Biomechanical Forces Shape the Tumor Microenvironment

Shieh, Adrian C.

doi:10.1007/s10439-011-0252-2

Cited by 152 publications

(132 citation statements)

References 104 publications

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“…Recent studies show that the mechanical microenvironment plays a major role in modulating tumor cell responses, tissue development, and maintenance. 32,33 It has been shown that flow induced shear stress in tumor cells upregulate various key genes ͑cyclin B1 and p21 CIP1 ͒ and downregulate several other genes ͑such as cyclins A, D1, cyclin dependent protein kinases͒. In addition to creating physiological shear stresses inside the microbubbles, perfusion flow also establishes a physiologically relevant drug concentration profile to the exposed spheroids.…”

Section: Resultsmentioning

confidence: 99%

Continuously perfused microbubble array for 3D tumor spheroid model

et al. 2011

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Multi-cellular tumor spheroids ͑MCTSs͒ have been established as a 3D physiologically relevant tumor model for drug testing in cancer research. However, it is difficult to control the MCTS testing parameters and the entire process is timeconsuming and expensive. To overcome these limitations, we developed a simple microfluidic system using polydimethylsiloxane ͑PDMS͒ microbubbles to culture tumor spheroids under physiological flow. The flow characteristics such as streamline directions, shear stress profile, and velocity profile inside the microfluidic system were first examined computationally using a COMSOL simulation. Colo205 tumor spheroids were created by a modified hanging drop method and maintained inside PDMS microbubble cavities in perfusion culture. Cell viability inside the microbubbles was examined by live cell staining and confocal imaging. E-selectin mediated cell sorting of Colo205 and MDA-MB-231 cell lines on functionalized microbubble and PDMS surfaces was achieved. Finally, to validate this microfluidic system for drug screening purposes, the toxicity of the anti-cancer drug, doxorubicin, on Colo205 cells in spheroids was tested and compared to cells in 2D culture. Colo205 spheroids cultured in flow showed a threefold increase in resistance to doxorubicin compared to Colo205 monolayer cells cultured under static conditions, consistent with the resistance observed previously in other MCTS models. The advantages presented by our microfluidic system, such as the ability to control the size uniformity of the spheroids and to perform real-time imaging on cells in the growth platform, show potential for high throughput drug screening development.

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Section: Resultsmentioning

confidence: 99%

Continuously perfused microbubble array for 3D tumor spheroid model

et al. 2011

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“…In addition to the rigidity of the matrix, stroma-associated cells, including the highly contractile myofibroblasts, produce forces in the ECM as they remodel and migrate through the matrix (Goffin et al, 2006;Shieh, 2011;Tripathi et al, 2012). During the remodeling process, a tugging force is generated on the surrounding collagen fibers as they are bundled and arranged (Castella et al, 2010;Goffin et al, 2006;Murrell et al, 2015;Oudin et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro

Gasparski

Ozarkar

Beningo

2017

Journal of Cell Science

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Cancer cell invasion is influenced by various biomechanical forces found within the microenvironment. We have previously found that invasion is enhanced in fibrosarcoma cells when transient mechanical stimulation is applied within an in vitro mechano-invasion assay. This enhancement of invasion is dependent on cofilin (CFL1), a known regulator of invadopodia maturation. Invadopodia are actin-rich structures present in invasive cancer cells that are enzymatically active and degrade the surrounding extracellular matrix to facilitate invasion. In this study, we examine changes in gene expression in response to tugging on matrix fibers. Interestingly, we find that integrin β3 expression is downregulated and leads to an increase in cofilin activity, as evidenced by a reduction in its Ser3 phosphorylation levels. As a result, invadopodia lengthen and have increased enzymatic activity, indicating that transient mechanical stimulation promotes the maturation of invadopodia leading to increased levels of cell invasion. Our results are unique in defining an invasive mechanism specific to the invasive process of cancer cells that is triggered by tugging forces in the microenvironment, as opposed to rigidity, compression or stretch forces.

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“…81,82 For cancer cells, the stiffness of their surrounding ECM can influence metastasis, invasion, proliferation, and chemoresistance. [83][84][85][86] Numerous studies have proven that stiffer substrates enhance the metastatic phenotypes of cancer cells. [87][88][89][90][91] However, within the field of ovarian cancer, studies have resulted in contradictory findings.…”

Section: Ecm Stiffness Within the Ovarian Cancer Mechanical Microementioning

confidence: 99%

Review: Mechanotransduction in ovarian cancer: Shearing into the unknown

2018

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Perspective: The role of mechanobiology in the etiology of brain metastasis APL Bioengineering 2, 031801 (2018) Ovarian cancer remains a deadly diagnosis with an 85% recurrence rate and a 5-year survival rate of only 46%. The poor outlook of this disease has improved little over the past 50 years owing to the lack of early detection, chemoresistance and the complex tumor microenvironment. Within the peritoneal cavity, the presence of ascites stimulates ovarian tumors with shear stresses. The stiff environment found within the tumor extracellular matrix and the peritoneal membrane are also implicated in the metastatic potential and epithelial to mesenchymal transition (EMT) of ovarian cancer. Though these mechanical cues remain highly relevant to the understanding and treatment of ovarian cancers, our current knowledge of their biological processes and their clinical relevance is deeply lacking. Seminal studies on ovarian cancer mechanotransduction have demonstrated close ties between mechanotransduction and ovarian cancer chemoresistance, EMT, enhanced cancer stem cell populations, and metastasis. This review summarizes our current understanding of ovarian cancer mechanotransduction and the gaps in knowledge that exist. Future investigations on ovarian cancer mechanotransduction will greatly improve clinical outcomes via systematic studies that determine shear stress magnitude and its influence on ovarian cancer progression, metastasis, and treatment.

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Biomechanical Forces Shape the Tumor Microenvironment

Cited by 152 publications

References 104 publications

Continuously perfused microbubble array for 3D tumor spheroid model

Continuously perfused microbubble array for 3D tumor spheroid model

Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro

Review: Mechanotransduction in ovarian cancer: Shearing into the unknown

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