Migration dynamics of breast cancer cells in a tunable 3D interstitial flow chamber

Haessler, Ulrike; Teo, Jeremy C. M.; Foretay, Didier; Renaud, Philippe; Swartz, Melody A.

doi:10.1039/c1ib00128k

Cited by 170 publications

(188 citation statements)

References 43 publications

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“…Data of Haessler et al revealed that interstitial flow increases the percentage of cells that become migratory as well as increases the migrational speed in about 20% of the cells 42 . In addition to study the chemotactic behavior of cells, e.g., leukocytes/lymphocytes or tumor cells, a 3D microfluidic setting is also a suitable tool to study tumor cell intravasation and endothelial barrier function 43 .…”

Section: Discussionmentioning

confidence: 99%

Analysis of Cell Migration within a Three-dimensional Collagen Matrix

Rommerswinkel

Niggemann

Keil

et al. 2014

JoVE

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The ability to migrate is a hallmark of various cell types and plays a crucial role in several physiological processes, including embryonic development, wound healing, and immune responses. However, cell migration is also a key mechanism in cancer enabling these cancer cells to detach from the primary tumor to start metastatic spreading. Within the past years various cell migration assays have been developed to analyze the migratory behavior of different cell types. Because the locomotory behavior of cells markedly differs between a two-dimensional (2D) and three-dimensional (3D) environment it can be assumed that the analysis of the migration of cells that are embedded within a 3D environment would yield in more significant cell migration data. The advantage of the described 3D collagen matrix migration assay is that cells are embedded within a physiological 3D network of collagen fibers representing the major component of the extracellular matrix. Due to time-lapse video microscopy real cell migration is measured allowing the determination of several migration parameters as well as their alterations in response to pro-migratory factors or inhibitors. Various cell types could be analyzed using this technique, including lymphocytes/leukocytes, stem cells, and tumor cells. Likewise, also cell clusters or spheroids could be embedded within the collagen matrix concomitant with analysis of the emigration of single cells from the cell cluster/ spheroid into the collagen lattice. We conclude that the 3D collagen matrix migration assay is a versatile method to analyze the migration of cells within a physiological-like 3D environment. Video LinkThe video component of this article can be found at

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Section: Discussionmentioning

confidence: 99%

Analysis of Cell Migration within a Three-dimensional Collagen Matrix

Rommerswinkel

Niggemann

Keil

et al. 2014

JoVE

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“…IF has been shown to induce rheotaxis when cells are seeded at sufficiently high density for paracrine chemokine fields to interfere with autocrine chemokine fields (17), and cells migrating upstream have been shown to migrate with increased persistence (35). We seeded cells at a density shown to induce preferential upstream migration of MDA-MB 231 (6 × 10 5 cells per mL) and applied 4.6 μm/s flow for 8 h, tracking the cells by taking images every 15 min.…”

