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Cited by 663D Printing in Biomedical ResearchMicrofluidic and Capillary Electrophoresis ApplicationsCancer Cells and Metastasis

Cancer-on-chip models for metastasis: importance of the tumor microenvironment

Open access
Jouybar, Mohammad, de Winde, Charlotte M., Wolf, Katarina, Friedl, Peter, Mebius, Reina E., den Toonder, Jaap M.J.·2024·Trends in Biotechnology
DOI 10.1016/j.tibtech.2023.10.001
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Abstract

Cancer-on-chip (CoC) models, based on microfluidic chips harboring chambers for 3D tumor-cell culture, enable us to create a controlled tumor microenvironment (TME). CoC models are therefore increasingly used to systematically study effects of the TME on the various steps in cancer metastasis. Moreover, CoC models have great potential for developing novel cancer therapies and for predicting patient-specific response to cancer treatments. We review recent developments in CoC models, focusing on three main TME components: (i) the anisotropic extracellular matrix (ECM) architectures, (ii) the vasculature, and (iii) the immune system. We aim to provide guidance to biologists to choose the best CoC approach for addressing questions about the role of the TME in metastasis, and to inspire engineers to develop novel CoC technologies.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that cancer-on-chip (CoC) models are increasingly used to study metastasis by controlling key tumor microenvironment (TME) components, especially anisotropic ECM, vasculature, and immune cells. It classifies CoC designs and highlights both their mechanistic and therapeutic potential and the remaining challenges for standardization, physiological fidelity, and clinical translation.

Key findings

  • ECM stiffening and alignment are central to invasion: connective tissue around tumor-loaded mammary glands stiffens up to eight-fold (from 0.2 to 1.5 kPa), densifies, and straightens in murine cancer models and clinical biopsies. CoC models can generate anisotropic ECM via engineered, flow-derived, or cell-derived approaches, with collagen type I hydrogels tunable in stiffness (0.01–1 kPa) and porosity (0.2–15 μm pore diameters).
  • Vasculature studies in CoC models show that TME cues modulate intravasation and extravasation: macrophage-secreted TNF-α increased endothelial permeability and enhanced cancer-cell invasion/intravasation; cyclic stretch mimicking breathing suppressed intravasation; paclitaxel reduced tumor growth; and CXCR2/CXCL5 regulation significantly altered extravasation.
  • Immune components can be incorporated into CoC models: NK cells killed tumor cells in a dose-dependent manner and more efficiently with an immunotherapeutic antibody; CAR T cells entirely invaded breast and lung tumors and killed tumor cells over several days; TCR-engineered T-cell cytotoxicity decreased under hypoxic conditions; monocytes suppressed TCR T-cell cytotoxicity; and CAFs inhibited trastuzumab’s antitumor effect.
  • Lymphoid organ models are emerging: a human artificial lymph node supported long-term experiments (14–30 days), and a bone-marrow-on-a-chip supported HSPC differentiation into monocytes and neutrophils, with breast-cancer cells invading both bone-marrow niches at a similar rate but not ECM-only chambers.

Methods

  • Narrative review synthesizing and classifying recent CoC literature, with a focus on three TME components: anisotropic ECM architectures, vasculature, and the immune system.
  • The paper reviews studies using four major CoC classes—compartmentalized channel, porous membrane, template-based, and self-assembly models—and lists experimental details in Table 1 and Table S1.
  • No primary experiments, systematic search strategy, or quantitative meta-analysis are reported; the work is a literature synthesis and perspective.

