The metastatic niche: adapting the foreign soil

Abstract

The 'seed and soil' hypothesis for metastasis sets forth the concept that a conducive microenvironment, or niche, is required for disseminating tumour cells to engraft distant sites. This Opinion presents emerging data that support this concept and outlines the potential mechanism and temporal sequence by which changes occur in tissues distant from the primary tumour. To enable improvements in the prognosis of advanced malignancy, early interventions that target both the disseminating seed and the metastatic soil are likely to be required.

Figure 1. A model of the evolution of a metastatic niche

This figure depicts the premetastatic, micrometastatic to macrometastatic transition. (A) In response to growth factors secreted by the primary tumour including vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and transforming growth factor-b (TGF- b), inflammatory S100 chemokines and serum amyloid A (SAA) 3^, are upregulated in premetastatic sites leading to clustering of bone marrow-derived haematopoietic progenitor cells (HPCs). Platelet-deployed stromal-derived growth factor (SDF)-1 is also chemotactic for CXCR4⁺ HPCs and metastatic tumour cells (MTCs). HPCs secrete a variety of premetastatic factors including TNF-a, matrix metalloproteinase (MMP)-9 and TGF-β^{, ,} Activated fibroblasts secrete fibronectin, an important adhesion protein in the niche, and lysoyl oxidase (LOX) expression is increased, modifying the local extracellular matrix. (B) MTCs engraft the niche to populate micrometastases. The site specific expression of adhesion integrins on activated endothelial cells such as P-selectin and E-selectin may enhance MTC adhesion and extravasation at these sites, and cell-cell interactions such as CD44 ligation in the metastatic niche may promote MTC survival and enable proliferation. (C) Recruitment of endothelial progenitor cells (EPCs) to the early metastatic niche mediates the angiogenic switch and enables progression to macrometastases^, .

Figure 2. Stage-specific targeting of the metastatic microenvironment

Cellular and molecular targets relevant to each stage of metastatic development are suggested as ammunition for future anti-metastatic therapies.