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Editorial overview: Biological engineering: engineering systems for cancer modeling, diagnostics and therapeutics
Available online at www.sciencedirect.com
ScienceDirect Editorial overview: Biological engineering: engineering systems for cancer modeling, diagnostics and therapeutics Sharon Gerecht and Konstantinos Konstantopoulos Current Opinion in Chemical Engineering 2016, 11:iv–v For a complete overview see the Issue Available online 21st February 2016 http://dx.doi.org/10.1016/j.coche.2016.02.004 2211-3398/# 2016 Elsevier Ltd. All rights reserved.
Sharon Gerecht and Konstantinos Konstantopoulos Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA e-mails: Gerecht, Sharon ([email protected]) and Konstantopoulos, Konstantinos ([email protected]) Professor Gerecht earned her bachelor’s and doctoral degrees from the Technion - Israel Institute of Technology. Following a postdoctoral training at MIT, she joined Chemical and Biomolecular Engineering at the Johns Hopkins University in 2007. She also serves as the Associate Director of the Institute for NanoBioTechnology. Dr. Gerecht’s research focuses on employing engineering fundamentals to study basic questions in stem and cancer cell biology and how to apply them for blood vessel regeneration and repair and the limitation of cancer progression. Her group was the first to control the activation of vascular morphogenesis in a completely synthetic matrix, and the establishment of a new class of oxygen-controlling hydrogel materials. Professor Konstantopoulos received his Diploma in Chemical Engineering from the National Technical University of Athens, Greece, and his Ph.D. from Rice University. Following postdoctoral work at Rice University, he joined the faculty of Chemical & Biomolecular Engineering at the Johns Hopkins University in 1997. He has been serving as Department Chair since 2008. His research is at the interface of engineering and biology pertinent to cancer metastasis. Some of his key bioengineering research contributions are the discovery of novel selectin ligands involved in tumor cell adhesion in the vasculature, the biophysical characterization of these adhesive interactions at the single-molecule level, and the elucidation of novel signaling mechanisms during cell migration through physically confined microenvironments.
Cancer metastasis is a highly regulated and multistep process in which tumor cells disseminate from a primary tumor to colonize distant sites in the body. The metastatic cascade is complex, encompassing tumor angiogenesis, which refers to the ingrowth of new capillary vessels that feed the growing tumor, migration of cancerous cells away from the primary tumor followed by their entry (called intravasation) into the bloodstream or lymphatic system, their transit through circulation, and their exit (called extravasation) to secondary tissues to form a secondary tumor. The process of cancer metastasis represents an exquisite feat of chemical and biomolecular engineering. Physical and biochemical cues, such as cell and tissue stiffness, oxygen tension and nutrient gradients, actively regulate tumor formation, progression and metastasis. Although animal models have provided significant insights on cancer metastasis, they fail to delineate the relative contributions of the different intertwining physical and biochemical factors that influence this complex process. However, chemical engineers and bioengineers are uniquely poised to address these limitations through a synthesis of engineering, materials and microtechnology principles coupled with quantitative modeling and concepts from biophysics, biochemistry and molecular cell biology. In this section, there are seven contributions summarizing key advances in our understanding of cancer metastasis that were made possible by utilizing an integrated chemical engineering-based approach. In vitro organ-on-a-chip models for cancer metastasis have been recently developed to recapitulate major components of the metastatic process. Chen and his group provide an overview of the current angiogenesis-on-a-chip models, which exhibit phenotypes of physiological angiogenesis. However, tumor angiogenesis is distinct from normal angiogenesis given that the tumor vasculature displays irregular sprouting, tortuous networks of capillaries and leaky barrier properties. The authors posit that generation of relevant tumor angiogenesis models in vitro is key to understanding the abnormality of tumor endothelium, tumor drug delivery, tumor vascular mimicry and blood-borne metastasis. They also review models of tumor intravasation and extravasation, and discuss the challenges that need to be addressed for developing on-chip platforms that closely mimic the in vivo setting. Lewis and Gerecht provide a companion review on lab-on-a-chip technologies by focusing on the integration of microfluidics and hydrogels toward developing novel devices to study angiogenesis. The review highlights the
Current Opinion in Chemical Engineering 2016, 11:iv–v
www.sciencedirect.com
