3D Microenvironment Stiffness Regulates Tumor Spheroid Growth and Mechanics via p21 and ROCK.
Adv Biosyst
; 3(9): e1900128, 2019 09.
Article
en En
| MEDLINE
| ID: mdl-32648654
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Regulación Neoplásica de la Expresión Génica
/
Esferoides Celulares
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Hidrogeles
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Mecanotransducción Celular
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Inhibidor p21 de las Quinasas Dependientes de la Ciclina
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Quinasas Asociadas a rho
Límite:
Female
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Humans
Idioma:
En
Revista:
Adv Biosyst
Año:
2019
Tipo del documento:
Article
País de afiliación:
Alemania
Pais de publicación:
Alemania