Abstract
Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in tumor stroma, are important modifiers of tumor progression. However, the molecular mechanisms underlying the tumor-promoting properties of CAFs in gastric cancer remain unclear. Here, we show that CAFs isolated from gastric cancer produce significant amounts of interleukin-6 (IL-6). CAFs enhances the migration and EMT of gastric cancer cells through the secretion of IL-6 that activates Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT3) pathway in gastric cancer cells, while deprivation of IL-6 using a neutralizing antibody or inhibition of JAK/STAT3 pathway with specific inhibitor AG490 markedly attenuates these phenotypes in gastric cancer cells induced by CAFs. Moreover, silencing IL-6 expression in CAFs or inhibiting JAK2/STAT3 pathway in gastric cancer cells impairs tumor peritoneal metastasis induced by CAFs in vivo. Taken together, these results suggest that CAFs in the tumor microenvironment promote the progression of gastric cancer through IL-6/JAK2/STAT3 signaling, and IL-6 targeted therapy could be a complementary approach against gastric cancer by exerting their action on stromal fibroblasts.
Highlights
Gastric cancer, one of the most common primary malignant tumors, is the third leading cause of cancer death in worldwide with the highest estimated mortality rates in Eastern Asia [1]
We found IL-6 level were significantly higher in Cancer-associated fibroblasts (CAFs) compared to normal fibroblasts (NFs) and gastric cancer cells (Figure 1D)
We demonstrate that IL-6 secreted by CAFs plays an important role in the progression of gastric cancer
Summary
One of the most common primary malignant tumors, is the third leading cause of cancer death in worldwide with the highest estimated mortality rates in Eastern Asia [1]. Epithelial-mesenchymal transition (EMT), a wellcharacterized embryological process, has been identified to play a critical role in tumor progression, including invasion and metastasis, by which cancer cells could gain more aggressive properties. The enhanced motility and invasiveness afforded by EMT is critical in the initiation of metastasis for cancer progression, and the acquisition of a mesenchymal phenotype has been enhanced resistance to chemotherapy and poor prognosis [6, 7].The expression of these EMT markers can be induced by a number of growth factors/cytokines such as hepatocyte growth factor (HGF), transforming growth factor (TGF)-β, CXCL12 and hypoxia-inducible factor-1α (HIF-1α) [8,9,10,11]
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