Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function
By I. Zervantonakis, Shannon K. Hughes-Alford, J. Charest, J. Condeelis, F. Gertler, Roger D. Kamm. Proceedings of the National Academy of Sciences of the United States of America, 2012
804 citations recorded by the source corpus.
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.
Subfields: Modeling and Simulation, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/9c580a762104e3654e23ac4c3ce348ad722aa5b0
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Citations in the corpus
- Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy. (2020, background): “Culturing cancer cells, macrophages and epithelial cells in a compartmentalized chips have uncovered TAMs significantly increase the ability of cancer cells to impair the endothelial barrier and that different TAM subtypes can disperse cancer cell aggregates via different mechanisms (Bai et al., 201”
- Tumor microenvironment complexity and therapeutic implications at a glance (2020, background): “The results indicated that secretion of tumor necrosis factor-alpha (TNFα) by macrophages can impair endothelial barrier as validated by a higher number and faster dynamics of TC-EC interactions in highly invasive fibrosarcoma cells [56] .”
- Revisiting the hallmarks of cancer. (2017, neutral): “[123] Zervantonakis IK, Hughes-Alford SK, Charest”
- Microfluidic 3D cell culture: from tools to tissue models. (2015, methodology): “Using microfluidic 3D cell culture, effects such as angiogenesis [20 ,22 ,33], migration [49,50], intravasation [51] and extravasation [18,19,44,52] have been studied, and will be discussed in more detail.”
- Biology-inspired Microphysiological System Approaches to Solve the Prediction Dilemma of Substance Testing (2016, neutral): “, 2014), intravasation (Zervantonakis et al., 2012) extravasation (Bersini et al.”
- Systems Biology of Cancer Metastasis (2019, methodology): “…interactions can be modeled using spatially defined modeling with partial differential equations, or cellular automatons (Tape, 2016; Tape et al., 2016) Intravasation/Extravasation i. 3D vasculature models: Tissue models to study cancer-vasculature interactions(Zervantonakis et al., 2012) ii.”
- Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation (2014, background): “Based on previous experiments performed in our laboratory on cancer cell intravasation (20), we suggest the increased microvasculature permeability could be due to the macrophage secretion of the inflammatory cytokine TNF-α.”
- In Vitro Tumor Models: Advantages, Disadvantages, Variables, and Selecting the Right Platform (2016, background): “These devices have been used to image invasion, intravasation, extravasation, and tumor-driven angiogenesis under static flow conditions and have the potential to be used as high-throughput screens for cancer invasiveness (Zervantonakis et al., 2012; Jeon et al., 2013; Lee et al., 2014).”