Limitations

  • The paper states that CoC models require standardization, industrial fabrication methods, standards for devices, cell seeding and validation protocols, and compatibility with pharmaceutical and clinical laboratories; current devices are designed for single or few tests, whereas many applications need large-scale testing.
  • The paper states that oxygen supply through vessels is often not recapitulated, as most CoCs provide oxygen via culture medium or diffusion through chip materials; intra- and extravasation studies have concentrated on blood vessels, while lymphatic intravasation mechanisms are less explored; lymphoid OoC models lack lymph-node stromal cells; and adaptive immune cell incorporation requires donor matching.
  • Evident from the text: as a narrative review, it does not provide a systematic appraisal or pooled effect estimates, and it notes that chip designs, materials, and fabrication approaches vary widely even within the four categories.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.tibtech.2023.10.001

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation

    Electrospinning or 3D microextrusion printing enable production of highly aligned collagen sheets or hydrogels with spaces estimated 2-20 μm between aligned fibrils.

    “Furthermore, techniques such as electrospinning or 3D microextrusion printing enable the production of highly aligned collagen sheets, or hydrogels with spaces an estimated 2-20 μm between aligned fibrils [34,35].”
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    Preceding and accompanying invasion, cancer-associated fibroblasts (CAFs) may deposit fibronectin, collagen type I or type IV, or proteoglycans, resulting in stiffened, ECM-rich fibrous connective tissue.

    “Preceding and accompanying invasion, cancer-associated fibroblasts (CAFs) may deposit fibronectin, collagen type I or type IV, or proteoglycans, resulting in stiffened, ECM-rich fibrous connective tissue [17,18].”
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    Collagen type I-based hydrogels enable tunable mechanical and structural properties, in particular stiffness (0.01-1 kPa) and porosity (0.2-15 μm pore diameters), by changes in concentration, polymerization conditions, or glycation.

    “Collagen type I-based hydrogels enable tunable mechanical and structural properties, in particular stiffness (0.01-1 kPa) and porosity (0.2-15 μm pore diameters), by changes in concentration, polymerization conditions (such as pH or temperature changes), or glycation [26][27][28].”
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    ECM anisotropy is a hallmark in many cancers.

    “Because ECM anisotropy is a hallmark in many cancers”
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    Interstitial compartments are organized into various 3D architectures, including fibrillar porous networks or aligned bundles, heterogeneous in density, topology, and stiffness.

    “Interstitial compartments are organized into various 3D architectures, including fibrillar porous networks or aligned bundles, heterogeneous in density, topology, and stiffness [11,12].”
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    Premisecitation

    As a result of collagen remodeling, connective tissues surrounding tumor-loaded mammary glands stiffen up to eight-fold (from 0.2 to 1.5 kPa), densify, and straighten with tumor formation, as detected in murine cancer models and clinical biopsies.

    “As a result of collagen remodeling, connective tissues surrounding tumor-loaded mammary glands stiffen up to eight-fold (i.e., from 0.2 to 1.5 kPa), densify, and straighten with tumor formation, as detected in murine cancer models and clinical biopsies [20,21].”
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    Line patterns in the diameter range 50-100 μm can be realized by a lane configuration chip approach or photopatterning.

    “Line patterns in the diameter range 50-100 μm, reflecting the diameters of smaller collagen fibers providing alignment to cells, can be realized by a lane configuration chip approach, or photopatterning, for example, using a photomask with UV light for hydrogel crosslinking [32,33].”
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    Premisenone given

    The vasculature can be included in CoC models in various ways to model tumor-vasculature interaction, intravasation, and extravasation.

    “The vasculature is a key ingredient in any cancer model, and it can be included in CoC models in various ways to model tumor-vasculature interaction, intravasation, and extravasation.”
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    Anisotropic extracellular matrix (ECM) can be generated in CoC models using several methods.

    “Generation of anisotropic extracellular matrix (ECM) is important in the context of cancer research and can be done in CoC models using several methods.”
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    Premisecitation

    Interstitial spaces between randomly organized collagen fibril networks in human or mouse dermis are in the range 1-20 μm; fibrillar collagen aligned along myofibers or nerve bundles in mice provide clefts in the range 2-30 μm in diameter.

