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Diabetes promotes the progression of pancreatic ductal adenocarcinoma via the interaction between transforming acinar cells and cancer cells through AKT/CEBPβ/LCN2 pathway
Background
Pancreatic cancer, in which pancreatic ductal adenocarcinoma (PDAC) is the most common type, ranks the seventh most leading cause of cancer death in both sexes. PDAC is characterized by dense stroma (desmoplastic). PDAC possess high metastatic potency and display poor response to standard chemotherapies and immunotherapy that is thought to result from desmoplasia. In fact, most PDAC have undergone metastasis at the time of diagnosis thus contributing to extremely low five-year survival rate. One of the considerable risks contributing to the increase of pancreatic cancer prevalence and malignancy is diabetes mellitus (DM). However, the role of diabetes contributing to pancreatic cancer development and metastasis has not been clearly determined. Without tumors, DM itself could affect the microenvironment and immune system. Therefore, we analyzed the alteration in tumor microenvironment that enhanced the formation and progression of PDAC under diabetic condition. We also dissected the interaction between transforming acinar cells and cancer cells through LCN2, a protein functioning on both microenvironment and immunity, that contributed to the metastasis of PDAC.
Methods
PDAC-DM model was established by orthotopic engrafting mouse PDAC cell lines (Pan18GL) on the multi-low-dose of Streptozocin (MLDS)-induced diabetic C57BL/6J mice. The expression of LCN2 was assessed on both 266-6 acinar cells and PDAC tissues. Knockdown LCN2 receptor (SLC22A17) on Pan18GL was conducted to demonstrate the impact of extrinsic LCN2 on the malignancy of PDAC. PDAC exosome proteomics was done to analyze potential interaction pathway between PDAC cells and transforming acinar cells.
Results
In our study, we confirmed the alteration of tumor microenvironment under diabetes including abundant fibrosis and immune changes toward immunosuppression, which may promote the metastasis and mortality of DM-PDAC individuals. In detail, there was a decrease in systemic and tumor-infiltrating CD8 + -T cells as well as an increase in tumor-infiltrating CD4 + /CD25 + -T cells, which represented for regulatory T cells, in diabetic mice. LCN2 was up-regulated on transforming acinar parts and tumor-infiltrating neutrophils in diabetes. Knockdown LCN2 receptor on cancer cells led to the decrease in cancer cell migration, invasion and tumor metastasis. This implied the role of extrinsic LCN2 on cancer cell invasion, but not intrinsic LCN2. Notably, only acinar cells exposed to cancer cells under high glucose condition expressed high LCN2 suggesting the interaction between transforming acinar cells and cancer cells in diabetes. Indeed, we found that exosomes which were secreted from high glucose-cultured cancer cells possessed an abundance of proteins related to AKT pathway to enhance the AKT/CEBPβ/LCN2 activation.
Conclusions
To our best knowledge, the study is the first study which dissected the role of extrinsic transforming-acinar-cell-derived LCN2 on the progression of PDAC under the impact of diabetes. In addition, we also demonstrated the interaction of cancerous epithelial cells and their tumor microenvironment in high glucose through AKT/CEBPβ/LCN2 pathway. The findings suggested that control of diabetes could prevent not only diabetic complications but also the progression of PDAC in sensitive Kras-mutant individuals. In addition, diabetic PDAC patients can benefit from the treatments which target on AKT/CEBPβ/LCN2 pathway.
Legal entity responsible for the study
The author.
Funding
Has not received any funding.
Disclosures
All authors have declared no conflicts of interest.
