Myosin light chain kinase mediates transcellular intravasation of breast cancer cells through the underlying endothelial cells: a three-dimensional FRET study

Khuon, Satya; Liang, Luke; Dettman, Robert W.; Sporn, Peter H. S.; Wysolmerski, Robert B.; Chew, Teng Leong

doi:10.1242/jcs.053793

Cited by 112 publications

(108 citation statements)

References 53 publications

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“…Our findings in the present study further indicate that inhibiting MLC phosphorylation and blocking G actin polymerization inhibits VE-cad Tyr phosphorylation and the TEM of MDA-MB-231 cells. In line with these findings, blocking endothelial MLC phosphorylation has been shown to reduce the invasion of breast cancer cells (35). How phosphorylation of MLC leads to VE-cad Tyr phosphorylation needs further investigation.…”

Section: Discussionmentioning

confidence: 68%

Integrin α2β1 Mediates Tyrosine Phosphorylation of Vascular Endothelial Cadherin Induced by Invasive Breast Cancer Cells

Haidari

Zhang

Caivano

et al. 2012

Journal of Biological Chemistry

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Background:The disruption of endothelial barrier function by tumor cells was studied. Results: The attachment of tumor cells to endothelial cells leads to the disorganization of endothelial adherens junction. Conclusion: Interaction of tumor cells with endothelial cells alters endothelial signaling and facilitates cancer cell diapedesis. Significance: This study introduces new therapeutic targets for treating metastatic breast cancer.

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Section: Discussionmentioning

confidence: 68%

Integrin α2β1 Mediates Tyrosine Phosphorylation of Vascular Endothelial Cadherin Induced by Invasive Breast Cancer Cells

Haidari

Zhang

Caivano

et al. 2012

Journal of Biological Chemistry

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“…Despite progress in identifying critical regulators (16,(30)(31)(32) of tumor-endothelial interactions, it is not clear whether tumor cell entry into the blood stream requires an impaired endothelial barrier (30,33). In this work, we present a unique approach using a microfluidic-based in vitro assay that enables real-time visualization and quantification of the interactions between tumor cells and an endothelial monolayer in the context of tumor cell invasion and intravasation.…”

Section: Discussionmentioning

confidence: 99%

“…For example, a recent in vitro study identified changes in endothelial myosin light chain kinase upon tumor-endothelial cell contact (16), however this method did not allow for measurement of endothelial permeability or the accurate control of the microenvironmental stimuli. Compared to other in vitro models (16,21) and microfluidic models of tumor-endothelial interactions (25,35), our assay provides a number of unique features, such as high-resolution live cell imaging, the formation of an endothelial monolayer on a 3D ECM enabling us to model intravasation, and for precise quantification and control of critical tumor microenvironmental factors. The readily accessible apical side of the endothelium allows for the introduction of cell types in the tumor microenvironment, such as macrophages, the precise establishment of growth-factor gradients, fluid flow, and real-time spatially resolved endothelial barrier function measurements.…”

Section: Discussionmentioning

confidence: 99%

“…However, because of the lack of physiologically relevant in vitro models and the challenges of investigating cell-cell interactions in vivo, the underlying mechanism of intravasation remains poorly understood (14). In particular, a number of fundamental questions remain as to whether intravasation is an active or passive process (15) and whether tumor cells cross the endothelial barrier through cell-cell junctions (paracellular) or through the endothelial cell body [transcellular (16)]. Therefore, the development of experimental platforms enabling real-time visualization of tumor cell interactions with a vascular interface will enable studies for delineating the underlying molecular mechanisms, whereas these tools could also be used for drug screening and discovery.…”

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confidence: 99%

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Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function