    “As examples, interstitial spaces between randomly organized collagen fibril networks in human or mouse dermis are in the range 1-20 μm; likewise, fibrillar collagen aligned along myofibers or nerve bundles in mice provide clefts in the range 2-30 μm in diameter [13,14].”
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    CoC models are based on microfluidic chips harboring chambers for tumor-cell culture that enable control over cellular composition of the TME, local gradients, fluid flow, and tissue mechanics.

    “CoC models are based on microfluidic chips harboring chambers for tumor-cell culture that enable control over cellular composition of the TME, local gradients, fluid flow, and tissue mechanics.”
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    Oriented fiber tracks mediate focal contact orientation and contact guidance along 'highways', ultimately leading to higher tumor incidence.

    “oriented fiber tracks mediating focal contact orientation and contact guidance along 'highways', ultimately leading to higher tumor incidence [20,22,23].”
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    In the healthy organism, epithelial cells are positioned on a basement membrane composed mainly of collagen type IV and laminins, underlaid by interstitial tissue rich in collagen type I, elastin, and proteoglycans.

    “In the healthy organism, epithelial cells are positioned on a basement membrane composed mainly of collagen type IV and laminins, which is underlaid by interstitial tissue rich in collagen type I, elastin, and proteoglycans [10].”
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    In the TME, as a consequence of malignant transformation, cells break down the basement membrane and invade and remodel adjacent interstitial tissue.

    “In the TME, as a consequence of malignant transformation, cells break down the basement membrane [15,16] and invade and remodel adjacent interstitial tissue (Figure 1).”
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    The three TME components focused on (anisotropic ECM, vasculature, immune system) are relevant for developing ECM-targeting cancer treatments, evaluating drug dosing through the vasculature, and testing new immunotherapeutic strategies.

    “Also, these components are relevant for developing ECM-targeting cancer treatments [6], to evaluate effectiveness of drug dosing towards the tumor through the vasculature [7,8], and to test new immunotherapeutic strategies [9].”
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    Premisenone given

    CoC models can be classified into four major types: compartmentalized channel, porous membrane, template-based, and self-assembly.

    “CoC models can be classified into four major types, together allowing us to recapitulate key components of the tumor microenvironment (TME) relevant for our understanding of tumor development and for investigating potential therapies.”
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    Premisecitation

    ECM anisotropy, crosslinking, and stiffening are interlinked, with each promoting local carcinoma invasion by enhancing integrin signaling.

    “ECM anisotropy, crosslinking, and stiffening are interlinked, with each of them promoting local carcinoma invasion by enhancing integrin signaling”
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    More complex CoC models may harbor contractile CAFs and can be extended by adding endothelial or immune cells, supporting formation of multicell structures and processes in the TME.

    “More complex CoC models may harbor contractile CAFs [40][41][42], and can be further extended by adding endothelial or immune cells [42][43][44][45][46], altogether supporting the formation of multicell structures and processes in the TME, such as vessels, fibroblast networks, or immune influx (Figure 1).”
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    Interpretationreasoning

    Flow-derived generation of hydrogel anisotropy is a favorable methodology for CoC models because CoC models are designed to enable fluid flow.

    “CoC models are designed to enable fluid flow, and as such, flow-derived generation of hydrogel anisotropy represents a very favorable methodology.”
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    The formed microvessel network was perfusable and connected with the spheroid.

    “The formed microvessel network was perfusable and connected with the spheroid.”
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    Measurement of resulting fibril spacings can be quantified upon image analysis, and may range from 2-12 or 20 μm.

    “Even though space generation between fibrils can be less controlled as compared with engineered ECM patterning approaches as outlined previously, the measurement of resulting fibril spacings can be quantified upon image analysis, and for instance may range from 2-12 or 20 μm [21,37,38].”
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    Intravasation can be influenced or even triggered by multiple cues, including genetic, metabolic, or mechanical factors, or by cues in the TME such as oxygen tension, ECM, immune cells, and chemotactic gradients.

