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Sulfate plays an important role in maintaining normal structure and function of tissues, and its content is decreased in certain cancers including lung carcinoma. In this study, we investigated tumor growth in a mouse model of hyposulfatemia (Nas1−/−) and compared it to wild-type (Nas1+/+) mice. Lung epithelial tumor cells (TC-1 cell line) were injected subcutaneously into male Nas1−/− and Nas1+/+ mice on a mixed 129Sv and C57BL/6 genetic background. Tumor sections were stained with anti-glycosaminoglycan antibodies to assess the distribution of proteoglycans and Gomori’s trichrome to detect collagen. After 14 days, tumor weights were markedly increased (by ∼12-fold) in Nas1−/− mice when compared with Nas1+/+ mice. Histological analyses of tumors revealed increased (by ≈2.4-fold) vessel content, as well as markedly reduced collagen and immunoreactivity against glycosaminoglycan structural epitopes in the tumors from Nas1−/− mice. No significant differences were found for the growth of cultured TC-1 cells supplemented with Nas1−/− or Nas1+/+ serum, as determined by 3H-thymidine incorporation, implying that the cell culture conditions may not reflect the in vivo situation of enhanced tumor growth. This study has revealed increased tumor growth and an altered extracellular tumor matrix in hyposulfatemic Nas1−/− mice. These findings highlight the importance of blood sulfate levels as a possible modulator of tumor growth, and could lead to future cancer studies in humans with altered sulfate homeostasis. (Cancer Sci 2009; 00: 000–000)