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Engineering and physical sciences in oncology: challenges and opportunities

A Publisher Correction to this article was published on 18 October 2018

Key Points

  • Engineers and physical scientists have pioneered research into understanding cancer as more than simply malignant cells with genetic mutations and instead as aberrant organs composed of cancer cells and their surrounding stroma, referred to as the tumour microenvironment (TME). Many aspects of the microenvironment are abnormal, which fuels tumour progression and treatment resistance.

  • Recent work using advanced in vivo imaging, computational modelling and animal models has identified barriers in the TME that hinder therapy and promote tumour progression.

  • Under pathological conditions, remodelling of the extracellular matrix (ECM) leads to fibre alignment, bundling and stiffening, which in turn alters tumour and stromal cell–matrix mechanics and interactions to enhance pro-angiogenic secretion from a range of cells in the TME as well as the migration of cancer cells. This promotes the invasion of tumour cells from the primary site into the circulation and the recruitment of endothelial cells for vascularization of the tumour to initiate tumour growth, invasion into the surrounding stroma and, finally, metastasis.

  • Tumour cells with a larger glycocalyx than normal cells exhibit extended gaps between the membrane and ECM, clustering of integrins, the exclusion of glycopolymers from regions of integrin adhesion and membrane bending. Engineered glycoprotein mimetics have been used to study how the physical properties of the glycocalyx coating alter cellular signalling and promote tumour survival and metastasis.

  • Drug delivery scientists pioneered the development of engineering systems that deliver therapeutics in a safe, effective and targeted fashion. Recent advances have focused on new delivery systems for cancer immunotherapy and gene therapy, as well as implantable devices for developing personalized medicine regimens.

  • Engineers and physical scientists have advanced imaging in oncology through the development of macroscopic imaging techniques in clinical settings, in addition to intravital optical techniques used in research settings that are increasingly used to detect various biomarkers. Clinical imaging probes developed by engineers and material scientists, such as fluorescent proteins, nanomaterials and labelled small and large molecules, have complemented these modalities.

  • Advances in microfluidics and microfabrication have led to the development of tissue and organ models that can incorporate physiological fluid flow and real-time optical imaging to study tumour cell migration and mechanotransduction. Microfluidics are also used to create human 'organs-on-chip' models for high-throughput drug screening, as well as isolation of rare circulating tumour cells and exosomes from patient blood samples.

Abstract

The principles of engineering and physics have been applied to oncology for nearly 50 years. Engineers and physical scientists have made contributions to all aspects of cancer biology, from quantitative understanding of tumour growth and progression to improved detection and treatment of cancer. Many early efforts focused on experimental and computational modelling of drug distribution, cell cycle kinetics and tumour growth dynamics. In the past decade, we have witnessed exponential growth at the interface of engineering, physics and oncology that has been fuelled by advances in fields including materials science, microfabrication, nanomedicine, microfluidics, imaging, and catalysed by new programmes at the National Institutes of Health (NIH), including the National Institute of Biomedical Imaging and Bioengineering (NIBIB), Physical Sciences in Oncology, and the National Cancer Institute (NCI) Alliance for Nanotechnology. Here, we review the advances made at the interface of engineering and physical sciences and oncology in four important areas: the physical microenvironment of the tumour and technological advances in drug delivery; cellular and molecular imaging; and microfluidics and microfabrication. We discussthe research advances, opportunities and challenges for integrating engineering and physical sciences with oncology to develop new methods to study, detect and treat cancer, and we also describe the future outlook for these emerging areas.

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Figure 1: An overview of engineering and physical sciences in oncology.
Figure 2: Extracellular matrix stiffening promotes cancer progression.
Figure 3: Role of the cancer cell glycocalyx in cancer progression.
Figure 4: Drug delivery vehicles to enhance cancer immunotherapy.
Figure 5: Non-viral delivery vectors for RNA-based therapies.
Figure 6: Implantable drug delivery devices for simultaneous screening of many drugs in tumours.
Figure 7: Multiplexed ion beam imaging for detecting as many as 100 targets simultaneously in tumour tissue samples.
Figure 8: Microfluidics and microfabricated devices for 'organs-on-chip' tumour models and cancer diagnostics.

