Stromal cell-derived factor-1α (SDF-1α/CXCL12)-enhanced angiogenesis of human basal cell carcinoma cells involves ERK1/2–NF-κB/interleukin-6 pathway

Abstract

Stromal cell-derived factor 1alpha (SDF-1alpha) (CXCL12) has been observed to enhance tumor angiogenesis. However, the comprehensive role of SDF-1alpha (CXCL12)-CXCR4 interaction, exerted during angiogenesis, has not been well understood. We have previously demonstrated that human basal cell carcinoma (BCC) tissues and a BCC cell line (BCC-1/KMC) had significant expression of CXCR4, whose level was higher in invasive than in the non-invasive BCC types. Here, we observed that human BCC tissues with high expression levels of CXCR4 had higher vascularity. Further, among the 71 BCCs diagnosed between the years 2004-2005, BCCs with high CXCR4 expression had concomitantly higher microvessel density, as compared with those with low CXCR4 expression (P < 0.001). We found that SDF-1alpha induced angiogenic activity in human BCC cells, both in vitro and in vivo. SDF-1alpha significantly upregulated several angiogenesis-associated genes such as interferon-alpha-inducible protein 27, interleukin (IL)-6, bone morphogenetic protein (BMP)-6, SOCS2 and cyclooxygenase 2 (COX)-2 in human BCC cells. Among them, IL-6 was the earliest and highest upregulated gene whose induction was observed within 6 h of the commencement of SDF-1alpha-CXCR4 interaction. The mechanisms behind the SDF-1alpha-induced time and dose-dependent upregulation of messenger RNA expression and protein secretion of IL-6 were investigated. The transcriptional regulation of IL-6 by SDF-1alpha was mediated by phosphorylation of extracellular signal-related kinase 1/2 and activation of the nuclear factor-kappaB complex. The identification of the angiogenic profiles induced through SDF-1alpha-CXCR4 interactions in human BCC cells may contribute further insights into the mechanisms involved in the angiogenic potential of SDF-1alpha (CXCL12).

Hypoxia-inducible factor-2 is a novel regulator of aberrant CXCL12 expression in multiple myeloma plasma cells

“…These findings complement those of previous studies showing that tumor-derived CXCL12 stimulates angiogenesis in other human cancers. 24,50,51 However, in the context of MM, our data directly contradict findings published by Menu et al, 11 who showed that the administration of T140 had no effect on bone marrow microvessel density in myelomatous 5T33MM mice. This may, in part, be explained by the fact that 5T33MM cells do not express CXCL12 and as such, the ability of 5T33MM-derived CXCL12 to stimulate angiogenesis was not under direct investigation.…”

Does Basal Cell Carcinoma Belong to the Spectrum of Sorafenib-Induced Epithelial Skin Cancers?

“…Very recently, it has been shown that RAF inhibitors prime cells with wild-type RAF to activate the mitogen-activated protein kinase pathway [20,21]. This pathway plays a role in the pathogenesis of SCC of the skin [22], but potentially also in BCC [23]. …”

Differential Influence of Normal and Cancer-Associated Fibroblasts on the Growth of Human Epithelial Cells in an In vitro Cocultivation Model of Prostate Cancer

“…Furthermore, IL-6 triggered the migration of endothelial cells when added to NAFs, whereas TNFα inhibited the migration when added to CAFs, suggesting that these factors secreted by stromal fibroblasts were responsible for the observed effects. The up-regulation of IL-6 and the involvement of the IL-6 pathway by the p50 subunit of nuclear factor-κB or the involvement of the IL-6 pathway trough SDF-1A (CXCL12) in the progress of angiogenesis was recently shown (59,60). There could be a direct effect of IL-6 on the enhanced migration of endothelial cells via up-regulation of angiogenic relevant factors in the endothelial cells.…”