Initiation of Pancreatic Cancer: The Interplay of Hyperglycemia and Macrophages Promotes the Acquisition of Malignancy-Associated Properties in Pancreatic Ductal Epithelial Cells

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is still one of the most aggressive solid malignancies with a poor prognosis. Obesity and type 2 diabetes mellitus (T2DM) are two major risk factors linked to the development and progression of PDAC, both often characterized by high blood glucose levels. Macrophages represent the main immune cell population in PDAC contributing to PDAC development. It has already been shown that pancreatic ductal epithelial cells (PDEC) undergo epithelial–mesenchymal transition (EMT) when exposed to hyperglycemia or macrophages. Thus, this study aimed to investigate whether concomitant exposure to hyperglycemia and macrophages aggravates EMT-associated alterations in PDEC. Exposure to macrophages and elevated glucose levels (25 mM glucose) impacted gene expression of EMT inducers such as IL-6 and TNF-α as well as EMT transcription factors in benign (H6c7-pBp) and premalignant (H6c7-kras) PDEC. Most strikingly, exposure to hyperglycemic coculture with macrophages promoted downregulation of the epithelial marker E-cadherin, which was associated with an elevated migratory potential of PDEC. While blocking IL-6 activity by tocilizumab only partially reverted the EMT phenotype in H6c7-kras cells, neutralization of TNF-α by etanercept was able to clearly impair EMT-associated properties in premalignant PDEC. Altogether, the current study attributes a role to a T2DM-related hyperglycemic, inflammatory micromilieu in the acquisition of malignancy-associated alterations in premalignant PDEC, thus providing new insights on how metabolic diseases might promote PDAC initiation.

Macrophage-Related SPP1 as a Potential Biomarker for Early Lymph Node Metastasis in Lung Adenocarcinoma

“… Deng et al (2010) found that the abundant expression of tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) by macrophages can create a favorable inflammatory environment for the occurrence of colonic adenocarcinomas. Moreover, macrophages play a considerable role in the acquisition of the epithelial– mesenchymal transition (EMT) hallmarks observed in gastric cancer tissues ( Guan et al, 2021 ), pancreatic duct epithelial cells ( Otto et al, 2021 ), and tracheal epithelial cells ( Li et al, 2021 ), and EMT signatures plays a vital role in tumor metastasis ( Lu and Kang, 2019 ). Macrophages are heterogeneous cell clusters with intricate functions and forms.…”

Proteogenomic insights into the biology and treatment of pancreatic ductal adenocarcinoma

“…Intriguingly, combined with clinical features, we found the blood glucose were comparatively lower in Im-3 (featured with metabolism). Previous studies have indicated that the alteration of blood glucose levels greatly affected tumor microenvironment and patients’ prognosis [ 68 ]. Consistently, our data indicated blood glucose was negatively associated with overall survival (Fig.…”

STAT3 Inhibitors: A Novel Insight for Anticancer Therapy of Pancreatic Cancer

“…Tocilizumab has been shown to exert anticancer effects in pancreatic cancer in ex vivo experiments. In a mouse transplantation tumor model, tocilizumab blockade of IL-6 significantly abrogated mesenchymal stromal cell-mediated tumor promotion and delayed tumor formation [ 97 ], and inhibition of IL-6 signaling by tocilizumab partially reversed the EMT phenotype of pancreatic ductal epithelial Kras mutant cells [ 98 ]. PSCs and cancer cells in pancreatic cancer TME release ATP, which activates the P2X7 receptor, promoting PSC proliferation, collagen secretion, and IL-6 secretion, and P2X7R-conditioned cultures also stimulate PSCs to activate the JAK/STAT3 signaling pathway in cancer cells, leading to pancreatic cancer cell migration, which is inhibited by tocilizumab [ 99 ].…”