The mechanisms that determine where a primary tumour will form metastases, or why certain tumours metastasize to certain organs, are unknown. In Nature, Rosandra Kaplan et al. report that bone marrow-derived cells are among the first determinants of this site selection, migrating to specific tissues to establish an environment that attracts tumour cells and promotes the growth of metastases.
Bone marrow-derived cells make well-known contributions to transformation, tumour cell migration and tumour vascularization. Some bone marrow haematopoietic stem cells express vascular endothelial growth factor receptor 1 (VEGFR1) and participate in tumour angiogenesis. In studying the role of these cells in tumour progression, Kaplan et al. discovered that these VEGFR1+ cells actually colonize pre-metastatic sites before tumour cells arrive.
Using mouse models to track these cells and to follow tumour progression in vivo, the authors observed that depleting VEGFR1+ cells from the bone marrow of mice abrogated the formation of these pre-metastatic clusters and prevented tumour metastasis. So, how do the VEGFR1+ bone marrow cells choose the pre-metastatic site?
The authors showed that factors produced by the primary tumour induce the VEGFR1+ bone-marrow-derived cells to enter the bloodstream and mobilize to specific organs. Following the implantation of lung carcinomas or melanoma cells in mice, but before the mobilization of bone marrow-derived cells, increased expression of fibronectin was observed in the vicinity of the future metastatic niche. The authors observed that fibroblast-like stromal cells in these locations proliferated in response to the presence of a primary tumour in the mouse, and might be involved in depositing the fibronectin at pre-metastatic sites. VEGFR1+ haematopoietic stem cells that localized to the pre-metastatic sites expressed integrins that allowed them to bind to the fibronectin produced at these locations. Furthermore, the fibronectin–integrin interaction induced the haematopoietic stem cells to express matrix metalloproteinase 9 (MMP9), which helps prepare the stromal environment for the arrival of the metastatic tumour cells.
At the pre-metastatic site, the VEGFR1+ cells also contribute to the production of chemokines that attract chemokine receptor-expressing tumour cells to the pre-metastatic niche. Pre-metastatic cluster formation and subsequent metastasis was blocked in various mouse models with antibodies against VEGFR1 and integrins.
This is the first evidence that a non-neoplastic cell population can establish a future metastatic site. Targeting of the VEGFR1+ cells, or of other features of this niche, might be used to prevent metastasis in patients with early stage cancers.