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Diversity of the Angiogenic Phenotype in Non–Small Cell Lung Cancer

Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine; and Department of Surgery, Section of General Thoracic Surgery, University of Michigan Medical Center, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Douglas Arenberg, M.D., Division of Pulmonary & Critical Care Medicine, University of Michigan Medical Center, 1150 W. Medical Center Dr., 6301 MSRB III, Ann Arbor, MI 48109-0642. E-mail: darenber{at}umich.edu

Angiogenesis is crucial for tumor biology. There are many mechanisms by which tumors induce angiogenesis. We hypothesize that each individual tumor develops a unique mechanism to induce angiogenesis, and that activation of a particular angiogenic pathway suppresses the evolution of alternative pathways. We characterized 168 human non–small cell lung cancer (NSCLC) specimens for levels of angiogenic factors (angiogenic CXC chemokines, basic fibroblast growth factor, and vascular endothelial growth factor). We also induced lung tumor formation in A/J mice by injecting the tobacco carcinogen NNK. We dissected individual lung tumors and measured expression of angiogenic factors from three distinct families using real-time PCR. Finally, we controlled the angiogenic milieu using in vivo models to determine the resultant phenotype of the angiogenic factors expressed by NSCLC cells. Human tumors displayed marked variation in the expression of angiogenic factors. Individual mouse tumors, even from within the same mouse, displayed variability in their pattern of expression of angiogenic factors. In a sponge model of angiogenesis using murine lung cancer cells, implanting LLC cells with an angiogenic factor suppressed the expression of other angiogenic factors in implanted sponges. This suppressive effect was not seen in vitro. We conclude that lung cancer tumors evolve a unique and dominant angiogenic phenotype. Once an angiogenic pathway is activated, it may allow for tumor growth to proceed in the absence of a selection pressure to activate a second pathway.

Key Words: angiogenesis • mouse model • chemokines • cytokines • carcinogen

CLINICAL RELEVANCE This research demonstrates the diversity of mechanisms by which lung cancers induce angiogenesis and should change how the results of anti-angiogenic factors are viewed.

 

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