Figure 2.

Schematic of the involvement of CXCR3 in the invasion-metastasis cascade. In the primary tumor CXCR3 ligands are primarily derived from surrounding stromal cells including macrophages and fibroblasts. Here, CXCR3A and B have opposing roles with respect to cancer cell invasion. CXCR3A promotes tumor cell invasion, migration, and intravasation largely through increased expression of matrix metalloproteinases. In contrast CXCR3B has an inhibitory effect on these processes and limits access of cancer cells to vasculature through its angiostatic activity. Additionally, CXCR3 is involved in the recruitment of T-cells and NK-cells to the TME as well as the differentiation of these cells into functionally important subsets. The effect of immune cell recruitment and differentiation on the overall metastatic process appears to context dependent. During the intravascular phase of metastasis, CXCR3 ligands are largely derived from platelets in the form of PF4. CXCR3B may augment cancer cell survival by augmenting stem-like phenotype in cancer cells. Finally, at the secondary site, the pro-invasive and immunomodulatory effects of CXCR3A can play critical roles in the establishment of a metastatic niche and ultimately colonization of the distant site.