Effects of neoadjuvant FOLFIRINOX and gemcitabine-based chemotherapy on cancer cell survival and death in patients with pancreatic ductal adenocarcinoma
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Li Xie1,2, Leizhou Xia1,2, Ulla Klaiber1, Milena Sachsenmaier1, Ulf Hinz1, Frank Bergmann3, Oliver Strobel1, Markus W. Büchler1, John P. Neoptolemos1,2, Franco Fortunato1,2,* and Thilo Hackert1,*
1 Department of General, Visceral and Transplantation Surgery, University Clinic Heidelberg, Germany
2 Section Surgical Research, University Clinic Heidelberg, Germany
3 Institute of Pathology, University Clinic Heidelberg, Germany
* Co-senior authors
Keywords: autophagy; cell death; stroma; neoadjuvant therapy; prognosis
Received: October 11, 2019 Accepted: December 05, 2019 Published: December 31, 2019
Background: The progression and response to systemic treatment of cancer is substantially dependent on the balance between cancer cell death (apoptosis and necroptosis) and cancer cell survival (autophagy). Although well characterized in experimental systems, the status of cancer cell survival and cell death in human pancreatic ductal adenocarcinoma (PDAC), especially in response to chemotherapy and different types of chemotherapy is poorly described.
Results: The median (95% confidence interval) survival was 31.6 (24.5–44.5) months after FOLFIRINOX versus 15.8 (2.0–20.5) months after gemcitabine-based therapy (p = 0.039). PDAC tissue autophagy was reduced compared to normal pancreata based on reduced BECLIN-1 expression and LC3-Lamp-2 colocalization, whilst necroptosis (RIP-1) was increased. Neoadjuvant therapy was associated with further reduced autophagy based on p62/SQSTM-1 accumulation, and increased necroptosis (RIP3 and pMLKL) and apoptosis (BAX, cleaved CASPASE-9 and CASPASE-3) markers, increased nuclear p65 (NF-κB) and extracellular HMGB1 expression, with greater CD8+ lymphocyte infiltration. Survival was associated with reduced autophagy and increased apoptosis. Necroptosis (RIP-3, pMLKL) and apoptosis (BAX and cleaved CASPASE-9) markers were higher after FOLFIRINOX than gemcitabine-based treatment.
Patients and methods: Cancer cell autophagy, apoptosis, and necroptosis marker expression was compared in pancreatic tissue samples from 51 subjects, comprising four groups: (1) surgical resection for PDAC after FOLFIRINOX (n = 11), or (2) after gemcitabine-based (n = 14) neoadjuvant therapy, (3) patients undergoing PDAC resection without prior chemotherapy (n = 13), and (4) normal pancreata from 13 organ donors. Marker expression was undertaken using semi-automated immunofluorescence-FACS-like analysis, defining PDAC cells by CK-7+ expression.
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