Premetastatic niche formation in the liver: emerging mechanisms and mouse models

The liver is recognized as the target organ of metastases of almost all prominent malignancies. Its unique biology renders this organ particularly susceptible to circulating disseminated tumour cells (DTCs), and it can be assumed that very early metastasis occurs in the liver. The premetastatic niche concept may explain very early metastasis, as it defines priming of a future target organ of metastasis by factors that may already be secreted from premalignant lesions. This review shows that comprehensive knowledge on mechanisms of premetastatic niche formation in the liver is based on preclinical models only and still rather rare, mostly due to the scarcity of mouse liver metastasis models displaying a tumour cell-free period in the liver or lack of liver-tropic syngeneic tumour cells to probe for the niche. Attentive re-assessment of previous studies and reviews was undertaken revealing only two clearly identified tumour-derived secreted factors (TDSFs), both inducing infiltration of the liver by bone marrow-derived cells and increased liver metastasis, namely tissue inhibitor of metalloproteinases-1 (TIMP-1) and macrophage-inducing factor (MIF). Future directions of this research area will comprise elucidation of the impact of TDSFs on regulation and activity of myeloid-derived suppressor cells and/or the specific architecture and homeostasis of the liver, as well as development of prognostic TDSF detection in patients at risk of liver metastasis.