Zervantonakis

Hughes

Charest

et al. 2012

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

772

695

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Entry of tumor cells into the blood stream is a critical step in cancer metastasis. Although significant progress has been made in visualizing tumor cell motility in vivo, the underlying mechanism of cancer cell intravasation remains largely unknown. We developed a microfluidic-based assay to recreate the tumor-vascular interface in three-dimensions, allowing for high resolution, real-time imaging, and precise quantification of endothelial barrier function. Studies are aimed at testing the hypothesis that carcinoma cell intravasation is regulated by biochemical factors from the interacting cells and cellular interactions with macrophages. We developed a method to measure spatially resolved endothelial permeability and show that signaling with macrophages via secretion of tumor necrosis factor alpha results in endothelial barrier impairment. Under these conditions intravasation rates were increased as validated with live imaging. To further investigate tumor-endothelial (TC-EC) signaling, we used highly invasive fibrosarcoma cells and quantified tumor cell migration dynamics and TC-EC interactions under control and perturbed (with tumor necrosis factor alpha) barrier conditions. We found that endothelial barrier impairment was associated with a higher number and faster dynamics of TC-EC interactions, in agreement with our carcinoma intravasation results. Taken together our results provide evidence that the endothelium poses a barrier to tumor cell intravasation that can be regulated by factors present in the tumor microenvironment.T umor-endothelial cell interactions are critical in multiple steps during cancer metastasis, ranging from cancer angiogenesis to colonization. Cancer cell intravasation is a rate-limiting step in metastasis that regulates the number of circulating tumor cells and thus presents high risk for the formation of secondary tumors (1, 2). During the metastatic process tumor cells migrate out of the primary tumor (3), navigate into a complex tumor microenvironment, and enter into blood vessels (4). Cell-cell communication and chemotaxis (5) are key to this process and can occur via paracrine signals and/or direct contact between different cell types during tumor cell invasion (6) and metastatic colonization (7). Studies using multiphoton imaging in animal models have demonstrated that the ability of tumor cells to enter into the blood stream can be controlled both by tumor cell intrinsic factors (8-11) and other cells present in the tumor microenvironment, such as macrophages (12) and neutrophils (13). However, because of the lack of physiologically relevant in vitro models and the challenges of investigating cell-cell interactions in vivo, the underlying mechanism of intravasation remains poorly understood (14). In particular, a number of fundamental questions remain as to whether intravasation is an active or passive process (15) and whether tumor cells cross the endothelial barrier through cell-cell junctions (paracellular) or through the endothelial cell body [transcellular (16)]. Therefor...

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“…Crossing the endothelial barrier is commonly considered a rate-limiting step against tumor dissemination during metastatic progression (26). Two routes are used by tumor cells to cross the endothelial barrier: paracellular and transcellular transendothelial migration (TEM) (Figure 2) (25,26).…”

Section: Intravasationmentioning

confidence: 99%

Blood-brain Barrier Remodeling during Brain Metastasis Formation

Wrobel

Toborek

2016

Mol Med

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Our understanding of the process of metastatic progression has improved markedly over the past decades, yet metastasis remains the most enigmatic component of cancer pathogenesis. This lack of knowledge has serious health-related implications, since metastasis is responsible for 90% of all cancer-related mortalities. The brain is considered a sanctuary site for metastatic tumor growth, where the blood-brain barrier (BBB) and other components of the brain microenvironment, provide protection to the tumor cells from immune surveillance, chemotherapeutics and other potentially harmful substances. The interactions between tumor cells and the brain microenvironment, principally brain vascular endothelium, are the critical determinants in their progression toward metastasis, dormancy, or clearance. This review discusses current knowledge of the biology of metastatic progression, with a particular focus on the tumor cell migration and colonization in the brain. online address: http://www.molmed.org

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Myosin light chain kinase mediates transcellular intravasation of breast cancer cells through the underlying endothelial cells: a three-dimensional FRET study

Cited by 112 publications

References 53 publications

Integrin α2β1 Mediates Tyrosine Phosphorylation of Vascular Endothelial Cadherin Induced by Invasive Breast Cancer Cells

Integrin α2β1 Mediates Tyrosine Phosphorylation of Vascular Endothelial Cadherin Induced by Invasive Breast Cancer Cells

Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function

Blood-brain Barrier Remodeling during Brain Metastasis Formation

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