Section: Paxillin Is Required For Upstream Actin Polarization and Promentioning

confidence: 99%

Mechanotransduction of fluid stresses governs 3D cell migration

Polacheck

German

Mammoto

et al. 2014

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

225

215

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Solid tumors are characterized by high interstitial fluid pressure, which drives fluid efflux from the tumor core. Tumor-associated interstitial flow (IF) at a rate of ∼3 μm/s has been shown to induce cell migration in the upstream direction (rheotaxis). However, the molecular biophysical mechanism that underlies upstream cell polarization and rheotaxis remains unclear. We developed a microfluidic platform to investigate the effects of IF fluid stresses imparted on cells embedded within a collagen type I hydrogel, and we demonstrate that IF stresses result in a transcellular gradient in β1-integrin activation with vinculin, focal adhesion kinase (FAK), FAK PY397 , F actin, and paxillindependent protrusion formation localizing to the upstream side of the cell, where matrix adhesions are under maximum tension. This previously unknown mechanism is the result of a force balance between fluid drag on the cell and matrix adhesion tension and is therefore a fundamental, but previously unknown, stimulus for directing cell movement within porous extracellular matrix.mechanobiology | breast cancer | metastasis I ntegrins and associated focal adhesion (FA) proteins form a tension-sensitive mechanical link between the extracellular matrix (ECM) and the cytoskeleton, and serve as key components in the signaling cascade by which cells transduce mechanical signals into biological responses (mechanotransduction) (1, 2). Contractile stresses generated by the cell are balanced by tractions at cell-substrate adhesions, and the FA protein vinculin accumulates at regions of high substrate stress (3, 4). The FA protein paxillin colocalizes with vinculin (4) and mediates β1-integrin FA turnover through interaction with FA kinase (FAK) (5). The FAK-paxillin signaling axis recruits vinculin to β1 integrins at regions of high matrix adhesion tension (6), and paxillin-a key mechanosensor (7)-mediates protrusion formation at regions of high stress on 2D substrates (8), and FAK-paxillin-vinculin signaling is required for mechanosensing and durotaxis (9).The tumor microenvironment imparts mechanical and chemical signals on tumor and stromal cells (10), and advanced breast carcinomas are characterized by high interstitial fluid pressure (11), an indicator of poor prognosis (12). This elevated fluid pressure drives interstitial flow (IF) and alters chemical transport within the tumor (13), and IF influences tumor cell migration through the generation of autocrine chemokine gradients (14). Equally important, although not as well understood, is the physical drag imparted on the ECM and constitutive cells (15) by IF, which is analogous to the FA-activating shear stresses generated on endothelial cells by hemodynamic forces (16). With endothelial cells, shear stress can be the dominant mechanical stimulus that induces FAK activation and cytoskeletal remodeling; however, for cells embedded within a porous matrix scaffold, the ratio of the force due to the pressure drop across the cell to the total shear force is inversely proportional to hydrogel p...

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“…It has also been observed, at relatively lower cell densities, that tumor cells migrate in the direction of the flow. Haessler et al (2011) reported that an increase in interstitial flow was found in the microenvironment within a tumor mass and that the flow influenced tumor cell migration. In particular, autologous chemotaxis, a directed cell migration induced by interstitial flow, has been identified as a potentially important mechanism; in this case, cancer cells migrate in the direction of the flow (Shieh and Swartz 2011;Fleury et al 2006;Shields et al 2007).…”

Section: Effect Of Interstitial Flow On Hcc Cellsmentioning

confidence: 99%

“…Particularly, interstitial flow, the convective transport of fluid through tissue ECM, has been demonstrated to affect the morphology and migration of various cell types including endothelial cells and tumor cells (Haessler et al 2011). It is also known that interstitial flow is related to the metastasis of tumors and the guidance of tumor cell movement (Shieh and Swartz 2011).…”

Section: Introductionmentioning

confidence: 99%

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A three-dimensional microfluidic tumor cell migration assay to screen the effect of anti-migratory drugs and interstitial flow

Kalchman

Fujioka

Chung³

et al. 2012

Microfluid Nanofluid

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Most anti-cancer drug screening assays are currently performed in two dimensions, on flat, rigid surfaces. However, there are increasing indications that threedimensional (3D) platforms provide a more realistic setting to investigate accurate morphology, growth, and sensitivity of tumor cells to chemical factors. Moreover, interstitial flow plays a pivotal role in tumor growth. Here, we present a microfluidic 3D platform to investigate behaviors of tumor cells in flow conditions with anti-migratory compounds. Our results show that interstitial flow and its direction have significant impact on migration and growth of hepatocellular carcinoma cell lines such as HepG2 and HLE. In particular, HepG2/HLE cells tend to migrate against interstitial flow, and their growth increases in interstitial flow conditions regardless of the flow direction. Furthermore, this migratory activity of HepG2 cells is enhanced when they are co-cultured with human umbilical vein endothelial cells. We also found that migration activity of HepG2 cells attenuates under hypoxic conditions. In addition, the effect of Artemisinin, an antimigratory compound, on HepG2 cells was quantitatively analyzed. The microfluidic 3D platform described here is useful to investigate more accurately the effect of antimigratory drugs on tumor cells and the critical influence of interstitial flow than 2D culture models.

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Migration dynamics of breast cancer cells in a tunable 3D interstitial flow chamber

Cited by 170 publications

References 43 publications

Analysis of Cell Migration within a Three-dimensional Collagen Matrix

Analysis of Cell Migration within a Three-dimensional Collagen Matrix

Mechanotransduction of fluid stresses governs 3D cell migration

A three-dimensional microfluidic tumor cell migration assay to screen the effect of anti-migratory drugs and interstitial flow

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