Abstract
Recent studies indicate that cancer-associated fibroblasts (CAFs) are involved in tumor growth, invasion and metastasis, however, the underling mechanisms remain unclear. In the present study, we investigated the role of CAFs on the metastatic potential of lung cancer cells. The stromal fibroblasts we isolated from lung cancer tissues presented CAFs characteristics with high levels of α-smooth muscle actin (α-SMA) and fibroblast-activating protein (FAP). Our data showed that the conditioned medium from cultured CAFs (CAF-CM) dramatically enhanced migration and invasion of lung cancer cells. CAF-CM induced epithelial-mesenchymal transition (EMT) by regulating the expression of EMT-associated markers E-cadherin and vimentin, and also modulated metastasis-related genes MMP-2 and VEGF both in vitro and in vivo. Further mechanistic studies demonstrated that CAFs enhanced the metastatic potential of lung cancer cells by secreting IL-6, subsequently activating of JAK2/STAT3 signaling pathway. Additionally, the inhibition of IL-6/STAT3 signaling pathway by IL-6 neutralizing antibody or specific inhibitors of JAK2/STAT3 reversed CAF-CM induced EMT and migration of lung cancer cells. Taken together, these findings revealed a novel mechanism that CAFs induced EMT and promoted metastasis of lung cancer cells through the IL-6/STAT3 signaling pathway.
Highlights
Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death among males and the second leading cause of cancer death among females
We examined the mRNA expression of the activated myofibroblast marker α-smooth muscle actin (α-SMA) and fibroblast-activating protein (FAP) in cancer-associated fibroblasts (CAFs), normal fibroblasts (NFs) and lung cancer cell line A549 and SK-MES-1 cells by quantitative PCR (qPCR)
Lung cancer A549 and SK-MES-1 cells expressed high level of E-cadherin, and low level of α-SMA and vimentin (Figure 1C, 1D). These results suggest that primary cultured fibroblasts derived from patients with lung cancer retain the features of CAFs and NFs
Summary
Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death among males and the second leading cause of cancer death among females. It is estimated that there were 1.8 million new cases and 1.6 million deaths annually, accounting for about 19% of all cancer deaths [1]. The majority of lung cancer is non-small cell lung cancer (NSCLC), which comprises approximately 85% of total lung cancer. Tumor metastasis is a complicated biological process, including intravasation, extravasation, colonization, and many genes and signaling pathways are involved [3]. Numerous studies showed that the metastasis potential of cancer cells intensively depends on the tumor microenvironment [4]. Cancer-associated fibroblasts (CAFs) are one of the major components in the tumor stroma, they display a specific subset of markers, www.impactjournals.com/oncotarget including α-smooth muscle actin (α-SMA), fibroblastactivating protein (FAP), fibroblast-specific protein-1 (FSP1), tenascin C, and neural-glial antigen [5]
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