    “Intravasation can be influenced or even triggered by multiple cues, including genetic, metabolic, or mechanical factors, or by cues in the TME such as oxygen tension, ECM, immune cells, and chemotactic gradients [60][61][62][63]”
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    Self-assembly models for extravasation have been developed and used extensively.

    “Self-assembly models for extravasation have been developed and used extensively (Figure 3I) [83,84].”
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    ECM stiffness measurements in the 3D system may be obtained by Brillouin microscopy.

    “ECM stiffness measurements in the 3D system may be obtained by Brillouin microscopy [39].”
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    Premiseown data

    Flowing the chemotherapy drug paclitaxel through the microvessel network reduced tumor growth in a self-assembly model with patient-derived organoids and CAFs.

    “In addition, the influence of flowing the chemotherapy drug paclitaxel through the microvessel network was studied, and it was found that this drug reduced tumor growth.”
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    ECM networks in hydrogel-based 3D models can undergo secondary modification by cell-derived traction forces or proteolytic remodeling resulting in stretched and remodeled ECM structures.

    “Intrinsic to most hydrogel-based 3D models, ECM networks can undergo secondary modification by cell-derived traction forces or proteolytic remodeling resulting in stretched and remodeled ECM structures.”
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    Premisecitation

    Several studies have used compartmental channels or similar models for investigating extravasation.

    “Several studies have used compartmental channels or similar models for investigating extravasation [80][81][82].”
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    Because of abnormally high and continuous expression levels of angiogenic factors in cancer, the vasculature becomes ill-defined; vessel wall unstable and highly permeable, architecture tortuous and irregularly shaped, and density increased.

    “Because of the abnormally high and continuous expression levels of angiogenic factors in cancer, the vasculature becomes illdefined; the vessel wall is unstable and remains highly permeable, architecture of the vessel is tortuous and irregularly shaped, and the density of the vasculature is increased [50][51][52][53].”
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    CoC models can be applied to elucidate these effects, and researchers have developed vascularized CoC models to study extravasation to bone, brain, and other organs.

    “CoC models can be applied to elucidate these effects, and researchers have developed vascularized CoC models to study extravasation to bone [74][75][76], brain [77,78], and other organs [79]”
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    TNF-α secreted by macrophages increased endothelial permeability and enhanced cancer-cell invasion and intravasation in a compartmental channels model.

    “By using the compartmental channels model, it was found that the proinflammatory cytokine tumor necrosis factor α (TNF-α) secreted by macrophages increased the endothelial permeability and enhanced cancer-cell invasion and intravasation (Figure 3D) [64].”
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    The increased permeability of the endothelial barrier promoted tumor-cell extravasation and subsequent invasion via microtracks generated by the invading monocytes.

    “The increased permeability of the endothelial barrier promoted tumor-cell extravasation, and subsequently invasion via microtracks generated by the invading monocytes.”
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    Perfusion through side channels can establish chemokine gradients.

    “Perfusion through side channels can establish chemokine gradients.”
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    Inclusion of innate immune cells in cancer-on-chip models is relatively simple because cells from different donors can be combined.

    “Inclusion of innate immune cells in CoC models is relatively simple as cells from different donors can be combined.”
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    In an alginate hydrogel in a cancer-on-chip device, natural killer cells were attracted by tumor spheroids, invaded the tumor spheroid, and induced tumor-cell killing.

    “In an alginate hydrogel in a CoC device, NK cells were attracted by tumor spheroids where they invaded the tumor spheroid and induced tumor-cell killing [9].”
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    OoC models are based on microfluidic chips with micrometer-to millimeter-sized compartments and microchannels that enable controlled fluid transport.

    “Organ-on-chip (OoC) models are based on microfluidic chips with micrometer-to millimeter-sized compartments and microchannels that enable controlled fluid transport.”
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    The artificial lymph node system is now commercially exploited for drug screens before clinical trials.

