INTERFERON-GAMMA-INDUCIBLE-PROTEIN-10 (IP-10) IS AN ANGIOSTATIC FACTOR THAT INHIBITS HUMAN NONSMALL CELL LUNG-CANCER (NSCLC) TUMORIGENESIS AND SPONTANEOUS METASTASES

The success of solid tumor growth and metastasis is dependent upon ang iogenesis. Neovascularization within the tumor is regulated, in part, by a dual and opposing system of angiogenic and angiostatic factors. W e now report that IP-10, a recently described angiostatic factor, is a potent angiostatic factor that regulates non-small cell lung cancer ( NSCLC)-derived angiogenesis, tumor growth, and spontaneous metastasis. We initially found significantly elevated levels of IP-10 in freshly isolated human NSCLC samples of squamous cell carcinoma (SCCA). In con trast, levels of IP-10 were equivalent in either normal lung tissue or adenocarcinoma specimens. The neoplastic cells in specimens of SCCA w ere the predominant cells that appeared to express IP-10 by immunoloca lization. Neutralization of IP-10 in SCCA tumor specimens resulted in enhanced tumor-derived angiogenic activity. Using a model of human NSC LC tumorigenesis in SCID mice, we found that NSCLC tumor growth was in versely correlated with levels of plasma or tumor-associated IP-10. IP -10 in vitro functioned as neither an autocrine growth factor nor as a n inhibitor of proliferation of the NSCLC cell lines. Reconstitution o f intratumor IP-10 for a period of 8 wk resulted in a significant inhi bition of tumor growth, tumor-associated angiogenic activity and neova scularization, and spontaneous lung metastases; whereas, neutralizatio n of IP-10 for 10 wk augmented tumor growth. These findings support th e notion that tumor-derived IP-10 is an important endogenous angiostat ic factor in NSCLC.