well as in the number of tumour-infiltrating macrophages, extracellular volume (ECV) and collagen fibril density in carcinoma. In addition, pH was lowered in tumours treated with TNF alpha, suggesting decreased aerobic metabolism. Treatment with TNF alpha, however, had no effect on tumour growth, arterial blood pressure, tumour vessel density, plasma volume or body weight. Concentrations of locally produced VEGF and IL-1 beta in carcinoma interstitial fluid or in serum were not affected by TNF alpha. The study demonstrated that these cytokines are produced locally in the tumour. Furthermore, TNF alpha had no effect on efficacy of treatment with 5-FU. Conclusions: Locally administered TNF alpha did not affect DMBA-induced mammary tumour growth or vasculature, but reduced inflammation and ECM structure, suggesting the latter to be of importance in the observed reduction in TIFP.

Nyckelord

Angiogenesis

collagen fibrils

cytokines

interstitial fluid pressure

macrophages

mammary tumours

TNF alpha

MEDICINE

MEDICIN

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