    “This system is now commercially exploited for drug screens before clinical trials [113].”
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    CoC models can be applied to directly observe and quantify extravasation, and to study the influence of cell type.

    “These examples show that CoC models can be applied to directly observe and quantify extravasation, and to study the influence of cell type, but there is more potential to also investigate the influence of other TME components on this process.”
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    Cancer cells secrete soluble factors that attract monocytes to tissues and drive differentiation into M1 and M2 macrophage subsets with antitumor or protumor functions, respectively.

    “Cancer cells secrete soluble factors that attract monocytes to tissues, and here drive differentiation into M1 and M2 macrophage subsets with (respectively) antitumor or protumor functions.”
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    OoC compartments are optically accessible for live observation because chips are fabricated from transparent polymers.

    “Further, the compartments are optically accessible for live observation as the chips are fabricated from transparent polymers.”
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    Proinflammatory cytokines secreted by cancer-associated fibroblasts disrupt lymphatic vessel integrity, which could be reversed using blocking antibodies.

    “One study found that proinflammatory cytokines secreted by CAFs disrupt lymphatic vessel integrity, which could be reversed using blocking antibodies [121], thereby confirming the involvement of these cytokines.”
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    The first human artificial lymph node consisted of an extracellular matrix containing lymphocytes and dendritic cells, incorporated in a bioreactor for perfusion of oxygen and cell culture medium containing lymphocytes, enabling long-term experiments of 14-30 days.

    “The first human artificial LN [112] consisted of an ECM containing lymphocytes and DCs, incorporated in a bioreactor for perfusion of oxygen and cell culture medium containing lymphocytes, enabling long-term experiments (14-30 days).”
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    Breast-cancer cells invaded both bone-marrow niches at a similar rate, but they did not invade extracellular-matrix-only chambers.

    “Breast-cancer cells invaded both bone-marrow niches at a similar rate, but they did not invade ECM-only chambers.”
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    Upon tumor growth, more immune cells appear as natural killer cells, macrophages and dendritic cells become part of the tumor microenvironment, while T cells are necessary for a proper antitumor immune response.

    “Upon tumor growth, more immune cells appear, as natural killer (NK) cells, macrophages and dendritic cells (DCs) become part of the TME, while T cells are necessary for a proper antitumor immune response [98,99].”
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    Different TCR-engineered T cells had different cytotoxic effects, and cytotoxicity decreased under hypoxic conditions.

    “Different TCR-engineered T cells had different cytotoxic effects, and cytotoxicity decreased under hypoxic conditions [109].”
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    Tumors include fibroblasts and endothelial cells, and initially few immune cells.

    “Besides cancer cells, tumors include fibroblasts and endothelial cells, and initially few immune cells [97].”
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    In a device enabling growth of large tumor masses, CAR T cells entirely invaded breast and lung tumors, proliferated, and killed tumor cells over several days under dynamic conditions.

    “In a device enabling growth of large tumor masses, CAR T cells entirely invaded breast and lung tumors, proliferated, and killed tumor cells over several days under dynamic conditions [108].”
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    The small size of OoC models allows high control of cellular and matrix composition, local biochemical gradients and flows, and mechanical forces.

    “Their small size allows high control of the cellular and matrix composition, local biochemical gradients and flows, and mechanical forces.”
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    In compartmentalized channel model, endothelial cells infused into a side channel can form an endothelial layer on the interface with hydrogel, mimicking the blood-vessel wall.

    “Endothelial cells infused into a side channel can form an endothelial layer on the interface with hydrogel, mimicking the blood-vessel wall.”
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    Premisecitation

    Self-assembly models can be used to track and quantify extravasation kinetics and to differentiate between morphological states such as initial tumor-cell protrusion past the endothelium and complete transmigration.

