The role of TIMPs in tumorigenesis and metastasis

The process of tumorigenesis is influenced by the interaction of the developing tumor and its microenvironment. In this interaction, the families of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) play an important role in regulating a variety of mechanism that affect the various stages of tumor development. While the effects of altered TIMP expression in the tumor cell have been previously shown to significantly affect tumorigenesis, there is a considerable lack of information about whether TIMPs expressed by the host can affect this process. Here, we examined whether the lack of TIMP expression in the host could affect the processes of genetic instability, tumor growth, angiogenesis, and metastasis. Using a bi-transgenic model for both under-expression of TIMP-1 in the liver and lacZ as a reporter gene for somatic mutations, we show that the decreased levels of TIMP-1 did not affect the mutant frequency induced by the mutagenic challenge of ethyl-nitrosourea. Using timp-3 null embryonic stem cells and mice, we show that the absence of TIMP-3 in the host, but not in the tumor cell, results in increased tumor growth that is associated with enhanced angiogenesis. In addition, we show that the absence of host TIMP-3 results in increased metastatic dissemination of two murine tumor cell lines: B16F10 melanoma cells to lung and bone and EL-4 lymphoma cells to kidney and liver. Examination of the experimental lung metastasis assay shows that this enhanced metastatic dissemination is not mediated through changes in inflammation, angiogenesis or proliferation in the developing metastatic foci, but that this phenotype may be dependent on enhanced tumor cell extravasation and activation of pro-MMP-2. In contrast to the timp-3-/- mouse, we found no enhancement of tumor growth or angiogenesis in the timp-4 null mouse. However, the absence of TIMP-4 in the host resulted in significant increase in metastatic colonization of the lung by B16F10 melanoma cells. Our results are the first evidence that TIMP-3 and TIMP-4 deficiencies in the stroma significantly enhance metastasis. The data presented highlight that, distinct from other members of the TIMP family, TIMP-3 deficiency can also increase tumor growth and angiogenesis.