Role of the Endothelium during Tumor Cell Metastasis: Is the Endothelium a Barrier or a Promoter for Cell Invasion and Metastasis?

Mierke, Claudia Tanja

doi:10.1155/2008/183516

Cited by 57 publications

(49 citation statements)

References 121 publications

(154 reference statements)

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“…Changes in cell–substrate adhesive characteristics have long been implicated in the progression of cancer (Cavallaro and Christofori 2001, Lu et al 2001, Mierke 2008). Thus we have asked if the strength of adhesion changes with metastatic capacity and how this aligns with the measurements of traction stress.…”

Section: Resultsmentioning

confidence: 99%

Anin vitrocorrelation of mechanical forces and metastatic capacity

et al. 2011

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Mechanical forces have a major influence on cell migration and are predicted to significantly impact cancer metastasis, yet this idea is currently poorly defined. In this study we have asked if changes in traction stress and migratory properties correlate with the metastatic progression of tumor cells. For this purpose, four murine breast cancer cell lines derived from the same primary tumor, but possessing increasing metastatic capacity, were tested for adhesion strength, traction stress, focal adhesion organization and for differential migration rates in two-dimensional and three-dimensional environments. Using traction force microscopy (TFM), we were surprised to find an inverse relationship between traction stress and metastatic capacity, such that force production decreased as the metastatic capacity increased. Consistent with this observation, adhesion strength exhibited an identical profile to the traction data. A count of adhesions indicated a general reduction in the number as metastatic capacity increased but no difference in the maturation as determined by the ratio of nascent to mature adhesions. These changes correlated well with a reduction in active beta-1 integrin with increasing metastatic ability. Finally, in two dimensions, wound healing, migration and persistence were relatively low in the entire panel, maintaining a downward trend with increasing metastatic capacity. Why metastatic cells would migrate so poorly prompted us to ask if the loss of adhesive parameters in the most metastatic cells indicated a switch to a less adhesive mode of migration that would only be detected in a three-dimensional environment. Indeed, in three-dimensional migration assays, the most metastatic cells now showed the greatest linear speed. We conclude that traction stress, adhesion strength and rate of migration do indeed change as tumor cells progress in metastatic capacity and do so in a dimension-sensitive manner.

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Section: Resultsmentioning

confidence: 99%

Anin vitrocorrelation of mechanical forces and metastatic capacity

et al. 2011

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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%

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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“…The endothelial barrier integrity is maintained by a complex balance between cell-to-cell adherens junctions. In some pathological conditions, such as inflammation and cancer, endothelial junctions can be disrupted leading to the opening of intercellular gaps and inducing increased vascular permeability 31 . We focused our attention on the most important player in maintaining barrier integrity: VE-Cad.…”

Section: Discussionmentioning

confidence: 99%