The CXC chemokine, monokine induced by interferon-gamma, inhibits non-small cell lung carcinoma tumor growth and metastasis

Angiogenesis is an absolute requirement for tumor growth beyond 2 mm(3) in size. The balance in expression between opposing angiogenic and angiostatic factors controls the angiogenic process. The CXC chemokines are a group of chemotactic cytokines that possess disparate activity in the regulation of angiogenesis, Nonsmall cell lung carcinoma (NSCLC) has an imbalance in exp ression of ELR+ (angiogenic) compared with ELR- (angiostatic) CXC chemokine s that favors angiogenesis and progressive tumor growth. We found that the level of the ELR- CXC chemokine MIG (monokine induced by interferon gamma) in human specimens of NSCLC was not significantly different from that found in normal lung tissue. These results suggested that the increased expressi on of ELR+ CXC chemokines found in these tumor samples is not counterregula ted by a concomitant increase in the expression of the angiostatic ELR- CXC chemokine MIG. This would result in an even more profound imbalance in the expression of regulatory factors of angiogenesis that would favor neovascu larization, We hypothesized that MIG might be an endogenous inhibitor of NS CLC tumor growth in vivo and that reconstitution of MIG in the tumor microe nvironment would result in the inhibition of tumor growth and metastasis, I n support of this hypothesis, we demonstrate here that overexpression of th e ELR- CXC chemokine MIG, by three different strategies including gene tran sfer, results in the inhibition of NSCLC tumor growth and metastasis via a decrease in tumor-derived vessel density. These findings support the import ance of the ELR- CXC chemokine MIG in inhibiting NSCLC tumor growth by atte nuation of tumor-derived angiogenesis. Furthermore, these findings demonstr ate the potential of gene therapy as an alternative means to deliver and ov erexpress a potent angiostatic CXC chemokine,