Mechanical Stress Impairs Mitosis Progression in Multi-Cellular Tumor Spheroids

Desmaison, Annaïck; Frongia, Céline; Grenier, Katia; Ducommun, Bernard; Lobjois, Valérie

doi:10.1371/journal.pone.0080447

Cited by 57 publications

(72 citation statements)

References 35 publications

(38 reference statements)

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“…Therefore, we speculated that a percolation cluster with a different occupation probability should be suitable for describing the proliferation and spread of a tumor in an inhomogeneous surrounding matrix, which itself should be compressive to tumor proliferation and invasion. The results are basically in accordance with previous studies that showed that the surrounding matrix possesses a specific external pressure on a solid tumor [42][43][44]70]. …”

Section: Influence Of Tissue Inhomogeneity On Tumor Proliferation Andsupporting

confidence: 92%

“…This finding can be interpreted to mean that tumor cells are hampered by the sparse distribution of the surrounding matrix on an inhomogeneous percolation cluster and their further diffusion and migration are scarce when the occupation probability P is sufficiently low. The results are in accordance with research by Cheng et al [43] and Desmaison et al [44], showing that inhomogeneity in the mechanical properties of a confining environment could affect tumor cells distribution and morphology by inducing apoptosis.…”

Section: Comparison Of Several Lattice Constructorssupporting

confidence: 92%

“…Delarue et al found that the surrounding matrix behaves as a compressive stress and causes a reduction of the volume of multicellular tumor spheroids (MTS), leading to a reduction of the cell volume in the core of MTS; the surrounding tissue can be viewed as a restraint environment for tumor progression [41,42]. Cheng et al [43], Desmaison et al [44], and Deisboeck et al [45] also observed that the surrounding extracellular matrix (ECM) possesses a specific external pressure as well as tumors' interstitial pressure on a solid tumor, affecting considerably the migration of tumor cells. Hughes et al posited that the migration of tumor cells can be simplified into two types of mobility, random movement, and directional taxis [46].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Tumor proliferation and diffusion on percolation clusters

et al. 2016

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We study in silico the influence of host tissue inhomogeneity on tumor cell proliferation and diffusion by simulating the mobility of a tumor on percolation clusters with different homogeneities of surrounding tissues. The proliferation and diffusion of a tumor in an inhomogeneous tissue could be characterized in the framework of the percolation theory, which displays similar thresholds (0.54, 0.44, and 0.37, respectively) for tumor proliferation and diffusion in three kinds of lattices with 4, 6, and 8 connecting near neighbors. Our study reveals the existence of a critical transition concerning the survival and diffusion of tumor cells with leaping metastatic diffusion movement in the host tissues. Tumor cells usually flow in the direction of greater pressure variation during their diffusing and infiltrating to a further location in the host tissue. Some specific sites suitable for tumor invasion were observed on the percolation cluster and around these specific sites a tumor can develop into scattered tumors linked by some advantage tunnels that facilitate tumor invasion. We also investigate the manner that tissue inhomogeneity surrounding a tumor may influence the velocity of tumor diffusion and invasion. Our simulation suggested that invasion of a tumor is controlled by the homogeneity of the tumor microenvironment, which is basically consistent with the experimental report by Riching et al. as well as our clinical observation of medical imaging. Both simulation and clinical observation proved that tumor diffusion and invasion into the surrounding host tissue is positively correlated with the homogeneity of the tissue.

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Section: Influence Of Tissue Inhomogeneity On Tumor Proliferation Andsupporting

confidence: 92%

Section: Comparison Of Several Lattice Constructorssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Tumor proliferation and diffusion on percolation clusters

et al. 2016

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“…Studies of multicellular spheroids indicate that the mechanical pressure of the tissue environment can impair cell proliferation (33,34). Moreover, it has been predicted that cells in stiffer or more densely packed tissue environments, such as of an overgrown tumor, would require a more robust cell cortex and mitotic rounding response (9,35).…”

