Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts

Abstract

The aim of this study was to characterize the interaction of KYSE-410, an esophageal squamous cell carcinoma cell line, and fibroblasts with respect to the extracellular matrix component hyaluronan (HA) and chemokine expression. KYSE-410 cells induced the mRNA expression of HA synthase 2 (Has2) in normal skin fibroblasts (SF) only in direct co-cultures. Parallel to Has2 mRNA, Has2 antisense RNA (Has2os2) was up-regulated in co-cultures. Knockdown of LEF1, a downstream target of Wnt signaling, abrogated Has2 and Has2os2 induction. After knockdown of Has2 in SF, significantly less ␣-smooth muscle actin expression was detected in co-cultures. Moreover, it was investigated whether the phenotype of KYSE-410 was affected in co-culture with SF and whether Has2 knockdown in SF had an impact on KYSE-410 cells in co-culture. However, no effects on epithelial-mesenchymal transition markers, proliferation, and migration were detected. In addition to Has2 mRNA, the chemokine CCL5 was up-regulated and CCL11 was down-regulated in SF in co-culture. Furthermore, co-cultures of KYSE-410 cells and cancer-associated fibroblasts (CAF) were investigated. Similar to SF, Has2 and Ccl5 were up-regulated and Ccl11 was down-regulated in CAF in co-culture. Importantly and in contrast to SF, inhibiting HA synthesis by 4-methylumbelliferone abrogated the effect of co-culture on Ccl5 in CAF. Moreover, HA was found to promote adhesion of CD4 ؉ but not CD8 ؉ cells to xenogaft tumor tissues. In conclusion, direct co-culture of esophageal squamous cell carcinoma and fibroblasts induced stromal HA synthesis via Wnt/LEF1 and altered the chemokine profile of stromal fibroblasts, which in turn may affect the tumor immune response.

Human Microbiome Fusobacterium Nucleatum in Esophageal Cancer Tissue Is Associated with Prognosis

“…Accumulating evidence has demonstrated the crucial roles of chemokines and their receptors in tumor development and progression in several types of cancers (36)(37)(38)(39). Kretschmer and colleagues recently reported that esophageal SCC cells modulated chemokine expression in fibroblasts, affecting the tumor immune response (40). The most upregulated chemokine in F. nucleatumpositive esophageal cancers in the current study was CCL20.…”

Dissecting the role of hyaluronan synthases in the tumor microenvironment

“…In all cases, this enriched stroma can support HAS2 expression in tumor cells as well as stromal cells . Interestingly, HAS2 is one of the primary enzymes regulated in cancer‐associated fibroblasts suggesting the possibility that tumor cells induce stromal cells to produce HA. In breast cancers, a high HA deposition in the stroma is related to lymph node positivity, poor differentiation, and poor patient survival .…”

Esophageal Cancer Development: Crucial Clues Arising from the Extracellular Matrix

“…The tumor microenvironment plays a key role in tumor development and progression [15,[22][23][24][25][26]. This dynamic environment is formed by several cellular components that include not only cancer cells, but also fibroblasts, and immune and endothelial cells [15].…”