Cancer-associated fibroblasts promote the migration and invasion of gastric cancer cells via activating IL-17a/JAK2/STAT3 signaling

Abstract

Background: Cancer-associated fibroblasts (CAFs), as the activated stroma cells, contribute to tumor progression via the release of cytokines, growth factors, and hormones. However, neither the factors produced by CAFs nor the molecular mechanisms were illuminated very well in gastric cancer (GC).Methods: Immunohistochemical staining of alpha-smooth muscle actin (α-SMA) was applied to examine the number of CAFs in GC samples from 227 patients. ELISA and qRT-PCR were performed to detect the expression of interleukin 17a (IL-17a). The migration and invasion of GC cells were determined by the Transwell assay. The expressions of JAK2, STAT3, MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured by western blotting. IL-17a was blocked with a polyclonal antibody, and JAK2/STAT3 signaling pathway was blocked by a specific inhibitor AG490.Results: High CAFs in GC tissues were positively correlated with advanced TNM stage and perineural invasion. Furthermore, GC patients with high CAFs in tumor tissues had an obvious worse disease-free survival (DFS) and disease-special survival (DSS). Multivariate analysis showed that high CAFs in GC tissues were an independent risk factor for DFS and DSS. CAFs expressed IL-17a significantly after GC cell co-culture. CAFs markedly enhanced the migration and invasion abilities of AGS and SGC-7901 cells.Moreover, CAFs co-culture resulted in increased levels of MMP2/9, reduced expressions of TIMP1/2, and activation of the JAK2/STAT3 signaling pathway in the GC cells. IL-17a neutralizing antibody or JAK2 inhibitor AG490 can significantly inhibit the effects of CAFs on the migration, invasion, MMP2/9, TIMP1/2, and JAK2/STAT3 pathways of GC cells.Conclusions: CAFs correlated with unfavorable clinical features and poor prognosis of GC patients. CAFs secreted IL-17a, which promoted the migration and invasion of GC cells through activating JAK2/STAT3 signaling. These results may identify IL-17a as a promising prognostic marker and therapeutic target of GC.

Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer

“…Constitutive activation of JAKs and STATs was first identified as being associated with malignancy, 227 and accumulating evidence has shown that CAF-mediated JAK/STAT signaling pathway is widely involved in human cancers, including prostate, 228 lung, 229 breast, 230 colorectal, 231 gastric, 232 endometrial, 233 liver, 234 and oral 235 cancers, through various tumor biological processes, including in increased cell plasticity, proliferation, migration, invasion, EMT, angiogenesis, and metastasis. Notably, IL-6 represents the most investigated cytokine regulating the crosstalk between CAFs and cancer cells (Table 3 ).…”

“…In addition, CAF-derived IL-17a significantly promoted the migration and invasion of gastric cancer cells by activating the JAK2/STAT3 signaling pathway, and the effects of CAF-mediated cancer progression were inhibited significantly by treatment with an IL-17a-neutralizing antibody or JAK2 inhibitor (AG490). 232 In addition, Heichler et al found that IL-11 was frequently overexpressed in colorectal cancer and acted as a signal transducer and activator of STAT3, which was inversely correlated with patient prognosis. 231 Taken together, therapeutic agents targeting the JAK/STAT signaling pathway, including blocking antibodies against Netrin-1, cytokines including IL-6, IL-11, and IL-17a, or inhibitors of JAK kinase such as AG490 or STAT activity such as STAT3 siRNA, could be useful agents in antitumor treatment.…”

Time density curve of dynamic contrast‑enhanced computed tomography correlates with histological characteristics of pancreatic cancer

“…Cytokeratin AE1/AE3 is a pan-epithelial marker. Although there is no specific marker for CAFs, αSMA is widely used as a CAF marker in various human cancer types, such as lung cancer ( 18 ), cholangiocarcinoma ( 19 ), gastric cancer ( 20 ) and breast cancer ( 21 ). CD31 is a pan-vascular endothelial marker that is positive for both normal endothelial and tumor endothelial cells ( 22 ).…”

Helicobacter pylori induces gastric cancer via down‐regulating miR‐375 to inhibit dendritic cell maturation

“…In a previous report, we showed that the growth of gastric cancer was inhibited by blocking the activation of the JAK2‐STAT3 signaling pathway 17 . Abnormal activation of JAK2‐STAT3 has been regarded as a significant factor for unfavorable clinical features and poor prognosis in gastric cancer patients 18 . Therefore, it is important to explore the factors that affect the JAK2‐STAT3 signaling pathway.…”

“…17 Abnormal activation of JAK2-STAT3 has been regarded as a significant factor for unfavorable clinical features and poor prognosis in gastric cancer patients. 18 Therefore, it is important to explore the factors that affect the JAK2-STAT3 signaling pathway.…”