CAFs and TGF-β Signaling Activation by Mast Cells Contribute to Resistance to Gemcitabine/Nabpaclitaxel in Pancreatic Cancer
by
Letizia Porcelli 1,†, Rosa Maria Iacobazzi 1,†, Roberta Di Fonte 1, Simona Serratì 1, Angelica Intini 1, Antonio Giovanni Solimando 2
, Oronzo Brunetti 3, Angela Calabrese 4, Francesco Leonetti 5, Amalia Azzariti 1,*,† and Nicola Silvestris 6,†
, Oronzo Brunetti 3, Angela Calabrese 4, Francesco Leonetti 5, Amalia Azzariti 1,*,† and Nicola Silvestris 6,†
1
Experimental Pharmacology Laboratory, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy
2
Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine ‘G. Baccelli’, University of Bari Medical School Bari, 70124 Bari, Italy
3
Medical Oncology Unit, Ospedale Mons. R. Dimiccoli, 76121 Barletta (Bat), Italy
4
Radiology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy
5
Dipartimento di Farmacia-Scienze del Farmaco, University of Bari, 70125 Bari, Italy
6
Medical Oncology Unit and Scientific Direction, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2019, 11(3), 330; https://doi.org/10.3390/cancers11030330
Received: 23 January 2019 / Revised: 1 March 2019 / Accepted: 1 March 2019 / Published: 7 March 2019
(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)
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.
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Keywords:
CAFs; gemcitabine; mast cells; nabpaclitaxel; pancreatic cancer
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MDPI and ACS Style
Porcelli, L.; Iacobazzi, R.M.; Di Fonte, R.; Serratì, S.; Intini, A.; Solimando, A.G.; Brunetti, O.; Calabrese, A.; Leonetti, F.; Azzariti, A.; Silvestris, N. CAFs and TGF-β Signaling Activation by Mast Cells Contribute to Resistance to Gemcitabine/Nabpaclitaxel in Pancreatic Cancer. Cancers 2019, 11, 330.
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