Glycemic Variability Promotes Both Local Invasion and Metastatic Colonization by Pancreatic Ductal Adenocarcinoma

Abstract

Background & AimsAlthough nearly half of pancreatic ductal adenocarcinoma (PDAC) patients have diabetes mellitus with episodes of hyperglycemia, its tumor microenvironment is hypoglycemic. Thus, it is crucial for PDAC cells to develop adaptive mechanisms dealing with oscillating glucose levels. So far, the biological impact of such glycemic variability on PDAC biology remains unknown.MethodsMurine PDAC cells were cultured in low- and high-glucose medium to investigate the molecular, biochemical, and metabolic influence of glycemic variability on tumor behavior. A set of in vivo functional assays including orthotopic implantation and portal and tail vein injection were used. Results were further confirmed on tissues from PDAC patients.ResultsGlycemic variability has no significant effect on PDAC cell proliferation. Hypoglycemia is associated with local invasion and angiogenesis, whereas hyperglycemia promotes metastatic colonization. Increased metastatic colonization under hyperglycemia is due to increased expression of runt related transcription factor 3 (Runx3), which further activates expression of collagen, type VI, alpha 1 (Col6a1), forming a glycemic pro-metastatic pathway. Through epigenetic machinery, retinoic acid receptor beta (Rarb) expression fluctuates according to glycemic variability, acting as a critical sensor relaying the glycemic signal to Runx3/Col6a1. Moreover, the signal axis of Rarb/Runx3/Col6a1 is pharmaceutically accessible to a widely used antidiabetic substance, metformin, and Rar modulator. Finally, PDAC tissues from patients with diabetes show an increased expression of COL6A1.ConclusionsGlycemic variability promotes both local invasion and metastatic colonization of PDAC. A pro-metastatic signal axis Rarb/Runx3/Col6a1 whose activity is controlled by glycemic variability is identified. The therapeutic relevance of this pathway needs to be explored in PDAC patients, especially in those with diabetes.

COL6A1 promotes metastasis and predicts poor prognosis in patients with pancreatic cancer

“…However, our findings did not indicate a significant association between local lymph node metastasis and COL6A1 expression. In line with studies reporting a positive relationship between COL6A1 and distant metastasis (36), we found that 73.1% of COL6A1 + patients had distant metastasis. Also, 76.9% of our patients with COL6A1 expression had vascular encroachment at the time of surgery.…”

“…Several studies have detected increased expression of COL6A1 in tumors and is associated with tumor progression (36,37). Other reports have also shown that collagen VI can promote the adhesion, penetration and invasion of tumor cells in an autocrine manner (18).…”

“…In a quantitative secretomics functional analysis of metastasis-associated proteins, COL6A1 expression was reported to enhance metastatic abilities, while RNA interference-based knockdown of COL6A1 suppressed the metastatic activity of lung cancer cells (20). Furthermore, the migratory and metastatic activity of PC via runt-related transcription factor 3 (Runx3) signaling can be induced by the expression of COL6A1 (36,38). In our research, COL6A1 was found to be upregulated in BxPC-M8, and was associated with increased invasive and metastatic ability compared with parent BxPC-3 cells, suggesting a potential pro-metastatic role in PC.…”

Hyperglycemia enhances pancreatic cancer progression accompanied by elevations in phosphorylated STAT3 and MYC levels

“…A high-glucose environment without glycemic pretreatment triggers an invasive character with an elevation in pERK expression in pancreatic cancer cells [32,33]. When incubated for more than 4 weeks in high-or low-glucose medium, high-glucose medium-pretreated Kras-mutant pancreatic cancer cells show an enhanced metastatic ability, while low-glucose medium-maintained cells show a stronger tendency toward local invasion [34]. In our study, 72-hr incubation in a low-or high-glucose medium produced no changes in cell viability or sphere formation; however, after 28 days of pretreatment, the cell characteristics dramatically changed, with the promotion of cell proliferation and tumorigenesis.…”

RUNX family: Oncogenes or tumor suppressors (Review)

“…RUNX3 expression has been associated with mothers against decapentaplegic homolog 4 (SMAD4, also known as DPC4) copy number variants, and level patterns have been directly associated with relapse and the response to therapies (160). RUNX3 expression has also been associated with combined epigenetic programs and metabolic processes when it is part of the retinoic acid receptor β/RUNX3/collagen α-1(VI) chain signal axis, linking hypoglycemia with local invasion and angiogenesis, and hyperglycemia with metastatic colonization (162).…”