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Identifying versatile inhibitors of metastasis that operate in multiple sites against distinct cancer cell types is important for designing novel therapeutics for metastasis. We show that multiple tissues of timp-3-/- mice are more susceptible to metastatic colonization. Overall, a 5-14-fold increase in liver and kidney colonization occurred by EL-4 lymphoma cells, and a twofold increase upon targeting B16F10 melanoma cells to the bone or lung of timp-3-/- mice. There was a general lack of macrophage or neutrophil localization to metastases in the liver, kidney and lung, and of osteoclasts to bone in both genotypes. Analysis of lung showed that proliferation or angiogenesis were unaltered within the metastatic colonies. Lung-trap assays revealed that initial tumor cell trapping was similar in the lung vasculature of timp-3-/- and wild-type mice. However, more tumor cells were found in timp-3-/- lungs at 48 and 96 h after tumor cell injection indicating more efficient extravasation and initial proliferation. Activation of pro-MMP-2 was greater in timp-3-/- lungs at these time points. These data demonstrate TIMP-3 functions to inhibit metastatic dissemination of diverse cancer cells to multiple organs. TIMP-3 regulates MMP-2 activation to limit tumor cell extravasation and subsequent colonization of the lung, without augmenting inflammatory cell response.

Elevated levels of insulin-like growth factor (IGF)-II are associated with a poor prognosis in human pulmonary adenocarcinoma; however, a causal role for IGF-II in pulmonary adenocarcinoma has not been demonstrated. Here, we show that transgenic overexpression of IGF-II in lung epithelium induces lung tumors in 69% of mice older than 18 months of age. These tumors displayed morphological characteristics of human pulmonary adenocarcinoma such as their epithelial origin, tubulo-acinar architecture and expression of TTF-1, SP-B and proSP-C. Examination of signaling molecules downstream of the IGF-IR showed the activation of either the Erk1/Erk2 or p38 MAPK pathways, but not both, within the lung tumors. Notably, all lung tumors contained high levels of phosphorylated CREB, suggesting that both the Erk1/Erk2 and p38 MAPK pathways converged on this transcription factor. Moreover, IGF-II induced proliferation and CREB phosphorylation in human lung cancer cell lines, suggesting that IGF-II and CREB also contribute to the growth of human lung tumors. Thus, IGF-II is an important genetic factor in the development of lung tumorigenesis, in which activation of CREB is a ubiquitous event. The MMTV-IGF-II transgenic mice provide a critical model for elucidating the role of IGF-II in this fatal human disease.