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Hyperglycemic tumor microenvironment induces perineural invasion in pancreatic cancer.

ABSTRACT: Glucose intolerance and frank diabetes mellitus (DM) can increase the risk of cancer death for pancreatic cancer (PanCa). However, the mechanism by which these factors influence cancer deaths is not clear. In this study, we established a model system to mimic the pancreatic tumor microenvironment in patients with DM to examine the biological behavior of PanCa cells and nerves in cell culture and in animals. Our in vitro studies demonstrated that hyperglycemia promoted the proliferation and invasion of PanCa cell lines and upregulated the expression of nerve growth factor in these cells. Also, the migration of Schwann cells (SCs) was inhibited by hyperglycemia and neurites exerted pathological regeneration. Furthermore, the interaction between the PanCa cells and nerves was enhanced in the tumor microenvironment. We further showed that hyperglycemia promoted the perineural invasion (PNI) of PanCa in vivo. These data suggest that DM worsens the prognosis of PanCa because of aggravated PNI. Thus, our study illustrates a novel mechanism by which hyperglycemia decreases survival in patients with PanCa.

SUBMITTER: Li J

PROVIDER: S-EPMC4623034 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Hyperglycemic tumor microenvironment induces perineural invasion in pancreatic cancer.

Li Junhui J Ma Jiguang J Han Liang L Xu Qinhong Q Lei Jianjun J Duan Wanxing W Li Wei W Wang Fengfei F Wu Erxi E Ma Qingyong Q Huo Xiongwei X

Cancer biology & therapy 20150506 6

Glucose intolerance and frank diabetes mellitus (DM) can increase the risk of cancer death for pancreatic cancer (PanCa). However, the mechanism by which these factors influence cancer deaths is not clear. In this study, we established a model system to mimic the pancreatic tumor microenvironment in patients with DM to examine the biological behavior of PanCa cells and nerves in cell culture and in animals. Our in vitro studies demonstrated that hyperglycemia promoted the proliferation and invas ...[more]

PMID: 25946624

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Project description: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.

Project description:BACKGROUND:Cachexia is responsible for the low quality of life in pancreatic adenocarcinoma (PDAC). The rapid disease progression and patient deterioration seems related to perineural invasion, but the relationship between cachexia and perineural invasion for the evolution of the disease has been rarely studied. As perineural invasion is difficult to be highlighted, a biomarker such as the neurotrophic factor Midkine (MK) which promotes the neuronal differentiation and the cell migration could be helpful. Also, Activin (ACV) has been described as cachexia related to PDAC. However, their role for assessing and predicting the disease course in daily practice is not known. AIM:To assess the relationship between perineural invasion and cachexia and their biomarkers, MK and ACV, respectively, and their prognostic value. METHODS:This study included prospectively enrolled patients with proven adenocarcinoma and a matched group of controls without any malignancies. Patients with other causes of malnutrition were excluded. The plasma levels of ACV and MK were analyzed using western blotting and were correlated with the clinicopathological features and survival data. These results were validated by immunohistochemical analyses of the pancreatic tumor tissue of the patients included in the study and a supplementary group of surgically resected specimens from patients with a benign disease. RESULTS:The study comprised 114 patients with PDAC, 125 controls and a supplementary group of 14 benign pancreatic tissue samples. ACV and MK were both overexpressed more frequently in the plasma of patients with PDAC than in the controls (63% vs 32% for ACV, P < 0.001; 47% vs 16% for MK, P < 0.001), with similar levels in pancreatic tissue the MK protein expression was closely related to the advanced clinical stage (P = 0.006), the presence of metastasis (P = 0.04), perineural invasion (P = 0.03) and diabetes (P = 0.002), but with no influence on survival. No correlation between clinicopathological factors and ACV expression was noted. Cachexia, present in 19% of patients, was unrelated to ACV or MK level. Higher ACV expression was associated with a shorter survival (P = 0.008). CONCLUSION:The MK was a biomarker of perineural invasion, associated with tumor stage and diabetes, but without prognostic value as ACV. Cachexia was unrelated to perineural invasion, ACV level or survival.

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Hyperglycemic tumor microenvironment induces perineural invasion in pancreatic cancer.

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Hyperglycemic tumor microenvironment induces perineural invasion in pancreatic cancer.

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