Interaction of the Sympathetic Nerve with Pancreatic Cancer Cells Promotes Perineural Invasion through the Activation of STAT3 Signaling

BackgroundPerineural invasion (PNI) is an important pathologic feature of pancreatic cancer, and the incidence of PNI in pancreatic cancer is 70%-100%. PNI is associated with poor outcome, metastasis, and recurrence in pancreatic cancer patients. There are very few treatments for PNI in pancreatic cancer. Honokiol (HNK) is a natural product that is mainly obtained from Magnolia species and has been indicated to have anticancer activity. HNK also has potent neurotrophic activity and may be effective for suppressing PNI. However, the potential role of HNK in the treatment of PNI in pancreatic cancer has not been elucidated.MethodsIn our study, pancreatic cancer cells were treated with vehicle or HNK, and the invasion and migration capacities were assessed by wound scratch assays and Transwell assays. A cancer cell-dorsal root ganglion coculture model was established to evaluate the effect of HNK on the PNI of pancreatic cancer. Western blotting was used to detect markers of EMT and neurotrophic factors in pancreatic tissue. Recombinant TGF-β1 was used to activate SMAD2/3 to verify the effect of HNK on SMAD2/3 and neurotrophic factors. The subcutaneous tumor model and the sciatic nerve invasion model, which were established in transgenic engineered mice harboring spontaneous pancreatic cancer, were used to investigate the mechanism by which HNK inhibits EMT and PNI in vivo.ResultsWe found that HNK can inhibit the invasion and migration of pancreatic cancer cells. More importantly, HNK can inhibit the PNI of pancreatic cancer. The HNK-mediated suppression of pancreatic cancer PNI was partially mediated by inhibition of SMAD2/3 phosphorylation. In addition, the inhibitory effect of HNK on PNI can be reversed by activating SMAD2/3. In vivo, we found that HNK can suppress EMT in pancreatic cancer. HNK can also inhibit cancer cell migration along the nerve, reduce the damage to the sciatic nerve caused by tumor cells and protect the function of the sciatic nerve.ConclusionOur results demonstrate that HNK can inhibit the invasion, migration, and PNI of pancreatic cancer by blocking SMAD2/3 phosphorylation, and we conclude that HNK may be a new strategy for suppressing PNI in pancreatic cancer.

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Pancreatic cancer-educated macrophages protect cancer cells from complement-dependent cytotoxicity by up-regulation of CD59

Cell Death and Disease ◽

10.1038/s41419-019-2065-4 ◽

2019 ◽

Vol 10 (11) ◽

Cited By ~ 4

Author(s):

Ronghua Zhang ◽

Qiaofei Liu ◽

Junya Peng ◽

Mengyi Wang ◽

Xiang Gao ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

Signaling Pathway ◽

In Vitro Study ◽

Stat3 Signaling ◽

Pancreatic Cancer Cells ◽

Complement Dependent Cytotoxicity ◽

Stat3 Signaling Pathway

Abstract Tumor-associated macrophages (TAMs) are versatile immune cells that promote a variety of malignant behaviors of pancreatic cancer. CD59 is a GPI-anchored membrane protein that prevents complement activation by inhibiting the formation of the membrane attack complex, which may protect cancer cells from complement-dependent cytotoxicity (CDC). The interactions between CD59, TAMs and pancreatic cancer remain largely unknown. A tissue microarray of pancreatic cancer patients was used to evaluate the interrelationship of CD59 and TAMs and their survival impacts were analyzed. In a coculture system, THP-1 cells were used as a model to study the function of TAMs and the roles of pancreatic cancer-educated macrophages in regulating the expression of CD59 in pancreatic cancer cells were demonstrated by real-time PCR, western blot and immunofluorescence staining. The effects of macrophages on regulating CDC in pancreatic cancer cells were demonstrated by an in vitro study. To explore the potential mechanisms, RNA sequencing of pancreatic cancer cells with or without co-culture of THP-1 macrophages was performed, and the results showed that the IL-6R/STAT3 signaling pathway might participate in the regulation, which was further demonstrated by target-siRNA transfection, antibody neutralization and STAT3 inhibitors. Our data revealed that the infiltration of TAMs and the expression of CD59 of pancreatic cancer were paralleled, and higher infiltration of TAMs and higher expression of CD59 predicted worse survival of pancreatic cancer patients. Pancreatic cancer-educated macrophages could protect cancer cells from CDC by up-regulating CD59 via the IL-6R/STAT3 signaling pathway. These findings uncovered the novel mechanisms between TAMs and CD59, and contribute to providing a new promising target for the immunotherapy of pancreatic cancer.

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