    “Such models can be used to track and quantify the extravasation kinetics [84], and to differentiate between morphological states such as initial tumor-cell protrusion past the endothelium and complete transmigration.”
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    CoC is a particular application of OoC which is increasingly used to obtain crucial insights into cancer development.

    “Cancer-on-chip (CoC) is a particular application of OoC which is increasingly used to obtain crucial insights into cancer development.”
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    Premisereasoning

    OoC compartments can be used to reproducibly create an environment in which 3D cell-culture models can grow, develop, and interact within their own specified microenvironment, mimicking parts of human organs and tissues.

    “The compartments can be used to reproducibly create an environment in which 3D cell-culture models can grow, develop, and interact within their own specified microenvironment, as such mimicking (parts of) human organs and tissues.”
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    These lymphoid organ-on-chip models all lack lymph node stromal cells and as such do not fully recapitulate the specialized microenvironments required for lymph node function.

    “However, these lymphoid OoC models all lack LN stromal cells and as such do not fully recapitulate the specialized microenvironments required for LN function.”
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    Premisecitation

    Dendritic cells efficiently phagocytosed treated tumor cells, which enabled tumor antigen presentation.

    “Furthermore, DCs efficiently phagocytosed treated tumor cells [107], which enabled tumor antigen presentation.”
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  • May combine two claims.

    Premisecitation

    Lymphocytes in the artificial lymph node clustered together and responded to in vitro vaccination by secreting cytokines and antibodies.

    “Lymphocytes clustered together and responded to in vitro vaccination by secreting cytokines and antibodies.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inflammatory monocytes introduced into a compartmental channels device destroyed endothelial tight junctions and invaded into the surrounding hydrogel where they differentiated towards macrophages.

    “Once an endothelial monolayer was generated in a compartmental channels device, inflammatory monocytes were introduced, destroying endothelial tight junctions and invading into the surrounding hydrogel where they differentiated towards macrophages [103].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Natural killer cells killed tumor cells in a dose-dependent manner, and this was more efficient in the presence of an immunotherapeutic antibody.

    “Here, NK cells killed tumor cells in a dose-dependent manner, and this was even more efficient in the presence of an immunotherapeutic antibody (Figure 4B).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106]

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Immune cells in the tumor microenvironment not only kill tumor cells but can also support their metastatic behavior.

    “Immune cells in the TME not only kill tumor cells but can also support their metastatic behavior.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Both the tumor microenvironment and the lymph node are important for the steering or suppression of the antitumor response.

    “Thus, both the TME and the lymph node (LN) are important for the steering or suppression of the antitumor response.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given

    Cancer-on-chip models can be classified into four major types, which together allow recapitulation of the key components of the tumor microenvironment relevant for understanding tumor development and for investigating potential therapies.

    “CoC models can be classified in four major types, as shown in Figure 1, together allowing recapitulation of the key components of the TME relevant for understanding tumor development, as well as for investigating potential therapies.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Cancer-on-chip devices are designed to perform single or just a few tests simultaneously, whereas many applications require large-scale testing.

    “in addition, the CoC devices are designed to perform single or just a few tests simultaneously, whereas many applications require large-scale testing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    To fully represent the immune response in cancer-on-chip models, the lymph node must be included, with incorporation of lymphatic vessels to emulate tumor-lymphoid crosstalk.

    “To fully represent the immune response in CoC models, the lymph node must be included, with incorporation of lymphatic vessels to emulate tumor-lymphoid crosstalk, and a few recent publications are working in this direction.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationown data

    Current cancer-on-chip models can be categorized into four types, but specific chip designs, materials, and fabrication approaches are diverse even within these categories and vary between research laboratories, whereas large-scale implementation requires standardization.

    “Figure 1B shows that the current CoC models can be categorized into four types, but the specific chip designs, the materials used, and the corresponding fabrication approaches are quite diverse even within these categories, and they vary between research laboratories, whereas large-scale implementation requires standardization”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationreasoning

    To personalize cancer-on-chip models per patient case, a model should include all tumor microenvironment components relevant to the study to be done; specifically, for testing immunotherapies it is essential to use patient-matched adaptive immune cells (T lymphocytes).