Editorial overview Gerecht and Konstantopoulos v
advantages of these systems, which provide us with the ability to precisely control physical and biochemical cues, such as shear stress, nutrients and chemical transport. The authors also discuss a variety of fabrication techniques to create such devices, and elaborate on their applications and future directions of these new technologies. The tumor microenvironment plays a critical role in regulating tumor formation, progression and metastasis. Liu and Vunjak-Novakovic provide a comprehensive review on naturally-derived and synthetic biomaterials that have been developed to recapitulate the tumor cell– extracellular matrix interactions of the native three-dimensional tumor microenvironment. The authors also discuss semi-synthetic biomaterials developed by chemically modifying natural materials to engender the control over scaffold fabrication and/or to augment the bioactivity of synthetic materials. They also highlight the increasing clinical relevance of these tissue-engineered tumor models and their applications to disease modeling and pharmaceutical testing. Chemical engineers and bioengineers are uniquely poised to make significant contributions to the field of mechanotransduction in cancer, which refers to how cells sense and respond to mechanical cues by converting them to biochemical signals that elicit cellular responses. Janmey, Discher and colleagues focus on how the stiffness of the extracellular matrix regulates tumor cell mechanics and function pertinent to angiogenesis, migration and metastasis. The authors explain a seemingly paradoxical conclusion supported by numerous, independent studies showing that tumor tissues are stiff whereas tumor cells are softer than their normal counterparts. Tissue stiffening is associated with increased collagen deposition and collagen fibril alignment. Tumor cells need to generate traction for locomotion on stiff substrates but they also need to be soft to squeeze through narrow pores in order to disperse throughout the body. The team reviews key signaling pathways involved in tumor cell mechanosensing as well as novel biomaterials of tunable rigidity that are currently used to delineate the mechanisms of mechanotransduction in cancer. Elvassore and colleagues provide a companion review on mechanotransduction focusing on how the manipulation of the extracellular environment through microengineered features affects the spatial and temporal distribution and interactions of biochemical structures at the cell– substrate and cell–cell interface. The authors also posit
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that integration of live-cell imaging with novel tools capable of applying and quantifying forces and displacements with piconewton and nanometer resolutions will be key to further advancing the field of mechanotransduction in cancer. Stephen Paget was the first to postulate the ‘seed and soil’ hypothesis in 1889 to explain the non-random pattern of metastasis. Since then, researchers have directed their efforts at elucidating the genetic determinants of the seed (the cancer cell) and the properties of the soil (the extracellular matrix) that dictate tissue selectivity (tropism). Peyton and colleagues review engineered model systems to study the role of the extracellular matrix as a driver of metastasis to specific tissues in the body. The authors also discuss the role of physical forces in driving invasion and metastasis, with a focus on breast cancer. Finally, they review the research community’s ability to predict when and where tumor cells will metastasize, and provide insights on what these predictions mean for patient prognosis and drug treatment. During the metastatic process, cancerous cells separate from a primary tumor, migrate across blood vessel walls into the circulation and disperse throughout the body to seed secondary colonies. Only a few of the tumor cells in the circulation, referred to as circulating tumor cells (CTCs), survive, extravasate, and ultimately colonize secondary organs. CTCs are rare cells: typically 1–10 per mL of blood, which contains 4–6 millions blood cells. CTCs have potential as a liquid biopsy provided that they can be effectively isolated from surrounding blood cells. Nagrath and her group provide an overview of the different methods for capturing CTCs, and highlight the advantages and drawbacks of the various microfluidic-based isolation techniques. The authors conclude by stating that these techniques are being verified in the clinical setting, and can be used to track disease progression or response to treatment as well as to analyze genetic material and to expand captured cells with the objective of opening additional analytical doors. In closing, it has been a pleasure to interact with leading scientists and rising stars who offered their insights and perspectives in the broad area of engineering systems for cancer modeling, diagnostics and therapeutics. We are confident that the readers will benefit from the authors’ comprehensive reviews as well as their views of the future promise of this exciting area.
