A three-dimensional in vitro model of tumor cell intravasation
Open accessAbstract
Metastasis is the cause of over 90% of all human cancer deaths. Early steps in the metastatic process include: the formation of new blood vessels, the initiation of epithelial-mesenchymal transition (EMT), and the mobilization of tumor cells into the circulation. There are ongoing efforts to replicate the physiological landscape of human tumor tissue using three-dimensional in vitro culture models; however, few systems are able to capture the full range of authentic, complex in vivo events such as neovascularization and intravasation. Here we introduce the Prevascularized Tumor (PVT) model to investigate early events of solid tumor progression. PVT spheroids are composed of endothelial and tumor cells, and are embedded in a fibrin matrix containing fibroblasts. The PVT model facilitates two mechanisms of vessel formation: robust sprouting angiogenesis into the matrix, and contiguous vascularization within the spheroid. Furthermore, the PVT model enables the intravasation of tumor cells that is enhanced under low oxygen conditions and is also dependent on the key EMT transcription factor Slug. The PVT model provides a significant advance in the mimicry of human tumors in vitro, and may improve investigation and targeting of events in the metastatic process.
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Recent studies increasingly use microvascular networks whose permeability, architecture and diameters are more similar to in vivo microvascular beds.
“Recent studies are increasingly employing microvascular networks (µVNs)[21, 23, 24], where the permeability, architecture and diameters of vessels are more similar to those found in in vivo microvascular beds (Figure 2A) [21].”
From Microfluidics: A New Tool for Modeling Cancer–Immune Interactions (2016) · cites this paper as [23]
The Discussion (page not specified in our copy) describes a branched, lumenized vessel network whose heterogeneous diameters and morphology resemble tumor vasculature in vivo. This supports the architectural comparison, but the paper does not establish that the network’s permeability or vessel diameters are more similar to those of in vivo microvascular beds. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn an in vitro metastasis model, migrated tumor cells must be further exposed to varying microenvironments and oxygen gradients to simulate the process of in vivo intravasation.
“In an in vitro metastasis model, migrated tumor cells must be further exposed to varying microenvironments and oxygen gradients to simulate the process of in vivo intravasation126.”
From Tumor-on-a-chip: from bioinspired design to biomedical application (2021) · cites this paper as [126]
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References 54 · Cited by 196
Research works printed but not linked: 4
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- Authors
- Ehsan, S. M., Welch-Reardon, K. M., Waterman, M. L., Hughes, C. C. W., & George, S. C.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- George, Steven C.
- Venue
- Integrative Biology
- Publisher
- Oxford University Press (OUP)
- Published
- 2014
- Volume
- 6
- Issue
- 6
- Pages
- 603
- ISSN
- 1757-9694 (ISSN-L)
- 1757-9708
- PMC
- PMC4046910
- OpenAlex
- W2044228465
- Cited by
- 196
- References
- 54
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 6 · 2023: 11 · 2022: 16 · 2021: 27 · 2020: 18 · 2019: 18 · 2018: 24 · 2017: 21 · 2016: 21 · 2015: 13 · 2014: 4
- FWCI
- 9.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Integrative Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (UH2TR000481)
- National Heart, Lung, and Blood Institute (R01HL060067)
- National Cancer Institute (R01CA108697, R01CA170879, R01CA180122, P30CA062203)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Keywords
- tumor cell intravasation, metastasis, 3D tumor models, neovascularization, angiogenesis, endothelial cells, fibrin matrix, fibroblasts, epithelial-mesenchymal transition, Slug, hypoxia, tumor spheroids
- MeSH terms
- Snail Family Transcription Factors, Hypoxia, Fibrin, Humans, Microscopy, Fluorescence, Neoplasms, Neovascularization, Pathologic, Transcription Factors, Blotting, Western, RNA, Small Interfering, Endothelial Cells, Cell Line, Tumor, Epithelial-Mesenchymal Transition, In Vitro Techniques
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