    “To reach this goal (or to personalize CoCs per patient case), a CoC model should include all TME components relevant to the study to be done, to provide an adequate representation; specifically, for testing immunotherapies it is essential to use patient-matched adaptive immune cells (T lymphocytes) in the CoC model.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The inclusion of the immune system in cancer-on-chip models is a relatively recent development.

    “The inclusion of the immune system in CoC models is a relatively recent development.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Cancer-on-chip models have been mainly and successfully used to gain mechanistic insight into the role of specific tumor microenvironment components on tumor-cell behavior, but they can also be used to investigate the effect of cancer treatments.

    “Taken together, CoC models have been mainly and successfully used to gain mechanistic insight into the role of specific TME components on tumor-cell behavior, but they can also be used to investigate the effect of cancer treatments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Immune cells have been added in cancer-on-chip models, and they have been shown to largely affect tumor development.

    “Immune cells have been added in CoC models, and they have indeed been shown to largely affect tumor development.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Immune cells can play a decisive role in tumor development, being able to act both as protumor and antitumor agents.

    “immune cells can play a decisive role in tumor development, being able to act both as protumor and antitumor agents”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Incorporating immune cells in cancer-on-chip models is feasible and necessary for studying the antitumor immune response and the effect of immunotherapies.

    “Together, incorporating immune cells in CoC models is feasible and necessary for studying the antitumor immune response and the effect of immunotherapies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Cancer-on-chip models have been applied to understand the mutual influence between tumor and vasculature and to study intra- and extravasation under different conditions, such as the presence of immune cells and other cell types, dynamic strain, or biochemical gradients.

    “CoC models have been applied to understand the mutual influence between tumor and vasculature, and to study intra-and extravasation under different conditions, such as the presence of immune cells and other cell types, dynamic strain, or biochemical gradients.”
    Quote in the paperSubstantial claim
64 of 64

  • The paper relies on this without support.

    Cancer progression and fatal outcome are rarely caused by the primary tumor, but by secondary tumors formed through metastasis.

    “Cancer progression and fatal outcome are rarely caused by the primary tumor, but by secondary tumors formed through metastasis.”

  • The paper relies on this without support.

    The characteristic tumor microenvironment plays a pivotal role in the metastatic steps.

    “The characteristic tumor microenvironment (TME) has been indicated to play a pivotal role in these steps.”

  • The paper relies on this without support.

    Most CoC models still start with randomly organized, porous 3D hydrogel cultures.

    “To date, most CoC models still start with randomly organized, porous 3D hydrogel cultures.”

  • The paper relies on this without support.

    The vasculature plays a pivotal role in tumor progression because it nurtures the tumor and provides a transportation route for cancer cells to circulate throughout the body.

    “The vasculature plays a pivotal role in tumor progression since it nurtures the tumor and provides a transportation route for cancer cells to circulate throughout the body.”

  • The paper relies on this without support.

    T cells cannot recognize tumor cells by themselves and need antigen-presenting cells such as dendritic cells and macrophages to present tumor-specific antigens to them.

    “T cells cannot recognize tumor cells by themselves, and need antigen-presenting cellssuch as DCs and macrophagesto present tumor-specific antigens to them.”

  • The paper relies on this without support.

    Cancer cells metastasize to lymphoid organs via lymphatic vessels.

    “Cancer cells metastasize to lymphoid organs via lymphatic vessels.”

  • The paper relies on this without support.

    The extracellular matrix forms the structural basis for the development of a reactive tumor microenvironment by harboring fibroblasts, blood and lymph vessels, allowing biochemical gradients to establish, and providing a substrate for the migration of fibroblasts, immune cells, and cancer cells.

