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

Systemic treatment of malignancies with high doses of tumour necrosis factor-alpha (TNFalpha) has an anticancer effect, but also serious side effects. The aim of the present study was to elucidate the effects of local TNFalpha administration alone or in combination with chemotherapy on tumour stroma structure and physiology in di-methyl-benz-anthracene (DMBA)-induced mammary carcinomas in rats. TNFalpha (500 ng/mL in a volume of 5 microL) 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. Treatment with TNFalpha 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 TNFalpha, suggesting decreased aerobic metabolism. Treatment with TNFalpha, 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-1beta in carcinoma interstitial fluid or in serum were not affected by TNFalpha. The study demonstrated that these cytokines are produced locally in the tumour. Furthermore, TNFalpha had no effect on efficacy of treatment with 5-FU. Locally administered TNFalpha 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.