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Modelling cancer in microfluidic human organs-on-chips

Nature Reviews Cancer volume 19, pages 65–81 (2019)Cite this article

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Abstract

One of the problems that has slowed the development and approval of new anticancer therapies is the lack of preclinical models that can be used to identify key molecular, cellular and biophysical features of human cancer progression. This is because most in vitro cancer models fail to faithfully recapitulate the local tissue and organ microenvironment in which tumours form, which substantially contributes to the complex pathophysiology of the disease. More complex in vitro cancer models have been developed, including transwell cell cultures, spheroids and organoids grown within flexible extracellular matrix gels, which better mimic normal and cancerous tissue development than cells maintained on conventional 2D substrates. But these models still lack the tissue–tissue interfaces, organ-level structures, fluid flows and mechanical cues that cells experience within living organs, and furthermore, it is difficult to collect samples from the different tissue microcompartments. In this Review, we outline how recent developments in microfluidic cell culture technology have led to the generation of human organs-on-chips (also known as organ chips) that are now being used to model cancer cell behaviour within human-relevant tissue and organ microenvironments in vitro. Organ chips enable experimentalists to vary local cellular, molecular, chemical and biophysical parameters in a controlled manner, both individually and in precise combinations, while analysing how they contribute to human cancer formation and progression and responses to therapy. We also discuss the challenges that must be overcome to ensure that organ chip models meet the needs of cancer researchers, drug developers and clinicians interested in personalized medicine.

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Fig. 1: A timeline showing the development of different cancer organs-on-chips.
Fig. 2: Orthotopic breast cancer in situ chip.
Fig. 3: Neovascularization chips.
Fig. 4: Orthotopic invasive versus dormant lung cancer organs-on-chips.
Fig. 5: Metastatic cancer cell dissemination models.
Fig. 6: Modelling systemic metastasis in a body-on-chip.

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Acknowledgements

This work was supported by the Wyss Institute for Biologically Inspired Engineering at Harvard University and Defense Advanced Research Projects Agency (DARPA) under Cooperative Agreement Number W911NF-12-2-0036. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of DARPA or the US Government.

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Author notes

  1. Bryan A. Hassell

    Present address: Nirrin Analytics, Billerica, MA, USA

  2. These authors contributed equally: Alexandra Sontheimer-Phelps, Bryan A. Hassell

Authors and Affiliations

  1. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, USA

    Alexandra Sontheimer-Phelps, Bryan A. Hassell & Donald E. Ingber

  2. Graduate program, Faculty of Biology, University of Freiburg, Freiburg, Germany

    Alexandra Sontheimer-Phelps

  3. Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA

    Bryan A. Hassell & Donald E. Ingber

  4. Vascular Biology Program and Department Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Donald E. Ingber

Authors
  1. Alexandra Sontheimer-Phelps
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  2. Bryan A. Hassell
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  3. Donald E. Ingber
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Contributions

Both A.S.-P. and B.A.H. researched and compiled the data from the literature and drafted a first draft of the manuscript. D.E.I. edited and revised the manuscript, working with the other authors.

Corresponding author

Correspondence to Donald E. Ingber.

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Competing interests

D.E.I. is a founder of, holds equity in and chairs the scientific advisory board of Emulate Inc. A.S.-P. and B.A.H. declare no competing interests.

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Glossary

Matrigel

A commercial product containing an extracellular matrix hydrogel composed of tumour-derived basement membrane proteins used for cell culture.

Fluid shear stress

Physical drag forces created by fluid flow parallel to the surface of a material, such as the apical membrane of the endothelium in a blood vessel.

Hydrostatic pressure

Pressure exerted by a fluid owing to gravity, a pressurized reservoir, pump or centrifugal force.

Peristaltic deformations

Cyclic muscular contractions and relaxations within the wall of an organ, such as the intestine.

Barth syndrome

A rare genetic disorder characterized by weakened heart and muscles, low white blood cell count and short statue.

Chronic obstructive pulmonary disease

A chronic inflammatory lung disease involving chronic bronchitis and/or emphysema that causes obstructed airflow in the lungs, resulting in difficulties in breathing.

Epithelial–mesenchymal transition

(EMT). A process in which epithelial cells take on a mesenchymal phenotype and lose their polarity and cell–cell contacts, which is associated with increased migratory and invasive capacity.

Matrix metalloproteinases

Enzymes that degrade extracellular matrix.

Minimal residual disease

The few surviving tumour cells that remain in tissues after complete remission is achieved through a successful therapeutic intervention; these cells are thought to be responsible for relapse of cancer.

Sacrificial materials

Substances that are deposited within other materials to form a solid gel and can later be solubilized to create hollow compartments, such as microfluidic channels, within a structure.

Arteriovenous malformation

An abnormal connection between blood vessels mainly in the brain or spine disrupting normal blood flow and oxygen circulation.

Laminar flow

A flow regime in which fluid flows in parallel layers with no disruption between the layers and a constant velocity at any point in the fluid.

Pneumatic micro-valves

Air controlled valves at the micrometre scale for the regulation of system pressure, as well as the control of flow rate and direction.

Invadopodia

Dynamic actin-rich cell membrane protrusions that can be associated with cancer cell invasion.

M2A macrophages

A subpopulation of alternatively activated macrophages that are associated with a T helper 2 cell immune response and are induced as a result of stimulation by the cytokines interleukin-4 (IL-4) and IL-13 or during fungal and helminth infections.

Endosteal surface

A layer covering the endosteum, which is a thin membranous tissue containing bone stem cells, blood vessels and connective tissue fibres that coats the inside of long bones and surrounds the bone marrow-filled medullary cavity.

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Sontheimer-Phelps, A., Hassell, B.A. & Ingber, D.E. Modelling cancer in microfluidic human organs-on-chips. Nat Rev Cancer 19, 65–81 (2019). https://doi.org/10.1038/s41568-018-0104-6

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