Next Article in Journal
TRAIL and FasL Functions in Cancer and Autoimmune Diseases: Towards an Increasing Complexity
Next Article in Special Issue
Chemoradiotherapy (Gemox Plus Helical Tomotherapy) for Unresectable Locally Advanced Pancreatic Cancer: A Phase II Study
Previous Article in Journal
(−)-Oleocanthal Prevents Breast Cancer Locoregional Recurrence After Primary Tumor Surgical Excision and Neoadjuvant Targeted Therapy in Orthotopic Nude Mouse Models
Previous Article in Special Issue
Use of Machine-Learning Algorithms in Intensified Preoperative Therapy of Pancreatic Cancer to Predict Individual Risk of Relapse
Article Menu

Export Article

Open AccessArticle

Role of c-MET Inhibitors in Overcoming Drug Resistance in Spheroid Models of Primary Human Pancreatic Cancer and Stellate Cells

1
Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, 71348-14336 Shiraz, Iran
2
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV, Amsterdam, The Netherlands
3
Physics of Life Processes, Huygens-Kamerlingh Onnes Laboratory, Leiden University, 2333 CA, Leiden, The Netherlands
4
Division of Surgery, CLINTEC, Karolinska Institutet, SE-171, Stockholm, Sweden
5
Cancer Pharmacology Lab, AIRC Start Up Unit, University of Pisa, 56124 Pisa, Italy
6
Metabolic syndrome Research center, Mashhad University of Medical Sciences, 91778-99191 Mashhad, Iran
7
Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University, 00185, Rome, Italy
8
Fondazione Pisana per la Scienza, 56017, Pisa, Italy
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(5), 638; https://doi.org/10.3390/cancers11050638
Received: 20 March 2019 / Revised: 18 April 2019 / Accepted: 2 May 2019 / Published: 8 May 2019
(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)
  |  
PDF [3897 KB, uploaded 8 May 2019]
  |  

Abstract

Pancreatic stellate cells (PSCs) are a key component of tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) and contribute to drug resistance. c-MET receptor tyrosine kinase activation plays an important role in tumorigenesis in different cancers including PDAC. In this study, effects of PSC conditioned medium (PCM) on c-MET phosphorylation (by immunocytochemistry enzyme-linked immunosorbent assay (ELISA)) and drug response (by sulforhodamine B assay) were investigated in five primary PDAC cells. In novel 3D-spheroid co-cultures of cyan fluorescence protein (CFP)-firefly luciferase (Fluc)-expressing primary human PDAC cells and green fluorescence protein (GFP)-expressing immortalized PSCs, PDAC cell growth and chemosensitivity were examined by luciferase assay, while spheroids’ architecture was evaluated by confocal microscopy. The highest phospho-c-MET expression was detected in PDAC5 and its subclone sorted for “stage specific embryonic antigen-4” (PDAC5 (SSEA4)). PCM of cells pre-incubated with PDAC conditioned medium, containing increased hepatocyte growth factor (HGF) levels, made PDAC cells significantly more resistant to gemcitabine, but not to c-MET inhibitors. Hetero-spheroids containing both PSCs and PDAC5 (SSEA4) cells were more resistant to gemcitabine compared to PDAC5 (SSEA4) homo-spheroids. However, c-MET inhibitors (tivantinib, PHA-665752 and crizotinib) were equally effective in both spheroid models. Experiments with primary human PSCs confirmed the main findings. In conclusion, we developed spheroid models to evaluate PSC–PDAC reciprocal interaction, unraveling c-MET inhibition as an important therapeutic option against drug resistant PDAC.
View Full-Text
Keywords: pancreatic cancer; three-dimensional culture; drug resistance; cancer-associated fibroblasts; primary cultures pancreatic cancer; three-dimensional culture; drug resistance; cancer-associated fibroblasts; primary cultures
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

MDPI and ACS Style

Firuzi, O.; Che, P.P.; El Hassouni, B.; Buijs, M.; Coppola, S.; Löhr, M.; Funel, N.; Heuchel, R.; Carnevale, I.; Schmidt, T.; Mantini, G.; Avan, A.; Saso, L.; Peters, G.J.; Giovannetti, E. Role of c-MET Inhibitors in Overcoming Drug Resistance in Spheroid Models of Primary Human Pancreatic Cancer and Stellate Cells. Cancers 2019, 11, 638.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Cancers EISSN 2072-6694 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top