    “The ECM forms the structural basis for the development of a reactive TME by harboring fibroblasts, blood and lymph vessels, allowing biochemical gradients to establish, and providing a substrate for the migration of fibroblasts, immune cells, and cancer cells.”

  • The paper relies on this without support.

    By extracellular matrix deposition, stiffening, and fiber alignment, the extracellular matrix fibers promote directed tumor invasion, a hallmark of many solid cancers.

    “By ECM deposition, stiffening, and fiber alignment, the ECM fibers promote directed tumor invasion, a hallmark of many solid cancers.”

  • The paper relies on this without support.

    The co-dependent interaction between cancer cells and newly developed blood vessels supports tumor growth and generates a transportation route for tumor cells to metastasize.

    “the co-dependent interaction between cancer cells and (newly developed) blood vessels supports tumor growth and generates a transportation route for tumor cells to metastasize”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Tumor chips can capture many features including cell-cell and cell-ECM interactions, mechanical forces within the ECM, central hypoxia, desmoplasia, gradients of nutrients, pH, and soluble factors.

    “Tumor chips can capture many of these features, including cell-cell and cell-ECM interactions, mechanical forces within the ECM, central hypoxia, desmoplasia, gradients of nutrients, pH, and soluble factors (Koens et al., 2020; Miller et al., 2020; Jouybar et al., 2023).”

    From Microphysiological systems as models for immunologically ‘cold’ tumors (2024) · cites this paper as Jouybar et al., 2023

    The Abstract and the ECM in cancer-on-chip models section describe chips that control cell composition, biochemical gradients, tissue mechanics, and cell-driven ECM remodeling. The figure labeled Trends in Biotechnology lists nutrient and acidity gradients and dense ECM, while a model listed under Outstanding questions studies desmoplasia. However, the paper does not establish that chips capture *central* hypoxia; its discussion of oxygen gradients says most chips do not reproduce oxygen supply through vessels. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Blood-brain barrier model is cited to a bone-metastasis study

    Minor

    The text attributes a blood-brain barrier model to reference [74], but the paper's reference [74] is titled as a model of breast cancer metastasis to bone.

1 of 1

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Related

Authors
Jouybar, M., de Winde, C. M., Wolf, K., Friedl, P., Mebius, R. E., & den Toonder, J. M. J.
Affiliations
  • Eindhoven University of Technology (NL)
  • Radboud University Nijmegen (NL)
  • The University of Texas MD Anderson Cancer Center (US)
  • Cancer Center Amsterdam (NL)
ORCID
Venue
Trends in Biotechnology
Publisher
Elsevier BV
Published
2024-04
Volume
42
Issue
4
Pages
431-448
ISSN
0167-7799 (ISSN-L)
DOI
10.1016/j.tibtech.2023.10.001
OpenAlex
W4388049884
Semantic Scholar
28ea0016793c4daa379635e904063f19ab5ee0b7
Cited by
66
References
124
Citations by year
2026: 26 · 2025: 27 · 2024: 13
FWCI
1.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in biotechnology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • TU/e Research Portal (submittedVersion, other-oa)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
Funders
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Science-XL 2019.022, XL 2019.022, H2020-ECSEL-2019-IA-876190, 14641, 2019.022)
  • Electronic Components and Systems for European Leadership (H2020-ECSEL-2019-IA- 876190, 876190)
  • Cancer Center Amsterdam (CCA2020-9-73, CCA2019-9-57)
  • Horizon 2020 Framework Programme (H2020‐ECSEL‐2019‐IA‐876190)
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
  • Physical Sciences › Engineering › Biomedical Engineering › Microfluidic and Capillary Electrophoresis Applications
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
metastasis, tumor microenvironment, microfluidics, extracellular matrix, tumor vasculature, tumor immune system, cancer therapy development
MeSH terms
Extracellular Matrix, Humans, Neoplasms, Microfluidics, Tumor Microenvironment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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