TGFβ1 overexpression is associated with improved survival and low tumor cell proliferation in patients with early-stage pancreatic ductal adenocarcinoma

Abstract

The role of transforming growth factor beta-type-1 (TGFβ1) in pancreatic ductal adenocarcinoma (PDAC) progression is stage-dependent. We hypothesized that TGFβ1 expression is associated with survival and proliferation markers in patients with early-stage PDAC. We acquired clinicopathologic, treatment, and mRNA expression data from The Cancer Genome Atlas data set for 106 patients identified with stage I/II PDAC who underwent pancreaticoduodenectomy. Patients were categorized as high expression when mRNA expression was ≥75th percentile for each gene. Average log2 mRNA expression of TGFβ1 in patients with high expression was 11.6 ± 0.2 and 10.5 ± 0.6 in patients with low expression (P<0.001). Low TGFβ1 expression is associated with shorter median survival compared with high TGFβ1 expression (17 versus at least 60 months; P=0.005). Patients with tumors demonstrating high MKI67 (the gene encoding Ki-67) expression have shorter median survival versus those with lowerMKI67 expression (16 versus 20 months; P=0.026). TGFβ1 and MKI67 are inversely associated (P=0.009). On multivariate analysis, improved survival is associated with TGFβ1 overexpression (P=0.017), adjuvant chemotherapy (P=0.001), and adjuvant radiotherapy (P=0.017), whereas positive surgical margins are associated with worse survival (P=0.002). In patients who undergo pancreaticoduodenectomy for PDAC, high TGFβ1 expression may counteract the worse survival associated with high proliferation.

IL23 and TGF-ß diminish macrophage associated metastasis in pancreatic carcinoma

“…Gene expression data was obtained from The Cancer Genome Atlas (TCGA) and analyzed as previously described 17 . Briefly, IL23 mRNA gene expression was quantified amongst all patients samples with PDAC in the TCGA.…”

“…TGF-ß has a paradoxical relationship with survival in PDAC patients where it is a tumor suppressor in early stage PDAC and a tumor promotor in late stage PDAC 15 – 17 . While TGF-ß is known to drive inflammation in the TME, the role of interleukins in this TGF-ß paradox is not well understood 16 , 18 .…”

Functions of pancreatic stellate cell-derived soluble factors in the microenvironment of pancreatic ductal carcinoma

“…In PDAC, TGF-β is a key signaling mediator involved in stroma–tumor cross-talk, epithelial–mesenchymal transition (EMT), and tumor invasion, in addition, TGF-β was found to be produced by PSCs in the tumor stroma [ 31 – 33 ]. In the classic TGF-β/SMAD signaling pathway, TGF-β combines with its receptor in PSCs, and the activated receptor phosphorylates SMAD2/SMAD3, which combines with SMAD4 and this combination will be translocated to the PSC nucleus [ 34 ]. Then, PSCs produce ECM proteins, i.e., collagen, which can promote desmoplastic stroma in PDAC.…”

Deeper insights into long-term survival heterogeneity of Pancreatic Ductal Adenocarcinoma (PDAC) patients using integrative individual- and group-level transcriptome network analyses

“…In this work, we identified known PDAC driver genes associated with survival, including ROBO2, ZG16B, and PLXNA1 28,29 (appendix pp 2). A thorough investigation of gene expression differences between LT and ST PDAC survivors highlighted gene involvement in immune responses (CEACAM20, C6orf13, IRS4, CXCL17), cell cycle (SPDYE3, HLA-DQA2, CLDN) and metabolic pathways (GBA3, LIPN), further highlighting the importance of these pathways in PDAC disease sruvival 30,31 . All of these findings evidence that genes linked to immune responses could be useful in effective therapies for PDAC survival 32 .…”