Organotropism of Lung Cancer Metastasis and its Molecular Targeted Therapy

Abstract

The distribution of metastases is determined by an interaction between tumor cells ("seed") and the microenvironment of specific organs ("soil"). In fact, lung cancer produces metastasis to several particular organs, such as the liver, lung, lymph nodes, brain, and bone, suggesting organotropism on metastasis. But, the precise mechanisms determining organotropism remain unsolved. We established multiple-organ metastasis model by intravenous injection of human lung cancer cells into NK-cell depleted SCID mice. For the elucidation of the factors regulating organotropism of metastasis, we performed cDNA-microarray analyses (23,040 genes) of the metastatic foci of human lung cancer (SBC-5) cells developed in four different organs. Hierarchical clustering of 435 genes separated the four organ-specific groups of metastatic lesions very clearly. Of 435 genes, parathyroid hormone related-peptide (PTHrP) was highly expressed in bone metastasis, and inhibition of PTHrP resulting in specific inhibition of bone metastasis, suggesting usefulness of this approach to identify organ-specific therapeutic targets. Since no absolutely effective methods for curing metastatic tumors in different organs are available at present, combined use of the modalities which have anti-metastatic effect to single organ may be alternative approach to control multiple organ metastasis. Further examinations are warranted for developing novel molecular targeted therapy to control multiple-organ metastasis and improve the survival.