Recent evidence from large cohort studies suggests that there exists a higher cancer incidence in people with type 2 diabetes (DM2). However, to date, the potential reasons for this association remain unclear. Hyperglycemia, the most important feature of diabetes, may be responsible for the excess glucose supply for these glucose-hungry cells, and it contributes to apoptosis resistance, oncogenesis, and tumor cell resistance to chemotherapy. Considering associations between diabetes and malignancies, the effect of hyperglycemia on cancer progression in cancer patients with abnormal blood glucose should not be neglected. In this paper, we describe the role that hyperglycemia plays in cancer progression and treatment and illustrate that hyperglycemia may contribute to a more malignant phenotype of cancer cells and lead to drug resistance. Therefore, controlling hyperglycemia may have important therapeutic implications in cancer patients.

BackgroundHypoxia plays a vital role in cancer epithelial to mesenchymal transition (EMT) and invasion. However, it is not quite clear how hypoxia may contribute to these events. Here we investigate the role of Hedgehog (Hh) signaling in hypoxia induced pancreatic cancer EMT and invasion.MethodsPancreatic cancer cells were cultured under controlled hypoxia conditions (3% O2) or normoxic conditions. HIF-1α siRNA, cyclopamine (a SMO antagonist) and GLI1 siRNA were used to inhibit HIF-1α transcription or Hh signaling activation. The effect of hypoxia and Hh signaling on cancer cell EMT and invasion were evaluated by Quantitative real-time PCR analysis, Western blot analysis and invasion assay.ResultsHere, we show that non-canonical Hh signaling is required as an important role to switch on hypoxia-induced EMT and invasion in pancreatic cancer cells. Moreover, our data demonstrate hypoxia induces EMT process as well as invasion, and activates the non-canonical Hh pathway without affecting sonic hedgehog homolog (SHH) expression. Moreover, these effects are reversible upon HIF-1α siRNA interference with unchanged SHH and patched1 (PTCH1) level. Furthermore, our data demonstrate that hypoxia induced invasion and EMT process are effectively inhibited by Smoothened (SMO) antagonist cyclopamine and GLI1 siRNA. In addition, GLI1 interference inhibited EMT progress with significantly suppressed vimentin expression, whereas inhibition of SMO through cyclopamine could not reduce vimentin level. This data indicate that hypoxia could trigger other factors (such as TGF-β, KRAS or RTK) bypassing SMO to activate GLI1 directly.ConclusionsOur findings suggest that Hh signaling modulates hypoxia induced pancreatic cancer EMT and invasion in a ligand-independent manner. Thus, Hh signaling may represent a promising therapeutic target for preventing pancreatic cancer progression.

In our previous study, we found that blockade of SDF-1/CXCR4 signaling inhibits pancreatic cancer cell migration and invasion in vitro. However, the mechanism governing the downstream regulation of SDF-1/CXCR4-mediated invasion remains unclear. Here we report the role of SDF-1/CXCR4 in pancreatic cancer and the possible mechanism of SDF-1/CXCR4-mediated pancreatic cancer invasion. We show that there is a cross-talk between SDF-1/CXCR4 axis and non-canonical Hedgehog (Hh) pathway in pancreatic cancer. Furthermore, our data demonstrate that the ligand of CXCR4, SDF-1 induces CXCR4-positive pancreatic cancer invasion, epithelial–mesenchymal transition (EMT) process and activates the non-canonical Hh pathway. Moreover, we also demonstrate that the invasion of a pancreatic cancer and EMT resulting from the activation of SDF-1/CXCR4 axis is effectively inhibited by Smoothened (SMO) inhibitor cyclopamine and siRNA specific to Gli-1. Collectively, these data demonstrate that SDF-1/CXCR4 modulates the non-canonical Hh pathway by increasing the transcription of SMO in a ligand-independent manner. Taken together, SDF-1/CXCR4 axis may represent a promising therapeutic target to prevent pancreatic cancer progression.

Purpose: Pancreatic cancer is characterized by stromal desmoplasia and perineural invasion (PNI). We sought to explore the contribution of pancreatic stellate cells (PSC) activated by paracrine Sonic Hedgehog (SHH) in pancreatic cancer PNI and progression.Experimental Design: In this study, the expression dynamics of SHH were examined via immunohistochemistry, real-time PCR, and Western blot analysis in a cohort of carcinomatous and nonneoplastic pancreatic tissues and cells. A series of in vivo and in vitro assays was performed to elucidate the contribution of PSCs activated by paracrine SHH signaling in pancreatic cancer PNI and progression.Results: We show that SHH overexpression in tumor cells is involved in PNI in pancreatic cancer and is an important marker of biologic activity of pancreatic cancer. Moreover, the overexpression of SHH in tumor cells activates the hedgehog pathway in PSCs in the stroma instead of activating tumor cells. These activated PSCs are essential for the promotion of pancreatic cancer cell migration along nerve axons and nerve outgrowth to pancreatic cancer cell colonies in an in vitro three-dimensional model of nerve invasion in cancer. Furthermore, the coimplantation of PSCs activated by paracrine SHH induced tumor cell invasion of the trunk and nerve dysfunction along sciatic nerves and also promoted orthotropic xenograft tumor growth, metastasis, and PNI in in vivo models.Conclusions: These results establish that stromal PSCs activated by SHH paracrine signaling in pancreatic cancer cells secrete high levels of PNI-associated molecules to promote PNI in pancreatic cancer. Clin Cancer Res; 20(16); 4326-38. Ó2014 AACR.

Resveratrol (trans-3,4′,5-trihydroxystilbene), a natural polyphenolic compound detected in grapes, berries, and peanuts, possesses a wide spectrum of pharmacological properties, including anti-tumor metastasis activities. However, the underlying mechanisms through which resveratrol inhibits the metastasis of pancreatic cancer are still not fully elucidated. As epithelial-to-mesenchymal transition (EMT) is a key player for metastasis in tumor, the aim of this study is to determine whether resveratrol affects EMT in pancreatic cancer cells and the related mechanism. The results showed that resveratrol not only inhibited cell proliferation, migration, and invasion in a dose-dependent manner, but also mediated the expression of EMT-related genes (E-cadherin, N-cadherin, vimentin, MMP-2, and MMP-9) which are important for cancer cellular motility, invasiveness and metastasis during tumorigenesis. In addition, the levels of phospho-Akt and phospho-NF-κB in BxPC-3 and Panc-1 cells were reduced by both resveratrol and LY294002 (a PI3-K inhibitor). Furthermore, transforming growth factor-β (TGF-β)-induced alterations in cell morphology that are characteristic of EMT as well as increased cell invasive ability could also be reversed by resveratrol. Taken together, these data indicate that resveratrol suppresses pancreatic cancer migration and invasion through the inhibition of the PI-3K/Akt/NF-κB signaling pathway. This study suggests that resveratrol may be a potential anticancer agent for pancreatic cancer.