Current Opinion in Chemical Engineering 2016, 11:iv–v
ScienceDirect Editorial overview: Biological engineering: engineering systems for cancer modeling, diagnostics and therapeutics Sharon Gerecht and Konstantinos Konstantopoulos Current Opinion in Chemical Engineering 2016, 11:iv–v For a complete overview see the Issue Available online 21st February 2016 http://dx.doi.org/10.1016/j.coche.2016.02.004 2211-3398/# 2016 Elsevier Ltd. All rights reserved.
Sharon Gerecht and Konstantinos Konstantopoulos Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA e-mails: Gerecht, Sharon ([email protected]) and Konstantopoulos, Konstantinos ([email protected]) Professor Gerecht earned her bachelor’s and doctoral degrees from the Technion - Israel Institute of Technology. Following a postdoctoral training at MIT, she joined Chemical and Biomolecular Engineering at the Johns Hopkins University in 2007. She also serves as the Associate Director of the Institute for NanoBioTechnology. Dr. Gerecht’s research focuses on employing engineering fundamentals to study basic questions in stem and cancer cell biology and how to apply them for blood vessel regeneration and repair and the limitation of cancer progression. Her group was the first to control the activation of vascular morphogenesis in a completely synthetic matrix, and the establishment of a new class of oxygen-controlling hydrogel materials. Professor Konstantopoulos received his Diploma in Chemical Engineering from the National Technical University of Athens, Greece, and his Ph.D. from Rice University. Following postdoctoral work at Rice University, he joined the faculty of Chemical & Biomolecular Engineering at the Johns Hopkins University in 1997. He has been serving as Department Chair since 2008. His research is at the interface of engineering and biology pertinent to cancer metastasis. Some of his key bioengineering research contributions are the discovery of novel selectin ligands involved in tumor cell adhesion in the vasculature, the biophysical characterization of these adhesive interactions at the single-molecule level, and the elucidation of novel signaling mechanisms during cell migration through physically confined microenvironments.
Cancer metastasis is a highly regulated and multistep process in which tumor cells disseminate from a primary tumor to colonize distant sites in the body. The metastatic cascade is complex, encompassing tumor angiogenesis, which refers to the ingrowth of new capillary vessels that feed the growing tumor, migration of cancerous cells away from the primary tumor followed by their entry (called intravasation) into the bloodstream or lymphatic system, their transit through circulation, and their exit (called extravasation) to secondary tissues to form a secondary tumor. The process of cancer metastasis represents an exquisite feat of chemical and biomolecular engineering. Physical and biochemical cues, such as cell and tissue stiffness, oxygen tension and nutrient gradients, actively regulate tumor formation, progression and metastasis. Although animal models have provided significant insights on cancer metastasis, they fail to delineate the relative contributions of the different intertwining physical and biochemical factors that influence this complex process. However, chemical engineers and bioengineers are uniquely poised to address these limitations through a synthesis of engineering, materials and microtechnology principles coupled with quantitative modeling and concepts from biophysics, biochemistry and molecular cell biology. In this section, there are seven contributions summarizing key advances in our understanding of cancer metastasis that were made possible by utilizing an integrated chemical engineering-based approach. In vitro organ-on-a-chip models for cancer metastasis have been recently developed to recapitulate major components of the metastatic process. Chen and his group provide an overview of the current angiogenesis-on-a-chip models, which exhibit phenotypes of physiological angiogenesis. However, tumor angiogenesis is distinct from normal angiogenesis given that the tumor vasculature displays irregular sprouting, tortuous networks of capillaries and leaky barrier properties. The authors posit that generation of relevant tumor angiogenesis models in vitro is key to understanding the abnormality of tumor endothelium, tumor drug delivery, tumor vascular mimicry and blood-borne metastasis. They also review models of tumor intravasation and extravasation, and discuss the challenges that need to be addressed for developing on-chip platforms that closely mimic the in vivo setting. Lewis and Gerecht provide a companion review on lab-on-a-chip technologies by focusing on the integration of microfluidics and hydrogels toward developing novel devices to study angiogenesis. The review highlights the
Current Opinion in Chemical Engineering 2016, 11:iv–v
www.sciencedirect.com
Editorial overview Gerecht and Konstantopoulos v
