The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices

Autor: Daniella Munro, Bridget Calder, Nicholas Ekow Thomford, Kevin Dzobo, Nelson C. Soares, Tina Jonker, Dhirendra Govender, Jonathan M. Blackburn, Collet Dandara, Arielle Rowe, Dimakatso Alice Senthebane, Ambroise Wonkam, M. Iqbal Parker
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Male
Esophageal Neoplasms
Apoptosis
3D extracellular matrix
Extracellular matrix
lcsh:Chemistry
0302 clinical medicine
Cell Movement
Tumor Microenvironment
esophageal cancer
lcsh:QH301-705.5
Spectroscopy
Aged
80 and over
biology
Chemistry
Cell Cycle
chemoresistance
General Medicine
Middle Aged
targeted therapy
type I collagen
Computer Science Applications
Extracellular Matrix
030220 oncology & carcinogenesis
Carcinoma
Squamous Cell
Female
Collagen
Signal Transduction
Adult
Integrin
Antineoplastic Agents
Catalysis
Article
Inorganic Chemistry
03 medical and health sciences
fibronectin
Cell Line
Tumor
medicine
stroma
Humans
Physical and Theoretical Chemistry
Molecular Biology
Protein kinase B
Aged
Cell Proliferation
Tumor microenvironment
Cell growth
Gene Expression Profiling
Organic Chemistry
Cancer
medicine.disease
Fibronectins
Fibronectin
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
Drug Resistance
Neoplasm
Cancer cell
biology.protein
Cancer research
Laminin
signaling cascade
Zdroj: International Journal of Molecular Sciences
Volume 19
Issue 10
International Journal of Molecular Sciences, Vol 19, Iss 10, p 2861 (2018)
ISSN: 1422-0067
DOI: 10.3390/ijms19102861
Popis: Background: The functional interplay between tumor cells and their adjacent stroma has been suggested to play crucial roles in the initiation and progression of tumors and the effectiveness of chemotherapy. The extracellular matrix (ECM), a complex network of extracellular proteins, provides both physical and chemicals cues necessary for cell proliferation, survival, and migration. Understanding how ECM composition and biomechanical properties affect cancer progression and response to chemotherapeutic drugs is vital to the development of targeted treatments. Methods: 3D cell-derived-ECMs and esophageal cancer cell lines were used as a model to investigate the effect of ECM proteins on esophageal cancer cell lines response to chemotherapeutics. Immunohistochemical and qRT-PCR evaluation of ECM proteins and integrin gene expression was done on clinical esophageal squamous cell carcinoma biopsies. Esophageal cancer cell lines (WHCO1, WHCO5, WHCO6, KYSE180, KYSE 450 and KYSE 520) were cultured on decellularised ECMs (fibroblasts-derived ECM
cancer cell-derived ECM
combinatorial-ECM) and treated with 0.1% Dimethyl sulfoxide (DMSO), 4.2 µ
M cisplatin, 3.5 µ
M 5-fluorouracil and 2.5 µ
M epirubicin for 24 h. Cell proliferation, cell cycle progression, colony formation, apoptosis, migration and activation of signaling pathways were used as our study endpoints. Results: The expression of collagens, fibronectin and laminins was significantly increased in esophageal squamous cell carcinomas (ESCC) tumor samples compared to the corresponding normal tissue. Decellularised ECMs abrogated the effect of drugs on cancer cell cycling, proliferation and reduced drug induced apoptosis by 20&ndash
60% that of those plated on plastic. The mitogen-activated protein kinase-extracellular signal-regulated kinase (MEK-ERK) and phosphoinositide 3-kinase-protein kinase B (PI3K/Akt) signaling pathways were upregulated in the presence of the ECMs. Furthermore, our data show that concomitant addition of chemotherapeutic drugs and the use of collagen- and fibronectin-deficient ECMs through siRNA inhibition synergistically increased cancer cell sensitivity to drugs by 30&ndash
50%, and reduced colony formation and cancer cell migration. Conclusion: Our study shows that ECM proteins play a key role in the response of cancer cells to chemotherapy and suggest that targeting ECM proteins can be an effective therapeutic strategy against chemoresistant tumors.
Databáze: OpenAIRE
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