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Overall, the likelihood of FDA approval for a drug any disease indication that has entered phase I clinical trials is a mere 9. Lack of efficacy or toxicity is often not revealed until the later stages of clinical trials, despite promising preclinical data. This indicates that the current in vitro systems for drug screening need to be improved for better predictability of in vivo outcomes. Microphysiological systems MPS , or bioengineered 3D microfluidic tissue and organ constructs that mimic physiological and pathological processes in vitro, can be leveraged across preclinical research and clinical trial stages to transform drug development and clinical management for a range of diseases.
Here we review the current state-of-the-art in 3D tissue-engineering models developed for cancer research, with a focus on tumor-on-a-chip, or tumor chip, models. From our viewpoint, tumor chip systems can advance innovative medicine to ameliorate the high failure rates in anti-cancer drug development and clinical treatment.
Cancer is the second leading cause of death in the United States, with 1, people dying from the disease every day. Despite the high incidence, drug discovery has been slow to translate into clinical benefit for patients and the paucity of effective treatments in oncology is consequent to the high attrition rate during drug development.
Given the fact that about two thirds of drug development cost occurs during clinical trial phases, the ability to more accurately identify lead candidates and eliminate ineffective drugs earlier in the process will save a significant amount of time and resources, reduce human risk, and accelerate the translation of effective therapies to the clinic.
While animal models have advanced our understanding of complex diseases such as cancer and provide essential readouts of organism-level drug effects in vivo, these same models are expensive, time consuming and often fail to predict human responses during clinical trials. Cell growth in 2D versus 3D environments not only promotes changes in cellular morphology, function, response to stimuli, and gene expression patterns, but also leads to drug responses that vary dramatically from the in vivo situation.
To bridge the translational gap between current preclinical models and clinical outcomes, in vitro platforms that better mimic native tissue physiology are undergoing rapid evolution.
By leveraging microfluidics technology, physiological relevance can be built into the MPS to model the dynamic microenvironment and inter-cellular interactions of complex tissues or organ-systems. High-fidelity modeling of essentially any tissue in the human body to reproduce corresponding functional units is now possible. For example, microscaled platforms have been developed to model lung 16 , liver 17 , brain 18 , endocrine tissues 19 , intestine 20 , kidney 21 , 22 , and heart 23 , among many others.
In addition to these micro-organ platforms, MPS technology offers new opportunities for building and applying functional three-dimensional in vitro human tumor models for oncology research. Besides 3D cellular assembly, the tumor microenvironment consists of a complex combination of ECM, stromal cells and interstitial fluids.
This complex composition influences the tumor cell phenotype via mechanical and biochemical factors that ultimately contribute to tumor growth. Tumor chips have been arrayed for high throughput drug screening applications 44 , optimized for cancer metastasis studies such as tumor cell extravasation and micrometastasis generation 45 , and populated with patient-specific cells for personalized medicine approaches.
In this review, we first briefly describe the strengths and limitations of current model systems and highlight critical features of the tumor microenvironment that contribute to disease progression.
We then review the current state-of-the-art in 3D tissueengineering models developed for cancer research and outline how the technology is revolutionizing disease modeling, drug screening and personalized medicine for oncology. Within this context, we critically evaluate limitations in current tumor chip models and address challenges in the field by proposing solutions to accelerate the translation of tumor chips into mainstream use.
While assays derived from 2D monolayers of cell lines grown on plastic are low cost, easy to use and high throughput, these same models have limited predictive capability since they fail to mimic natural human physiology. Another major limitation of 2D assays is that artificial in vitro conditions for growing cells on plastic dishes prevents investigation and therapeutic targeting of many cell behaviors that lead to disease progression and treatment failure, such as immune suppression and metastasis.
This feature is critical for drug testing since environmental cues can have profound effects on cell functions, which often affect cellular responses to drugs. By maintaining tumor cells in a native 3D conformation, spheroid cultures address certain limitations in 2D cell models. Spheroids develop distinct areas of rapidly dividing cells on the outer layer vs necrotic and slow cycling cells at the center and intermediate layers, respectively. Three-dimensional models provide sound insight into the differences between normal and malignant epithelial cells and serve as an excellent basis for determining the intermediate steps that are responsible for the transition from a normal to a malignant fate.
Spheroids are useful models of avascular tumors but lack the structure and complexity seen in vascularized tumors in vivo. Due to static culture conditions, cells in spheroid models do not experience the same mechanical forces that would be expected in vivo and lack of dynamic flow also prevents long-term culture for drug sensitivity and toxicity studies.
Another significant limitation is that many tumor types, especially those with a highly invasive phenotype, do not readily form spheroids and so cannot be assayed in these cultures e. MDA-MB breast cancer cell line.
To address these shortcomings, tumor chips represent more sophisticated tissue-based culture models that mimic critical features not represented in traditional monolayer or spheroid cultures. Animal surrogates of human disease are a necessary component in the drug development pipeline because these in vivo models can emulate physiological complexity at the whole-organism level.
