Preparing the "soil": the premetastatic niche

Abstract

Current focus on cancer metastasis has centered on the intrinsic factors regulating the cell autonomous homing of the tumor cells to the metastatic site. Specific up-regulation of fibronectin and clustering of bone marrow-derived cellular infiltrates coexpressing matrix metalloproteinases in distant tissue sites before tumor cell arrival are proving to be indispensable for the initial stages of metastasis. These bone marrow-derived hematopoietic progenitors that express vascular endothelial growth factor receptor 1 mobilize in response to the unique array of growth factors produced by the primary tumor. Their arrival in distant sites represents early changes in the local microenvironment, termed the "premetastatic niche," which dictate the pattern of metastatic spread. Focus on the early cellular and molecular events in cancer dissemination and selectivity will likely lead to new approaches to detect and prevent metastasis at its earliest inception.

Figure 1

Top row, HPCs from bone marrow niche to premetastatic niche. Initiation, HPCs form cellular clusters in the lung before tumor cell arrival. Progression, migrating tumor cells adhere and grow specifically at these sites. Completion, angiogenic elements, such as VEGFR2⁺ EPCs, are required for completion of the vascularized metastatic lesion. Green, VEGFR1⁺ HPCs; red, tumor cells; blue, 4′,6-diamidino-2-phenylindole nuclear staining; yellow, overlap of green VEGFR1 ⁺ GFP HPCs and red tumor cells. Circular outline, blood vessel within the metastatic tumor. Bottom row, a schematic of the metastatic process. There is up-regulation of fibronectin by activated fibroblasts followed by attachment of VLA4⁺ VEGFR1⁺ HPCs. These cells form clusters that initiate microenvironmental changes necessary for future metastasis. Adhesion and proliferation of tumor cells occur at sites of VEGFR1⁺ cellular clusters. Influx of endothelial progenitor cells form vasculature to make a mature metastatic lesion. R1, VEGFR1⁺ HPCs (green); R2, VEGFR2⁺ CEPs (blue); T, tumor (red); yellow, fibronectin (FN); orange, fibroblasts (FB); TB, terminal bronchiole; BV, bronchiole vein.