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.

Curcumin attenuates hyperglycemia-driven EGF-induced invasive and migratory abilities of pancreatic cancer via suppression of the ERK and AKT pathways

“…Diabetes mellitus improves following pancreatectomy, suggesting that diabetes may be induced by pancreatic cancer (6). Our previous studies confirmed that a hyperglycemic condition could promote the proliferation, invasion, epithelial-mesenchymal transition (EMT) as well as the metastasis of pancreatic cancer (7,8).…”

“…Hyperglycemic conditions could worsen the prognosis of pancreatic cancer by enhancing invasive ability and promoting epithelial-mesenchymal transition (EMT) through the production of hydrogen peroxide (8). In addition, diabetes mellitus was also found to enhance perineural invasion in pancreatic cancer patients and to aggravate a poor prognosis (7). It has been verified that the addition of 5.5 and 25 mM glucose resulted in balanced osmotic pressure inside and outside the cell membrane (21), thus we used 5.5 and 25 mM of glucose as it has been applied worldwide in the related field as a classical high glucose model in the cell culture.…”

Regulation of Heparanase in Diabetes-Associated Pancreatic Carcinoma

“…Additionally, ability of the enzyme to augment insulin/insulin-like growth factor 1 receptor signaling (76,77), along with the well-documented hyperinsulinemia in PDAC patients [either in the setting of new inset or longstanding diabetes (3,8,9)], suggests that in heparanase-rich PDAC microenvironment insulin is expected to induce stronger pro-tumorigenic response. Thus, heparanase induction appears to be a part of the mechanism(s) through which diabetic state promotes PDAC and renders it highly aggressive, therapyresistant and associated with particularly poor prognosis (3,4,(10)(11)(12).…”

“…Additionally, positive association was reported between PDAC and insulin resistance/hyperinsulinemia (3,8,9). Conversely, recent reports suggest that diabetic state promotes PDAC and renders it highly aggressive, resistant to the existing therapies, and is associated with extremely poor prognosis (3,4,(10)(11)(12). Hence, PDAC and diabetes exhibit a unique bidirectional relationship, with diabetes being both an effect and etiological factor of the pancreatic cancer (3,4,11).…”

Sweet Predictions Speak Volumes for Early Detection of Pancreatic Cancer

“…10 KRAS further induces abnormal mitochondrial metabolism and enhance glycolysis, with alterations in glutamine and lipid metabolism. 14 As extrinsic factors, the acidic and oxygen/nutrient-deprived microenvironment also induces cancer cells to reprogram their metabolic pathway and exploit the ability of cancerassociated fibroblasts and immunocytes to communicate, thereby adapting to metabolic stress. 14 Secreted products of these cells may be used as biomarkers.…”