Although animal studies have advanced our understanding of complex diseases such as cancer, a major shortcoming of these models is that they often have only limited translatability to humans.
This procedure greatly facilitates tumor monitoring by palpation and visual inspection, but is poorly representative of tumor development in the native tissue microenvironment.
Less commonly, transplants are generated orthotopically, or in the original site of cancer, to better mimic tumor-specific disease evolution, although these procedures can present technical challenges both in establishing and monitoring the xenograft tumor. In contrast, tumor chips can be composed entirely of human cells and tissue-specific factors of the microenvironment can be readily incorporated into the chip by design to better mimic the organ site of tumor origin.
To better replicate the heterogeneity of human tumors, patient-derived xenograft PDX tumor models that are established from transplantation of primary tumors are increasingly being adopted for drug screening, disease modeling and personalized medicine applications.
While there have been increasing efforts to use PDX as models to study drug response, recent evidence suggests that PDX may not recapitulate parent tumor characteristics as faithfully as initially assumed.
Interestingly, individual PDX models often gained or lost CNAs and mutations in cancer-related genes during PDX passage, quickly diverging genomically from the parental tumors from which they derived. These changes in genomic landscape were comparable to those observed in primary-derived cells maintained and passaged in vitro, which included loss of recurrent chromosomal aberrations that are believed to have casual roles in tumor progression and therapy response.
These results suggest that primary-derived cells are critically influenced by the amount of time maintained outside of the body, and that MPS can address this limitation by providing an in vivo -like environment amenable to more rapid analysis. While severely immunocompromised mice are necessary to allow engraftment of human tumors, such models preclude the study and therapeutic targeting of interactions between adaptive immune cells and tumor cell populations.
Humanized mouse models are being developed to address this concern, whereby human immune components are incorporated to partially reconstitute the immune-inflammatory response during disease progression. Furthermore, spatially random and temporally rapid events such as tumor cell intravasation that can be easily visualized in real-time using tumor chips cannot be easily interrogated using animal models.
Transgenic mouse models have been genetically engineered to partially recapitulate aspects of human carcinogenesis in situ, however evidence suggests key differences in the signaling requirements for transformation of mouse and human cells. Although animal models represent a necessary component in the drug development pipeline and have provided useful information on disease processes, these same models require tremendous time and resources and thus represent a low throughput model system.
Even so, approximately 27 million vertebrate animals are used for research purposes in the US every year, highlighting the ethical burden associated with these studies. To create a realistic tumor model, several key features of an actual tumor must be replicated. A tumor comprises numerous cell types in a dynamic tumor microenvironment wherein a host of biochemical and biophysical cues dictate cellular responses.
Although tumor genetic heterogeneity remains a significant barrier to effective cancer eradication, it is now widely recognized that the tumor microenvironment plays an equally critical role in cancer initiation, progression and drug resistance, thus representing an attractive therapeutic target independent of the myriad genomic aberrations unique to each tumor.
These mechanical forces are generated by fluid forces, shear stresses, interstitial flow and ECM organization, composition and stiffness. Like normal tissues, tumors require delivery of oxygen and nutrients, and elimination of metabolic wastes, via the vascular supply.
In the absence of new vasculature, central necrosis will develop in a solid tumor due to limited diffusion of oxygen to the tumor core resulting in hypoxia, high acidity and the accumulation of wastes. Quiescent tumor cells are difficult to eradicate with conventional therapies that target rapidly proliferating cells, such as radiation and chemotherapy.
Synergistic interactions between malignant cells and the tumor microenvironment lead to active ECM remodeling that further promotes the recruitment of fibroblasts, immune-inflammatory cells, and perivascular cells to facilitate cancer cell dissemination and invasion to distant organs. Bissell and colleagues demonstrated the importance of faithfully recapitulating the tissue-specific tumor microenvironment in a series of seminal studies.
However, when the same mammary luminal epithelial cells were cultured in 3D collagen I gels, the self-assembled spheres failed to form a central lumen, demonstrated inverse cell polarity and did not produce milk protein. Interestingly, the physiological phenotype i. By extracting and comparing ECM from normal human colon tissue and colon tumor metastases, we found differences in protein composition and stiffness between the two reconstituted matrices with overrepresentation of a number of ECM proteins e.
When introduced in vivo, tumor ECM promoted enhanced vascularization to the cancer cells. A better understanding of interactions within the tumor microenvironment, gained through use of appropriate experimental models such as MPS, will be critical to overcome treatment resistance through the development of successful targeted therapeutics.
The ability to rapidly screen drugs and study disease mechanisms within a physiologically relevant context is critically important to facilitate clinical translation of preclinical findings. To address current limitations in preclinical models, multiple research groups have focused on innovating MPS that model both normal and pathological human tissue functions in vitro. Major advantages of on-chip tissue models are that they recapitulate both the 3D organization and multicellular complexity of tissues and at the same time enable enhanced dynamic control over the cellular microenvironment to accommodate systematic experimental intervention.
Microfabrication techniques such as soft lithography and replica molding are often used to manufacture tissue chips based on precise microfluidic designs.
