Paradoxical Effects of CXCL14 on Tumorigenesis

CXCL14/BRAK is a chemokine associated with tumor development. In non-cancerous tissue, CXCL14 is predominantly expressed in the epithelium, but during tumorigenesis, it shows an altered expression pattern. This change, in combination with the effects of CXCL14 on tumor cell proliferation, angiogenesis, and immune cell infiltration, may influence the progression of a range of cancers.

In some cancers, such as those of the prostate and pancreas, CXCL14 is upregulated.1,2 In contrast, CXCL14 expression is frequently suppressed in tumor cells of the head and neck, breast, cervix, and kidneys.3, 4 In cases of reduced tumor cell expression, production of CXCL14 can be maintained or upregulated in neighboring cells. In head and neck, renal cell, and prostate carcinomas for example, CXCL14 is upregulated in local fibroblasts and the surrounding epithelium.1, 5, 6 In breast cancer, CXCL14 is preferentially expressed by myoepithelial cells rather than tumor cells.2 A caveat here is that these studies determined CXCL14 expression by detection of mRNA or intracellular protein, approaches that may not accurately predict the amount of bioavailable CXCL14. This point is underscored by Peterson et al. who observed that immortalized cells and cancer cells can retain expression of the CXCL14 message but chemokine secretion is prevented by proteasome-dependent degradation.7 Interestingly, elevated levels of intracellular reactive oxygen species induce CXCL14 upregulation in breast cancer cells, leading to accumulation in the endoplasmic reticulum (ER). Under these circumstances, CXCL14 directly interacts with the inositol 1,4,5-trisphosphate (IP3) receptor in the ER to induce calcium release into the cytoplasm.8

CXCL14 Exerts Paradoxical Effects on Tumorigenesis.
View Larger Image 		CXCL14 Exerts Paradoxical Effects on Tumorigenesis. CXCL14 exhibits contradictory effects on tumorigenesis under different experimental conditions. In vitro, CXCL14 promotes breast and pancreatic tumor cell invasion and inhibits vascular endothelial cell (EC) migration. In vivo, overexpression of CXCL14 in oral squamous carcinoma cells (OSCC) and prostate cancer cells (PCC) suppresses tumorigenesis, while overexpression of CXCL14 in prostate cancer-associated fibroblasts induces tumor growth and vascularization. Fibroblast-derived CXCL14 also stimulates monocyte migration in vitro suggesting that it may promote macrophage recruitment in vivo.

CXCL14 exerts paradoxical effects on tumor growth. Exogenous CXCL14 increases the motility and invasiveness of breast and pancreatic cancer cells in vitro.4, 8 In contrast, overexpression of CXCL14 in tumor cells of xenograft mouse models of oral squamous cell and prostate cancers suppresses the number and size of the resulting tumors.3, 9 To study the function of stromal cells in tumorigenesis, Augsten et al. implanted mice with a mixture of fibroblasts and non-tumorigenic prostate cancer cells.6 Under these conditions, the mice developed tumors, and the use of CXCL14-overexpressing fibroblasts accelerated tumor growth and vascularization. The increased density of tumor vascularization was potentially due to CXCL14-induced upregulation of FGF basic and VEGF-A, -B, and -C in the fibroblasts rather than a direct effect of CXCL14 on the vasculature.6 In fact, Shellenberger et al. showed that CXCL14 inhibits the activity of angiogenic factors on human umbilical vein endothelial cells and human microvascular endothelial cells, possibly through its ability to directly bind to immobilized CXCL8/IL-8 and FGF basic.5

Tumor cell-derived CXCL14 promotes an influx of immature dendritic cells in vivo and triggers their activation in vitro.10 Downregulation of CXCL14 production in tumors facilitates tumor growth by attracting fewer dendritic cells, thereby limiting the initiation of an anti-tumor immune response.10 Leukocytes, vascular endothelial cells, and tumor cells are all potential effectors of CXCL14 activity. They express high and low affinity binding sites for CXCL14 that can be blocked by heparin, although the identity of these receptors remains unknown.2, 5

There are clearly unexplained aspects of the role of CXCL14 in tumorigenesis, notably its inconsistent expression among tumor types and the discrepancy between its in vitro and in vivo effects on tumor cell growth. Elucidation of the participation of local stromal cells and characterization of a CXCL14 receptor will advance the understanding of how CXCL14 influences tumor development.

References

  1. Schwarze, S.R. et al. (2005) Prostate 64:67.
  2. Wente, M.N. et al. (2008) Cancer Lett. 259:209.
  3. Frederick, M.J. et al. (2000) Am. J. Pathol. 156:1937.
  4. Allinen, M. et al. (2004) Cancer Cell 6:17.
  5. Shellenberger, T.D. et al. (2004) Cancer Res. 64:8262.
  6. Augsten, M. et al. (2009) Proc. Natl. Acad. Sci. USA 106:3414.
  7. Peterson, F.C. et al. (2006) J. Mol. Biol. 363:813.
  8. Pelicano, H. et al. (2009) Cancer Res. 69:2375.
  9. Ozawa, S. et al. (2006) Biochem. Biophys. Res. Commun. 348:406.
  10. Shurin, G.V. et al. (2005) J. Immunol. 174:5490.

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