Biomarkers of TGF-β Signaling Pathway and Prognosis of Pancreatic Cancer

Abstract

BackgroundTransforming growth factor (TGF)-β signaling pathway, may act both as a tumor suppressor and as a tumor promoter in pancreatic cancer, depending on tumor stage and cellular context. TGF-β pathway has been under intensive investigation as a potential therapeutic target in the treatment of cancer. We hypothesized a correlation between TGF-βR2/SMAD4 expression in the tumor, plasma TGF-β1 ligand level, genetic variation in TGF-B pathway and prognosis of pancreatic cancer.MethodWe examined TGF-βR2 and SMAD4 protein expression in biopsy or surgical samples from 91 patients with pancreatic ductal adenocarcinoma (PDAC) using immunohistochemistry. Plasma level of TGF-β1 was measured in 644 patients with PDAC using ELISA. Twenty-eight single nucleotide polymorphisms (SNP) of the TGF-β1, TGF-β2, TGF-β3, TGF-βR1, TGF-βR2, and SMAD4 genes were determined in 1636 patients with PDAC using the Sequenom method. Correlation between protein expression in the tumor, plasma TGF-β1 level, and genotypes with overall survival (OS) was evaluated with Cox proportional regression models.ResultsThe expression level of TGF-βR2 and SMAD4 as an independent marker was not associated with OS. However, patients with both low nuclear staining of TGF-βR2 and high nuclear staining of SMAD4 may have better survival (P = 0.06). The mean and median level of TGF-β1 was 15.44 (SD: 10.99) and 12.61 (interquartile range: 8.31 to 19.04) ng/ml respectively. Patients with advanced disease and in the upper quartile range of TGF-β1 level had significantly reduced survival than those with low levels (P = 0.02). A significant association of SMAD4 SNP rs113545983 with overall survival was observed (P<0.0001).ConclusionOur data provides valuable baseline information regarding the TGF-β pathway in pancreatic cancer, which can be utilized in targeted therapy clinical trials. High TGF-β1 plasma level, SMAD4 SNP or TGF-βR2/SMAD4 tumor protein expression may suggest a dependence on this pathway in patients with advanced pancreatic cancer.

Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver

“…High levels of TGFβ in patients with pancreatic cancers is associated with poor prognosis 42 . Anti-TGFβ compounds have shown efficacy in preclinical and clinical studies 43,44 , suppressing liver metastasis by acting on both incoming tumor cells and the liver microenvironment 45 .…”

A current perspective on stereotactic body radiation therapy for pancreatic cancer

“…A rapid autopsy study from Johns Hopkins showed a correlation between the loss of SMAD4/DPC4 expression and greater propensity for metastatic disease 8. Within the same pathway, high transforming growth factor-β1 plasma levels, the SMAD4 single-nucleotide polymorphism rs11354983, and high transforming growth factor-βR2/SMAD4 expression are similarly correlated with poor outcomes 35. SMAD4 is a stratification factor, alongside CA19-9 levels, in ongoing cooperative group studies 36…”

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

“…TGF-β ligand expression is elevated in PDAC, and patients with high levels of TGF-β1 ligand in their serum have a significantly worse prognosis (46). However, mutations that inactive the canonical TGF-β-Smad signaling pathway are common in PDAC, with around 55% of PDAC patients having inactivating mutations in SMAD4 (47).…”