CXCR3/Ligands Are Significantly Involved in the Tumorigenesis of Basal Cell Carcinomas

Abstract

Basal cell carcinoma (BCC) is the most common skin malignancy encountered worldwide. We hypothesized that CXC chemokines, small cytokines involved in inducing directed leukocyte chemotaxis, could play a key role in the modulation of BCC growth. In this study, quantitative RT-PCR revealed that the chemokines CXCL9, 10, 11, and their receptor CXCR3 were significantly upregulated by an average 22.6-fold, 9.2-fold, 26.6-fold, and 4.9-fold, respectively in BCC tissue samples as compared with nonlesional skin epithelium. Immunohistochemistry analysis revealed that CXCR3, CXCL10, and CXCL11, but not CXCL9, colocalized with cytokeratin 17 (K17) in BCC keratinocytes. In addition, CXCR3 and its ligands were expressed in cells of the surrounding BCC stroma. The chemokines and K17 were also expressed in cultured human immortalized HaCaT keratinocytes. Exposure of HaCaT cells or primary BCCderived cells to CXCL11 peptides in vitro significantly increased cell proliferation. In primary BCC-derived cell cultures, addition of CXCL11 progressively selected for K17؉ /CXCR3 ؉ co-expressing cells over time. The expression of CXCR3 and its ligands in human BCC keratinocytes, the enhancement of keratinocyte cell proliferation by CXCL11, and the homogeneity of K17 ؉ BCC cells in human BCC-isolated cell population supported by CXCR3/CXCL11 signaling all suggest that CXCR3 and its ligands may be important autocrine and/or paracrine signaling mediators in the tumorigenesis of

Role of aquaporins in cell proliferation: What else beyond water permeability?

“…4). 13,24 CXCL9 and CXCL10, the two most upregulated genes in our analysis, both have important pro-tumor roles [114][115][116][117] and can both be activated by the transcription factor NF-kb, as suggested in our model (Fig. 4).…”

Roles for Aberrant CXCR3 Signaling in Basal Cell Carcinoma

“…6 -8 The work of Lo et al now provides new evidence linking CXCR3 to BCC. 3 Based on microarray data and qRT-PCR, Lo and colleagues 3 showed that expression of both CXCR3 and its ligands was increased significantly in BCC lesions relative to nonlesional skin tissue. In fact, CXCL11, CXCL10, and CXCL9 were the three most upregulated genes in the BCC tumor samples.…”

“…To understand the role of CXCR3/ligand signaling in BCC, Lo and colleagues 3 focused on the ligand CXCL11, which was noted to increase the most dramatically in BCC tissues. Human immortalized HaCaT keratinocytes were first used as a model to test the function of CXCL11, which clearly stimulated HaCaT cell proliferation.…”

“…3 Perhaps more interesting is the virtual elimination of the K17 Ϫ /CXCR3 ϩ stromal population in the presence of CXCL11, an observation that was not explained but may play an important role in vivo. The existence of three alternatively spliced forms of CXCR3 may help account for this observation.…”

“…The existence of three alternatively spliced forms of CXCR3 may help account for this observation. Although Lo et al 3 were unable to distinguish between CXCR3 isotypes in the tumor mass due to the lack of specific antibodies, they did show using qRT-PCR that RNAs encoding all three CXCR3 isotypes were upregulated in BCC tumor tissues, especially the CXCR3-B form (enhanced eightfold). Because the K17 Ϫ /CXCR3 ϩ population consisted of infiltrating inflammatory cells (CXCR3-A ϩ ), endothelial cells (CXCR3-B ϩ ), and other stromal cell types, it could be postulated that CXCL11 provokes differential responses in cells within the BCC mass expressing different receptor isotypes.…”