Differential Expression of Polyamine Pathways in Human Pancreatic Tumor Progression and Effects of Polyamine Blockade on Tumor Microenvironment

Abstract

Pancreatic cancer is the fourth leading cause of cancer death. Existing therapies only moderately improve pancreatic ductal adenocarcinoma (PDAC) patient prognosis. The present study investigates the importance of the polyamine metabolism in the pancreatic tumor microenvironment. Relative mRNA expression analysis identified differential expression of polyamine biosynthesis, homeostasis, and transport mediators in both pancreatic epithelial and stromal cells from low-grade pancreatic intraepithelial neoplasia (PanIN-1) or primary PDAC patient samples. We found dysregulated mRNA levels that encode for proteins associated with the polyamine pathway of PDAC tumors compared to early lesions. Next, bioinformatic databases were used to assess expression of select genes involved in polyamine metabolism and their impact on patient survival. Higher expression of pro-polyamine genes was associated with poor patient prognosis, supporting the use of a polyamine blockade therapy (PBT) strategy for inhibiting pancreatic tumor progression. Moreover, PBT treatment of syngeneic mice injected intra-pancreatic with PAN 02 tumor cells resulted in increased survival and decreased tumor weights of PDAC-bearing mice. Histological assessment of PBT-treated tumors revealed macrophage presence and significantly increased expression of CD86, a T cell co-stimulatory marker. Collectively, therapies which target polyamine metabolism can be used to disrupt tumor progression, modulate tumor microenvironment, and extend overall survival.

Salivary Metabolomics for Oral Cancer Detection: A Narrative Review

“…Recently, polyamine-related aberrance was reported in PC. A transcriptomics study found that the gene expression of proteins associated with polyamine synthesis pathways is associated with the prognosis of PC [ 46 ]. In addition, polyamine concentration patterns accurately distinguished among PC, chronic pancreatitis, and HC samples [ 47 ].…”

Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses

“…Interestingly, although combined DFMO (1% w/v) and Trimer PTI (1.8 mg/kg) conferred significant survival benefits in the orthotopic Pan02 model of gemcitabine-resistant pancreatic cancer, it did not further reduce tumor burden when compared to DFMO or PTI alone [31]. Nakkina et al increased the Trimer44NMe dosage to 4 mg/kg, (DFMO: 0.25% w/v) and observed a significant increase in survival, reduction in Pan02 pancreatic tumor burden, and increase in co-stimulatory marker CD86 expression when compared to either treatment alone [32].…”

Potential Metabolite Markers for Pancreatic Cancer Identified by Metabolomic Analysis of Induced Cancer-Associated Fibroblasts

“…Polyamines are involved in various physiological functions, such as cell division and proliferation, and nucleic acid and protein synthesis; studies have also determined their roles in cancer cells [29][30][31]. Since we identified several polyamine metabolites in the PC2 axis in the PCA analysis (Figure 1), we also analyzed the polyamine synthesis pathway.…”