Tumor metastasis but not tumor growth is dependent on Src-mediated vascular permeability.
Vascular endothelial growth factor (VEGF)-induced vascular permeability (VP) is a hallmark of tumor growth and metastasis. Previous studies have shown a requirement for Src kinase in VEGF-mediated VP and signaling in blood vessels. In this study, we have examined the effect of Src-mediated reduced VP on tumor growth and metastasis. The growth and spontaneous metastasis of VEGF-expressing tumor cells were determined in Src-knockout (src(-/-)) or control mice (src(+/+) or src(+/-)). In comparison to control mice, src-null mice had a significant reduction in tumor-induced VP as well as a subsequent reduction in spontaneous metastasis. In contrast, primary tumor weight and vascular density were unchanged between src-null and control mice. Consistent with a role for Src in the extravasation of tumor cells from the circulation, direct intravenous injection of lung carcinoma cells resulted in a more than 2-fold reduction in lung tumor burden in src-null mice compared to control mice. The comparison of the results from the experimental metastasis and the spontaneous metastasis models suggests that there are defects in VP in the primary site of Src-deficient mice and that there may be an essential role for Src and Src-mediated VP in tumor metastasis to the lung.
La Jolla Institute for Molecular Medicine, Division of Cancer Biology, San Diego, CA 92121, USA.
Michele L
ML
Criscuoli
Mai
M
Nguyen
Brian P
BP
Eliceiri
D000818:Animals; D002199:Capillary Permeability / Q000235:genetics / Q000502:physiology*; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005337:Fibrin / Q000037:antagonists & inhibitors / Q000378:metabolism; D005338:Fibrin Fibrinogen Degradation Products / Q000037:antagonists & inhibitors / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D005338:Fibrin Fibrinogen Degradation Products; D042461:Vascular Endothelial Growth Factor A; D005337:Fibrin; D019061:src-Family Kinases