α-Smooth Muscle Actin Expressing Stroma Promotes an Aggressive Tumor Biology in Pancreatic Ductal Adenocarcinoma

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Abstract
Objectives: Pancreatic ductal adenocarcinoma (PDAC) is often characterized by a prominent desmoplastic stroma that is induced partially by α-smooth muscle actin (SMA)-expressing activated pancreatic stellate cells (PSCs). This study aimed to investigate the significance of α-SMA expression in PDAC and the correlation between α-SMA mRNA levels and the patient prognosis. Methods: We obtained formalin-fixed, paraffin-embedded tissue samples from 109 patients with PDAC, who underwent pancreatectomy at our institution from 1992 to 2007. We measured α-SMA mRNA levels by quantitative real-time reverse transcription-polymerase chain reaction and investigated the association of α-SMA mRNA expression with clinicopathologic parameters and survival time. We also assessed the influence of activated PSCs on malignant behaviors of pancreatic cancer cells using in vitro experiments. Results: α-SMA immunoreactivity was detected exclusively in the stroma of PDAC. The group with high α-SMA expression showed a significantly shorter survival, as shown by univariate analysis (P = 0.005) and multivariate analysis (P < 0.0001). α-SMA-expressing activated PSCs enhanced the invasiveness, proliferation, and colony formation of pancreatic cancer cells. Conclusions: Quantitative analysis of α-SMA mRNA expression using formalin-fixed, paraffin-embedded tissue samples was useful to predict the prognosis of patients with PDAC. Activated PSCs may regulate the malignant behavior of pancreatic cancer cells. Abbreviations: PDAC - pancreatic ductal adenocarcinoma, PSCs - pancreatic stellate cells, α-SMA - α-smooth muscle actin, FFPE - formalin-fixed paraffin-embedded, qRT-PCR - quantitative real-time reverse transcription-polymerase chain reaction, ECM - extracellular matrix, GFP - green fluorescent protein, CM - conditioned media, UICC - Union Internationale Contre le Cancer and the American Joint Committee on Cancer, COL1 - collagen type I, AC - adjuvant chemotherapy