These bioengineering approaches allow manipulation of fluids at ultralow volumes i. Since fluid flow in microfluidic channels is laminar, it can be easily mathematically modeled, allowing theoretical predictions of complex biological phenomena 48 that, when coupled with experimental analysis, provide a robust in vitro system for understanding tissue function and testing promising approaches for treating disease.
Microfluidic devices for biomedical purposes are often fabricated using poly dimethylsiloxane PDMS , an elastic silicone-based polymer that is biocompatible, oxygen-permeable, and optically transparent, allowing for continuous observation of tissue constructs by microscopy for real-time assessment of cell behavior and response to treatment.
Current on-chip approaches mainly rely on combining pre-differentiated cells in particular ratios, often within an ECM or hydrogel that acts as scaffolding for cell growth, to emulate the native tissue composition. Based on advances in tissue-engineering strategies, individual organ-on-a-chip platforms are now being linked together to generate multi-organ systems for the study of drug pharmacokinetics, pharmacodynamics and toxicity.
Organ-on-a-chip platforms are rapidly evolving as powerful tools for oncology research see Table 1. By replacing healthy cells and associated ECMs in tissue-specific constructs with those of cancer origins, so called tumor-on-a-chip or tumor chip systems have emerged.
Tumor chips can ideally reproduce specific key aspects of the tumor microenvironment, such as biochemical gradients and niche factors, dynamic cell-cell and cell-matrix interactions, and complex tissue structure comprised of tumor and stromal cells. Moreover, tumor chips are able to reproduce cell confinement, a parameter imposed on cell movement in the interstitial space of tissues that is totally absent in 2D assays yet essential for studying the behavior of motile cells such as immune and cancer cells.
Nearly every tissue in the human body, including those of malignant origin, depends for survival on a supply of oxygen and nutrients delivered through blood vessels. Angiogenesis refers to the sprouting of new vessels from pre-existing vasculature, and vasculogenesis occurs when vessels form de novo from progenitor cells. In combination they represent the fundamental processes by which new blood vessels are formed reviewed in — and are critical during physiological processes such as tissue homeostasis, wound healing, pregnancy and fetal development.
However, during malignant progression angiogenesis and, to a lesser degree, vasculogenesis are co-opted to feed the growing tumor mass, while also providing a means for metastasis.
Indeed, anti-angiogenic drugs have been developed extensively for use in cancer but with mixed clinical trial outcomes and oftentimes marginal survival gains. To advance drug development in this area, our group and others have designed microvascularized tissue constructs on-chip in which vascular and perivascular cells self-organize de novo into a living and perfused vascular network in response to fluid flow and shear stress.
For realistic tumor modeling and anti-cancer drug screening, our group has adapted our base vascularized micro-organ VMO platform 32 , 33 , for cancer studies by incorporating tumor cells into the model to generate vascularized micro-tumors, or VMTs Fig.
Importantly, the VMO recapitulates the barrier functions of vessels in vivo, with fully perfused and non-leaky vessels that show permeability coefficient values in line with values obtained from capillaries Fig.
Differences in growth rate, vessel development, and collagen synthesis suggests that each tumor cell line uniquely remodels the tumor microenvironment within the VMT. Different levels of medium in the four vials drive flow. Tumor cells are labeled in blue. Tumor significantly regresses with treatment compared to control. We next performed drug screening to test VMT response to FDA-approved chemotherapeutics and small molecule receptor tyrosine kinase RTK inhibitors representing both anti-cancer and anti-angiogenic drugs, including the standard-of-care therapies indicated for specific tumor types.
This indicates that 2D models fail to accurately model certain critical features of in vivo tumors and that certain survival-signaling pathways essential for tumor progression in vivo are not activated in 2D culture. The anti-angiogenic multi-kinase inhibitors sorafenib and pazopanib were also tested in the VMT model and induced marked vascular regression in response to treatment. Additional drug screening results indicate that the VMT robustly recapitulates anticipated drug response based on mechanism of action, animal studies and clinical trial results.
Recent contributions by Kamm and colleagues 35 , , , have provided an unprecedented, high-resolution view of tumor cell extravasation through microvessels formed in a microfluidic device Fig. The authors employed a de novo vascularized platform to study the process of tumor cell extravasation from within in vitro microvessels and were able to track each step in real-time.
The microvessels formed tight cell-cell endothelial junctions, deposited basement membrane and demonstrated physiologic vascular permeability. Breast cancer cells MDA-MB were introduced into the device and high-resolution time-lapse microscopy revealed the highly dynamic nature of extravasation events Fig 2f. The cancer cells first penetrated the EC barrier by extending thin fillipodial protrusions that continued to increase and branch out while the remaining body on the apical side of the lumen maintained its sphericity, even as the nucleus traversed the vessel.
Throughout the process, tumor cells underwent significant shape changes as the cell body extruded through a gap in the microvessel of subnuclear dimensions. Interestingly, staining for VE-cadherin revealed that EC cell-cell junctions remained largely intact.
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