EMT6 is a transplantable mouse mammary tumor cell line that has been utilized widely as a model system to study the effects of various treatments on local tumor growth and pulmonary metastasis. In this study, we examined the cellular mechanisms by which scatter factor (SF), a fibroblast-derived cytokine that stimulates epithelial cell motility, may contribute to tumor-cell dissemination, using the EMT6 model system. In vitro, SF stimulated EMT6 cell motility, invasiveness and cell-surface expression of urokinase (an enzyme required for cell migration through tissue). SF differentially stimulated EMT6 cell adhesion to and migration onto surfaces coated with collagen I and laminin. EMT6 cells treated in vitro with SF and injected i.v. into isogeneic BALB/c-Rw mice showed a small but significant increase (1.7-fold) in lung colony formation as compared with control cells. For EMT6 cells in vitro, SF had no effect on DNA synthesis, cell proliferation, cell size distribution, or in vitro colony-forming ability. Thus, the increase in lung colonization may be due to enhanced ability of SF-treated cells to adhere to subendothelial basement membrane or to invade through tissue. Studies of the tissue distribution of SF in BALB/c-Rw mice demonstrated high levels of active factor in the lung. Thus, the presence of endogenous pulmonary SF may have reduced the degree to which SF treatment stimulated EMT6 lung colonization. Significant SF activity was also found in extracts of EMT6 tumors. Cultured EMT6 cells did not produce SF, but did produce high titers of a soluble low-molecular-weight protein activity that is capable of stimulating SF production in human fibroblasts 3- to 5-fold. EMT6 tumor extracts contained high titers of a similar SF-inducing activity. These observations suggest that SF may contribute to the invasive and metastatic phenotype of EMT6 cells via a paracrine mechanism in which tumor cells induce the production of SF in stromal fibroblasts.

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Radiation-induced lung injury frequently limits the total dose of thoracic radiotherapy that can be delivered, and the determinants of host susceptibility are poorly understood. To test the hypothesis that vitamin A status may be an important, modifiable host determinant of radiation-induced lung injury, we determined the effect of altered vitamin A status on radiation-induced lung inflammation in rats. WAG-Rij Y rats were fed a diet deficient in or supplemented with vitamin A (0 units/kg or 80,000 units/kg diet). After 5 wk of consuming the prescribed diet, rats were irradiated with 15 Gy of 250 kV X-rays to the whole thorax. At 4-5 wk post-irradiation, there were significantly fewer neutrophils on bronchoalveolar lavage in rats fed the vitamin A-supplemented diet (8.8 +/- 1.2% neutrophils) compared with those fed the vitamin A-deficient diet (20.8 +/- 3.4% neutrophils, P < 0.01). At the termination of the experiment, 4-5 wk postradiation, lung retinol levels of the vitamin A-supplemented group were 19.6 +/- 1.8 nmol/g, whereas those in the vitamin A-deficient group were significantly lower, 1.7 +/- 0.5 nmol/g (P < 0.01). These findings suggest that supplemental vitamin A may reduce lung inflammation after thoracic radiation and be an important modifiable radioprotective agent in the lung.

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SUMMARY RSR13, 2[4-[[(3,5Dimethylanilino)carbonyl]methyl]phenoxy]-2-methylpropionic acid, a synthetic allosteric modifier of hemoglobin, reduces the affinity of hemoglobin for oxygen. The experiments reported here examined the effect of treatment with RSR13, combined with oxygen breathing, on the radiation response of EMT6 mammary tumors in BALB/c mice and of two normal tissues. RSR13 plus oxygen breathing increased the response of EMT6 tumors to irradiation. RSR13 had no discernible effects on tumors rendered maximally hypoxic by nitrogen asphyxiation, no discernible cytotoxic effects in EMT6 tumors, and no effect on the viability or radiation response of EMT6 cells in vitro under either aerobic or hypoxic conditions. The effects of RSR13 therefore reflect changes in tumor oxygenation, rather than a direct cytotoxic or radiosensitizing effect of the drug. RSR13 plus oxygen reduced the hypoxic fraction to 9% from the value of 24% found in both air-breathing and oxygen-breathing mice. Treatment with RSR13 plus oxygen did not alter the radiation response of the bone marrow progenitor cells (CFU-S) or acute radiation reactions in the skin. The improvement in tumor radiation response produced by treatment with RSR13 plus oxygen, combined with the absence of enhanced radiation reactions in the normal tissues, support further testing of RSR13 as an adjunct to radiotherapy.