Secreted phosphoprotein 1 (spp1), the gene encoding osteopontin (OPN), is expressed in many human carcinomas, although its in vivo functions remain unclear. To delineate the role of OPN during tumor progression, we have subjected OPN null mutant mice to repeated applications of a mutagen/carcinogen to induce cutaneous squamous cell carcinoma. OPN null animals exhibited accelerated tumor growth and progression and had a greater number of metastases per animal compared with wild-type animals. However, metastases in the OPN null animals were significantly smaller than in controls. When injected into nude mice, the growth of OPN null tumor lines and the same lines engineered to reexpress spp1 recapitulated the growth differences observed in the progression study. These differences in tumor growth inversely correlated with the degree of macrophage infiltration. Slower-growing, OPN-producing tumors contained significantly more macrophages, although a higher proportion were mannose receptor positive, a characteristic of differentiated resting macrophages. In vitro, OPN null cell lines displayed decreased survival at clonal density compared with OPN-producing lines, an observation consistent with the smaller metastases of the OPN null mice. Overall, we provide evidence for a model where host-derived OPN acts as a macrophage chemoattractant, whereas tumor-derived OPN is able to inhibit macrophage function and enhances the growth or survival of metastases.


This project was supported by Grant 5T32CA90592-09 from the National Cancer Institute and Grant RPG-97-093-01-CNE from the American Cancer Society (to L. L.), NIH Grant R01 CA46843, and the Vanderbilt Cancer Center Support Grant P30 CA68485 (to L. M. M.). H. C. C. was supported by postdoctoral fellowship F32 CA67429 from the NIH.

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