3D Microenvironment Stiffness Regulates Tumor Spheroid Growth and Mechanics via p21 and ROCK.
Acrylic Resins
/ chemistry
Actins
/ genetics
Biomechanical Phenomena
Cell Culture Techniques
Cell Proliferation
/ drug effects
Cyclin-Dependent Kinase Inhibitor p21
/ genetics
Female
G1 Phase Cell Cycle Checkpoints
/ genetics
Gene Expression Regulation, Neoplastic
Heparin
/ chemistry
Humans
Hydrogels
/ chemical synthesis
MCF-7 Cells
Mechanotransduction, Cellular
/ genetics
Polyethylene Glycols
/ chemistry
Single-Cell Analysis
/ methods
Spheroids, Cellular
/ drug effects
Tumor Microenvironment
/ drug effects
rho-Associated Kinases
/ genetics
3D culture
atomic force microscopy
cell mechanics
compression
stress sensor
tumor microenvironment
tumor spheroid
Journal
Advanced biosystems
ISSN: 2366-7478
Titre abrégé: Adv Biosyst
Pays: Germany
ID NLM: 101711718
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
03
06
2019
entrez:
11
7
2020
pubmed:
11
7
2020
medline:
20
9
2020
Statut:
ppublish
Résumé
The mechanical properties of cancer cells and their microenvironment contribute to breast cancer progression. While mechanosensing has been extensively studied using 2D substrates, much less is known about it in a physiologically more relevant 3D context. Here it is demonstrated that breast cancer tumor spheroids, growing in 3D polyethylene glycol-heparin hydrogels, are sensitive to their environment stiffness. During tumor spheroid growth, compressive stresses of up to 2 kPa build up, as quantitated using elastic polymer beads as stress sensors. Atomic force microscopy reveals that tumor spheroid stiffness increases with hydrogel stiffness. Also, constituent cell stiffness increases in a Rho associated kinase (ROCK)- and F-actin-dependent manner. Increased hydrogel stiffness correlated with attenuated tumor spheroid growth, a higher proportion of cells in G0/G1 phase, and elevated levels of the cyclin-dependent kinase inhibitor p21. Drug-mediated ROCK inhibition not only reverses cell stiffening upon culture in stiff hydrogels but also increases tumor spheroid growth. Taken together, a mechanism by which the growth of a tumor spheroid can be regulated via cytoskeleton rearrangements in response to its mechanoenvironment is revealed here. Thus, the findings contribute to a better understanding of how cancer cells react to compressive stress when growing under confinement in stiff environments.
Identifiants
pubmed: 32648654
doi: 10.1002/adbi.201900128
doi:
Substances chimiques
Acrylic Resins
0
Actins
0
Cyclin-Dependent Kinase Inhibitor p21
0
Hydrogels
0
Polyethylene Glycols
3WJQ0SDW1A
polyacrylamide
9003-05-8
Heparin
9005-49-6
rho-Associated Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1900128Informations de copyright
© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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