Relationships of Alpha-SMA-Positive Fibroblasts and SDF-1-Positive Tumor Cells with Neoangiogenesis in Nasopharyngeal Carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) is one of the most prevalent malignant tumors with poor prognosis in Southern China and Southeast Asia. Angiogenesis-related molecules can be promising therapeutic targets in NPC. To investigate the relationships of cancer-associated fibroblasts (CAFs) and chemokine-related molecules with neoangiogenesis, we compared immunohistochemical analyses of alpha-smooth-muscle actin (α-SMA), stroma-derived factor-1 (SDF-1), and its receptor CXCR4 in primary NPC specimens and chronic nasopharyngitis tissues. In addition, we examined the expression of vascular endothelial growth factor (VEGF-A), and CD133- and VEGF- receptor-2 (VEGFR-2) double positive cells, as endothelial progenitor cells (EPCs). We also assessed CD34-positive microvessels. Significantly higher expression of α-SMA was observed in fibroblasts in NPC stroma. The immunoreactive intensities of SDF-1 and CXCR4 were significantly higher in NPC cells. CXCR4-positive cells and CD133/VEGFR-2- double positive cells were observed in the stroma surrounding cancer nests, and VEGF was detected in both cancer and stromal cells. Microvessel density was significantly higher in the stroma of NPC tissues compared to chronic nasopharyngitis tissues. Our data suggest that CAFs and NPC tumor cells may enhance neoangiogenesis in a VEGF- and SDF-1-dependent manner by recruiting EPCs from the bone marrow into tumor stroma.

Cancer-Associated Fibroblasts in Undifferentiated Nasopharyngeal Carcinoma: A Putative Role for the EBV-Encoded Oncoprotein, LMP1

“…In line with previous observations in which NPC biopsies displayed SDF-1/CXCL12-expressing tumour cell nests surrounded by αSMA-expressing CAFs [21,57], it is interesting to note that LMP1 expression in NPC biopsies also correlates with higher levels of CXCR4 and its nuclear localisation, but intriguingly, there was no correlation with SDF-1/CXCL12 expression [76], suggesting that LMP1 does not itself modulate the expression of this growth-promoting chemokine. However, LMP1 has been shown to upregulate CXCR4 mRNA in murine embryonic fibroblasts in an NF-κB-dependent manner [77], and in NPC cells, LMP1 is able to regulate CXCR4 activity through post-translational modification, resulting in enhanced metastatic characteristics [78].…”

“…In a study by Wang et al (2014), immunohistochemical staining revealed significantly higher levels of αSMA in the stroma surrounding nests of NPC tumour cells, alongside high levels of SDF-1 (also known as CXCL12) in the tumour cells themselves. The authors also demonstrated a correlation between αSMA and CD34 expression-an indicator of microvessel density used as a measure of neoangiogenesis, lending additional support to the role of CAFs in NPC pathogenesis [21].…”

“…However, less is known about other stromal cells that home to the tumour microenvironment (TME) in NPC. Some reports describe a body of activated fibroblasts, also known as cancer-associated fibroblasts (CAFs), surrounding nests of tumour cells in NPC biopsies [21,22], yet the interaction between the virus, its latent gene products and the recruitment and activation of CAFs in NPC pathogenesis is poorly understood. This short opinion piece will review the current body of evidence for the importance of CAFs in the clinical course of NPC, and discuss a putative role for the EBV-encoded oncoprotein, LMP1, in the formation of CAFs in the TME.…”

Molecular mechanism underlying the tumor-promoting functions of carcinoma-associated fibroblasts

“…Numerous studies have demonstrated that CAFs could promote tumor angiogenesis, mainly through releasing growth factors (VEGF, FGF, EPO) or recruiting endothelial progenitor cells (EPCs) into carcinomas [52]. For example, co-cultures of esophageal squamous cell carcinoma cells and esophageal fibroblasts suggest that the carcinoma-derived TGF-β can regulate angiogenic process through stimulating the VEGF production by fibroblasts, and the presence of fibroblasts is necessary for the formation of efficient human microvascular endothelial cell network [53].…”

The Combination of Vascular Endothelial Growth Factor and Stromal Cell-Derived Factor Induces Superior Angiogenic Sprouting by Outgrowth Endothelial Cells

“…This combination of factors may potentially increase microvessel density in tissue-engineered vascular networks as well as in models of cancer or ischemic disease [31,32]. The results of these experiments also emphasize the enhanced sprouting capacity of OECs compared to that of mature endothelial cells, and support further investigation of the clinical uses of these cells.…”