Interferon-gamma-inducible protein 10 (IP-10) is an angiostatic factor that inhibits human non-small cell lung cancer (NSCLC) tumorigenesis and spontaneous metastases.
The success of solid tumor growth and metastasis is dependent upon angiogenesis. Neovascularization within the tumor is regulated, in part, by a dual and opposing system of angiogenic and angiostatic factors. We now report that IP-10, a recently described angiostatic factor, as 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 contrast, levels of IP-10 were equivalent in either normal lung tissue or adenocarcinoma specimens. The neoplastic cells in specimens of SCCA were the predominant cells that appeared to express IP-10 by immunolocalization. Neutralization of IP-10 in SCCA tumor specimens resulted in enhanced tumor-derived angiogenic activity. Using a model of human NSCLC tumorigenesis in SCID mice, we found that NSCLC tumor growth was inversely correlated with levels of plasma or tumor-associated IP-10. IP-10 in vitro functioned as neither an autocrine growth factor nor as an inhibitor of proliferation of the NSCLC cell lines. Reconstitution of intratumor IP-10 for a period of 8 wk resulted in a significant inhibition of tumor growth, tumor-associated angiogenic activity and neovascularization, and spontaneous lung metastases, whereas, neutralization of IP-10 for 10 wk augmented tumor growth. These findings support the notion that tumor-derived IP-10 is an important endogenous angiostatic factor in NSCLC.
Arenberg
D A
DA
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109-0360, USA.
Kunkel
S L
SL
Polverini
P J
PJ
Morris
S B
SB
Burdick
M D
MD
Glass
M C
MC
Taub
D T
DT
Iannettoni
M D
MD
Whyte
R I
RI
Strieter
R M
RM
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000473:pathology; D009389:Neovascularization, Pathologic; D011817:Rabbits
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines