Abstract
Tumor–stroma interactions are of key importance for pancreatic ductal adenocarcinoma (PDAC) progression. Our aim was to investigate whether cancer associated fibroblasts (CAFs) and mast cells (MC) affected the sensitivity of PDAC cells to gemcitabine/nabpaclitaxel (GEM/NAB). For this purpose, the combination cytotoxicity and the effect on tumor invasion and angiogenesis were evaluated with or without a conditioned medium from the mast cell line HMC-1 (human mast cell line-1 cells) and CAFs. Beside the clinical outcome of a homogenous population of PDAC patients, receiving GEM/NAB, was correlated to the circulating levels of mast cell tryptase and to a panel of inflammatory and immunosuppressive cytokines. CAFs neither affected drugs’ cytotoxicity nor the inhibition of angiogenesis, but promoted tumor cell invasion. The MC instead, caused resistance to drugs by reducing apoptosis, by activating the TGF-β signalling and by promoting tumor invasion. Indeed, the inhibition of TβRI serine/threonine kinase activity by galunisertib restored drugs cytotoxicity. Moreover, MC induced the release of TGF-β1, and increased expression of PAR-2, ERK1/2 and Akt activation. Accordingly, TGF-β1, tryptase and other pro-inflammatory and immunosuppressive cytokines increased in the unresponsive patients. In conclusion, MC play a pivotal role in the resistance to GEM/NAB. A correlation between high level of circulating pro-inflammatory/ immunosuppressive cytokines and unresponsiveness was found in PDAC patients.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a5-year overall survival of less than 5%
Since upon degranulation serine proteases such as tryptase are the major constituent of secretory granules released by mast cells, in addition to cytokines, growth factors and other bioactive molecules [15], we focused on the transforming growth factor-β (TGF-β) signalling and on the G protein-coupled receptor proteinase-activated receptor 2 (PAR2) pathway, that in response to activation by serine proteinases, such as tryptase, drives the progression of pancreatic cancer
To further investigate the role that tumor–stroma interactions can have on the response to GEM/NAB treatment in pancreatic ductal adenocarcinoma (PDAC), we evaluated the levels of several cytokines involved in inflammation, immunosuppression and angiogenesis in pancreatic cancer [24] (GM-CSF, IFN-gamma, IL-10, IL-1beta, IL-2, IL-6, IL-8/CXCL8, I-TAC/CXCL11, MIF, SDF-1a + b/CXCL12, TNF-alpha, and TGF-β1) and of mast cell tryptase in the blood of PDAC patients
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a5-year overall survival of less than 5%. Pancreatic cancer develops in a microenvironment, the stroma, enriched with extracellular matrix proteins, mainly produced by stellate cells known as cancer-associated fibroblasts (CAFs), inflammatory cells such as mast cells (MC), and small blood vessels that recent evidence suggests are a dynamic compartment rather than a mechanical barrier, strongly involved in the process of tumor formation, progression, invasion and metastasis [4,5]. The paracrine cross-talk of tumor cells and stroma cells has been demonstrated to play a pivotal role in tumor cells’ transformation and recently even in chemoresistance [6,7]. In vitro evidence suggested that among stroma cells, CAFs played a major role in the acquisition of the hallmarks of pancreatic cancer, including chemoresistance [8,9]
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