advantages of these systems, which provide us with the ability to precisely control physical and biochemical cues, such as shear stress, nutrients and chemical transport. The authors also discuss a variety of fabrication techniques to create such devices, and elaborate on their applications and future directions of these new technologies. The tumor microenvironment plays a critical role in regulating tumor formation, progression and metastasis. Liu and Vunjak-Novakovic provide a comprehensive review on naturally-derived and synthetic biomaterials that have been developed to recapitulate the tumor cell– extracellular matrix interactions of the native three-dimensional tumor microenvironment. The authors also discuss semi-synthetic biomaterials developed by chemically modifying natural materials to engender the control over scaffold fabrication and/or to augment the bioactivity of synthetic materials. They also highlight the increasing clinical relevance of these tissue-engineered tumor models and their applications to disease modeling and pharmaceutical testing. Chemical engineers and bioengineers are uniquely poised to make significant contributions to the field of mechanotransduction in cancer, which refers to how cells sense and respond to mechanical cues by converting them to biochemical signals that elicit cellular responses. Janmey, Discher and colleagues focus on how the stiffness of the extracellular matrix regulates tumor cell mechanics and function pertinent to angiogenesis, migration and metastasis. The authors explain a seemingly paradoxical conclusion supported by numerous, independent studies showing that tumor tissues are stiff whereas tumor cells are softer than their normal counterparts. Tissue stiffening is associated with increased collagen deposition and collagen fibril alignment. Tumor cells need to generate traction for locomotion on stiff substrates but they also need to be soft to squeeze through narrow pores in order to disperse throughout the body. The team reviews key signaling pathways involved in tumor cell mechanosensing as well as novel biomaterials of tunable rigidity that are currently used to delineate the mechanisms of mechanotransduction in cancer. Elvassore and colleagues provide a companion review on mechanotransduction focusing on how the manipulation of the extracellular environment through microengineered features affects the spatial and temporal distribution and interactions of biochemical structures at the cell– substrate and cell–cell interface. The authors also posit
www.sciencedirect.com
that integration of live-cell imaging with novel tools capable of applying and quantifying forces and displacements with piconewton and nanometer resolutions will be key to further advancing the field of mechanotransduction in cancer. Stephen Paget was the first to postulate the ‘seed and soil’ hypothesis in 1889 to explain the non-random pattern of metastasis. Since then, researchers have directed their efforts at elucidating the genetic determinants of the seed (the cancer cell) and the properties of the soil (the extracellular matrix) that dictate tissue selectivity (tropism). Peyton and colleagues review engineered model systems to study the role of the extracellular matrix as a driver of metastasis to specific tissues in the body. The authors also discuss the role of physical forces in driving invasion and metastasis, with a focus on breast cancer. Finally, they review the research community’s ability to predict when and where tumor cells will metastasize, and provide insights on what these predictions mean for patient prognosis and drug treatment. During the metastatic process, cancerous cells separate from a primary tumor, migrate across blood vessel walls into the circulation and disperse throughout the body to seed secondary colonies. Only a few of the tumor cells in the circulation, referred to as circulating tumor cells (CTCs), survive, extravasate, and ultimately colonize secondary organs. CTCs are rare cells: typically 1–10 per mL of blood, which contains 4–6 millions blood cells. CTCs have potential as a liquid biopsy provided that they can be effectively isolated from surrounding blood cells. Nagrath and her group provide an overview of the different methods for capturing CTCs, and highlight the advantages and drawbacks of the various microfluidic-based isolation techniques. The authors conclude by stating that these techniques are being verified in the clinical setting, and can be used to track disease progression or response to treatment as well as to analyze genetic material and to expand captured cells with the objective of opening additional analytical doors. In closing, it has been a pleasure to interact with leading scientists and rising stars who offered their insights and perspectives in the broad area of engineering systems for cancer modeling, diagnostics and therapeutics. We are confident that the readers will benefit from the authors’ comprehensive reviews as well as their views of the future promise of this exciting area.
Current Opinion in Chemical Engineering 2016, 11:iv–v