Section: Discussionmentioning

confidence: 99%

Mechanical control of mitotic progression in single animal cells

Cattin

Düggelin

Martínez-Martín

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Despite the importance of mitotic cell rounding in tissue development and cell proliferation, there remains a paucity of approaches to investigate the mechanical robustness of cell rounding. Here we introduce ion beam-sculpted microcantilevers that enable precise force-feedback-controlled confinement of single cells while characterizing their progression through mitosis. We identify three force regimes according to the cell response: small forces (∼5 nN) that accelerate mitotic progression, intermediate forces where cells resist confinement (50-100 nN), and yield forces (>100 nN) where a significant decline in cell height impinges on microtubule spindle function, thereby inhibiting mitotic progression. Yield forces are coincident with a nonlinear drop in cell height potentiated by persistent blebbing and loss of cortical F-actin homogeneity. Our results suggest that a buildup of actomyosin-dependent cortical tension and intracellular pressure precedes mechanical failure, or herniation, of the cell cortex at the yield force. Thus, we reveal how the mechanical properties of mitotic cells and their response to external forces are linked to mitotic progression under conditions of mechanical confinement.

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“…Cells that can survive in the absence of oxygen are therefore at a growth advantage compared to cells that cannot. Therefore, MCS, which mimic in vivo tumors with proliferative cells in the periphery and hypoxic centers (27), were used to evaluate hypoxia in vitro. When SCC9β6KDFyn cells were placed under hypoxic conditions a variety of changes occurred such as a 3-fold decrease in FN expression and a 2.5-fold decrease in Ncadherin expression (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Multicellular Spheroids as a Model for Hypoxia-induced EMT

Lee

Siu

Ramos

2016

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Abstract. Oral cancer is aggressive and invasive. The 5-year survival rate is around 50% and has not improved in over 50 years. One-third of oral cancer patients develop local and/or regional tumor recurrence following treatment. We continue to use our multicellular spheroid (MCS) model to better understand how the extracellular matrix contributes to epithelial to mesenchymal transition and how hypoxia contributes to the progression of oral squamous cell carcinoma (SCC).Oral cancer is the sixth most common type of cancer in the world. In the United States, 37,000 new cases are diagnosed annually and each year 8,000 individuals die from this disease (1). Squamous cell carcinoma (SCC) makes up 96% of all oral cancers (2). Despite advances in treatment, the prognosis for oral SCC has not improved in over 50 years.The 5-year survival rate for oral SCC is approximately 50% (3). The poor prognosis of SCC is due to invasion and local recurrence. Interactions between primary SCC cells and the surrounding extracellular matrix (ECM) facilitate invasion. As a tumor grows its available resources, including oxygen availability, become extremely limited which may affect tumor cell behavior. In this study, we aimed to determine the effect of hypoxia on EMT in OSCC spheroids.SCC cells undergo a transformative process known as epithelial-mesenchymal transition (EMT). EMT is a process by which epithelial cells lose their cell polarity, decrease cellcell adhesion, and gain migratory and invasive properties. EMT involves changes in expression, distribution, and function of a number of proteins for cells to transition between the epithelial and mesenchymal phenotype. During EMT, Ecadherin expression is lost; thereby disrupting desmosomes, promoting invasion and de-differentiation (4). N-cadherin acquisition also promotes invasive SCC behavior (4,5).Previous studies show that the αvβ6 integrin, an epithelial specific integrin, is instrumental to EMT in colorectal and oral cancer (6, 7). The αvβ6 integrin is an epithelial-specific adhesion receptor normally not expressed in oral keratinocytes. However, upon wounding or neoplastic transformation, αvβ6 is highly expressed by the same keratinocytes. The αvβ6 integrin is an adhesion receptor for fibronectin (FN) and tenascin-C, and also activates TGFβ1 (8, 9). Binding of αvβ6 integrin to FN results in the activation of FYN kinase in oral SCC. The activation of FYN kinase promotes activation of RAF/MAPK which induces EMT (10). Our laboratory demonstrated that expression of the full-length β6 subunit is required for maintenance of the mesenchymal phenotype thus promoting EMT (7).Keratins are the major structural components of the epithelial cell cytoskeleton and play a strategic role in their architectural integrity (11). It has been shown that gene mutations in keratin are responsible for a large number of inherited skin disorders thus, reinforcing their role in structural integrity of the epithelium (11). In addition to cytoskeletal changes, it is a common process for the ECM to undergo a...

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Mechanical Stress Impairs Mitosis Progression in Multi-Cellular Tumor Spheroids

Cited by 57 publications

References 35 publications

Tumor proliferation and diffusion on percolation clusters

Tumor proliferation and diffusion on percolation clusters

Mechanical control of mitotic progression in single animal cells

Multicellular Spheroids as a Model for Hypoxia-induced EMT

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