Contribution of CXCR3-mediated signaling in the metastatic cascade of solid malignancies

Abstract

Metastasis is a significant cause of the mortality resulting from solid malignancies. The process of metastasis is complex and is regulated by numerous cancer cell-intrinsic and -extrinsic factors. CXCR3 is a chemokine receptor that is frequently expressed by cancer cells, endothelial cells and immune cells. CXCR3A signaling in cancer cells tends to promote the invasive and migratory phenotype of cancer cells. Indirectly, CXCR3 modulates the anti-tumor immune response resulting in variable effects that can permit or inhibit metastatic progression. Finally, the activity of CXCR3B in endothelial cells is generally angiostatic, which limits the access of cancer cells to key conduits to secondary sites. However, the interaction of these activities within a tumor and the presence of opposing CXCR3 splice variants clouds the picture of the role of CXCR3 in metastasis. Consequently, thorough analysis of the contributions of CXCR3 to cancer metastasis is necessary. This review is an in-depth examination of the involvement of CXCR3 in the metastatic process of solid malignancies.

Keywords: CXCR3; Cytokines; Metastasis; Tumor microenvironment; cancer.

Figure 1.

Schematic of CXCR3 chromosomal organization and signaling. Top). CXCR3 is located on the X chromosome and is composed of two exonic segments. Differential splicing of CXCR3 gives rise to three described splice variants A, B and Alt. CXCR3B is encoded entirely by a retained intronic sequence and exon 2. Bottom) CXCR3 A and B signaling is mediated by heterotrimeric G proteins (HTGP). CXCR3A couples with Gai/q and results in downstream activation of Ras/Raf/ Erk as well as PI3K/Akt signaling leading to cell proliferation, survival, and migration/invasion. CXCR3B signals through Gas resulting in activation of adenyl cyclase and PKA as well as p38 and p21 activation leading to sensitization of cells to death.

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.