Abstract
Pancreatic cancer consists of a heterogenous bulk of tumor cells and stroma cells which contribute to tumor progression by releasing angiogenic factors. Those factors can be detected as circulating serum factors. We performed a compartment-specific analysis of tumor-derived and stroma-derived angiogenic factors to identify biomarkers and molecular targets for the treatment of pancreatic cancer. Kryo-frozen tissue from primary ductal adenocarcinomas (n = 51) was laser-microdissected to isolate tumor and stroma tissue. Expression of 17 angiogenic factors (angiopoietin-2, follistatin, GCSF, HGF, interleukin-8, leptin, PDGF-BB, PECAM-1, VEGF, matrix metalloproteinase -1, -2, -3, -7, -9, -10, -12, and -13) was analyzed using a multiplex elisa assay for tissue-derived proteins and corresponding serum. Our study reveals a compartment-specific expression profile for several angiogenic factors and matrix metalloproteinases. ROC analysis of corresponding serum samples reveals MMP-7 and MMP-12 as strong classifiers for the diagnosis of patients with pancreatic cancer vs. healthy control donors. High expression of tumor-derived PDGF-BB and MMP-1 correlates with prolonged survival in univariate and multivariate analysis. In conclusion, a distinct expression patterns for angiogenic cytokines and MMPs in pancreatic cancer and surrounding stroma may implicate them as novel targets for cancer treatment. Tumor-derived PDGF-BB and MMP-1 are significant and independent prognostic markers for poor survival.
Highlights
Pancreatic cancer is the fourth leading cause of cancer-related death in the Western hemisphere [1, 2]
Stage IV patients in our cohort received a similar postoperative treatment and follow-up with a curative attempt as patients with stage II or stage III pancreatic cancer. 28 specimens were diagnosed with a tumor grade of 2, 23 specimens were diagnosed with a tumor grade of 3
Pancreatic cancer is composed of a heterogenous bulk of tumor cells and adjacent stroma cells, with both of these compartments regulating tumor progression and dissemination through the release of angiogenesisassociated cytokines and matrix-metalloproteinases [17]
Summary
Pancreatic cancer is the fourth leading cause of cancer-related death in the Western hemisphere [1, 2]. The cumulative overall 5-year survival of all patients with pancreatic cancer remains less than 5%, with a median survival of 4 to 6 months [6]. In an effort to improve the clinical outcome of pancreatic cancer, there is an increasing focus on tailoring therapeutics to individual tumor biology [7]. This involves the use of prognostic biomarkers, including lymph node status, tumor differentiation grade, and tumor size [8,9,10]. Additional biomarkers are actively sought in an attempt to further stratify patients into different risk groups that might benefit from a more individualized therapy
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