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Acknowledgements

This work was supported in part by a Cancer Center Support (core) Grant P30-CA14051 from the National Cancer Institute and a grant from the Koch Institute's Marble Centre for Cancer Nanomedicine (to R.L.) and the National Cancer Institute (P01-CA080124, R01-CA126642, R01-CA115767, R01-CA096915, R01-CA085140, R01-CA098706) and NCI Outstanding Investigator Award (R35-CA197743) (to R.K.J.). M.J.M. was supported by a Burroughs Wellcome Fund Career Award at the Scientific Interface, an NIH F32 fellowship (award number CA200351) and a grant from the Burroughs Wellcome Fund (no. 1015145). The authors thank V. Chauhan, M. Oberli, K. Kozielski, K. Wang, B. R. Seo, D. Fukumura, L. Munn and T. Stylianopoulos for helpful discussions and feedback on the manuscript. The authors thank K. Wang for assisting with conceptualization of figures.

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Contributions

M.J.M., R.K.J. and R.L. conceived the ideas, researched the data for the manuscript, discussed the manuscript content and wrote the manuscript. M.J.M. designed the display items. All authors reviewed and edited the article before submission.

Corresponding authors

Correspondence to Michael J. Mitchell or Rakesh K. Jain or Robert Langer.

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The authors declare no competing financial interests.

PowerPoint slides

Glossary

Tumour microenvironment

(TME). The microenvironment surrounding cancer cells, which is composed of blood and lymphatic vessels, fibroblasts, immune cells and other non-malignant host cells, all embedded within extracellular matrix.

Interstitial fluid pressure

(IFP). Pressure exerted by free interstitial tissue fluid. Increased IFP in tumours pushes fluid, growth factors, administered therapeutic molecules and cells to the peri-tumour tissue, aiding tumour progression.

Enhanced permeability and retention

(EPR). An effect based on proposed mechanisms for selective tumour delivery of drugs. These mechanisms include the greater permeability of tumour vessels than normal vessels to macromolecules and the retention of macromolecules in tumours due to poor lymphatic clearance.

Computed tomography

(CT). A diagnostic imaging test used to create images of internal organs, bones, soft tissue and blood vessels. In oncology, cross-sectional CT images are used to confirm the location and size of tumours.

Solid stresses

Stresses exerted by and accumulated within solid components of tissues (that is, cells and extracellular matrix) during growth and progression. In tumours, solid stress is elevated due to growth and is independent of high interstitial fluid pressure.

Tumour deformation assays

An assay to quantify stress in tumours. Excised tumours are cut in the middle of the tumour, and stress relaxation is quantified as the extent of tumour opening normalized to the diameter of the tumour.

Desmoplasia

The formation and growth of fibrous tissue. In cancer, desmoplasia may occur around a neoplasm, causing dense fibrosis around the tumour.

Ultrasonography

A technique using echoes of ultrasound pulses to delineate objects or areas of different density in the body. In cancer, ultrasonography is used to detect solid tumours.

Matricellular-enriched fibrosis

The thickening and scarring of tissue surrounding a tumour, composed of dynamically expressed, non-structural proteins that are present in the extracellular matrix.

Hyaluronidase

An enzyme that catalyses the degradation of hyaluronic acid, a component of the extracellular matrix that contributes to tumour growth.

Adjuvant

A substance that enhances the body's immune response to foreign antigens.

Replicon mRNA

A self-replicating nucleic acid that amplifies production of the encoded protein and prolongs translation.

Scavenger receptors

A group of receptors that recognize low-density lipoprotein that has been modified by oxidation or acetylation.

Microdoses

Doses of a drug on the microgram scale, or about one-millionth of the systemic dose of a drug, that are intended to produce a beneficial result while avoiding undesirable side effects.

Bacteriophages

Long, tubular viruses that infect specific bacteria; they have been used as scaffolds for nanoparticles and targeting ligands for imaging tumours using magnetic resonance imaging (MRI).

Autologous chemotaxis

A mechanism by which a tumour cell can receive directional cues while at the same time being the source of such cues, enabling dissemination into the lymphatic system.

Surface plasmon resonance

An optical technique for detecting the interaction of two different molecules or particles, in which one is mobile and one is fixed on a thin gold film.

Deterministic lateral displacement pillar arrays

Arrays of pillars fabricated from silicon used to sort, separate and enrich microscale particles including parasites, bacteria, blood cells and tumour cells under flow conditions.

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Mitchell, M., Jain, R. & Langer, R. Engineering and physical sciences in oncology: challenges and opportunities. Nat Rev Cancer 17, 659–675 (2017). https://doi.org/10.1038/nrc.2017.83

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