Tumor microenvironment is a complex niche consisting of cancer cells and stromal cells in a network of extracellular matrix proteins and various soluble factors. Dynamic interactions among cellular and non-cellular components of the tumor microenvironment regulate tumor initiation and progression. Fibroblasts are the most abundant stromal cell type and dynamically interact with cancer cells both in primary tumors and in metastases. Cancer cells activate resident fibroblasts to produce and secrete soluble signaling molecules that support proliferation, migration, matrix invasion, and drug resistance of cancer cell and tumor angiogenesis. In recent years, various forms of three-dimensional tumor models have been developed to study tumor–stromal interactions and to identify anti-cancer drugs that block these interactions. There is currently a technological gap in development of tumor models that are physiologically relevant, scalable, and allow convenient, on-demand addition of desired components of the tumor microenvironment. In this review, we discuss three studies from our group that focus on developing bioengineered models to study tumor-stromal signaling. We will present these studies chronologically and based on their increasing complexity. We will discuss the validation of the models using a CXCL12-CXCR4 chemokine-receptor signaling present among activated fibroblasts and breast cancer cells in solid tumors, highlight the advantages and shortcomings of the models, and conclude with our perspectives on their applications. Impact statement Tumor stroma plays an important role in progression of cancers to a fatal metastatic disease. Modern treatment strategies are considering targeting tumor stroma to improve outcomes for cancer patients. A current challenge to develop stroma-targeting therapeutics is the lack of preclinical physiologic tumor models. Animal models widely used in cancer research lack human stroma and are not amenable to screening of chemical compounds for cancer drug discovery. In this review, we outline in vitro three-dimensional tumor models that we have developed to study the interactions among cancer cells and stromal cells. We describe development of the tumor models in a modular fashion, from a spheroid model to a sophisticated organotypic model, and discuss the importance of using correct physiologic models to recapitulate tumor-stromal signaling. These biomimetic tumor models will facilitate understanding of tumor-stromal signaling biology and provide a scalable approach for testing and discovery of cancer drugs.
more »
« less
Microengineered 3D Tumor Models for Anti-Cancer Drug Discovery in Female-Related Cancers
The burden of cancer continues to increase in
society and negatively impacts the lives of numerous patients.
Due to the high cost of current treatment strategies, there is a
crucial unmet need to develop inexpensive preclinical platforms
to accelerate the process of anti-cancer drug discovery
to improve outcomes in cancer patients, most especially in
female patients. Many current methods employ expensive
animal models which not only present ethical concerns but
also do not often accurately predict human physiology and
the outcomes of anti-cancer drug responsiveness. Conventional
treatment approaches for cancer generally include
systemic therapy after a surgical procedure. Although this
treatment technique is effective, the outcome is not always
positive due to various complex factors such as intratumor
heterogeneity and confounding factors within the tumor
microenvironment (TME). Patients who develop metastatic
disease still have poor prognosis. To that end, recent efforts
have attempted to use 3D microengineered platforms to
enhance the predictive power and efficacy of anti-cancer drug
screening, ultimately to develop personalized therapies.
Fascinating features of microengineered assays, such as
microfluidics, have led to the advancement in the development
of the tumor-on-chip technology platforms, which have
shown tremendous potential for meaningful and physiologically
relevant anti-cancer drug discovery and screening.
Three dimensional microscale models provide unprecedented
ability to unveil the biological complexities of cancer and
shed light into the mechanism of anti-cancer drug resistance
in a timely and resource efficient manner. In this review, we
discuss recent advances in the development of microengineered
tumor models for anti-cancer drug discovery and
screening in female-related cancers. We specifically focus on
female-related cancers to draw attention to the various
approaches being taken to improve the survival rate of
women diagnosed with cancers caused by sex disparities. We
also briefly discuss other cancer types like colon adenocarcinomas
and glioblastoma due to their high rate of occurrence
in females, as well as the high likelihood of sex-biased
mutations which complicate current treatment strategies for
women. We highlight recent advances in the development of
3D microscale platforms including 3D tumor spheroids,
microfluidic platforms as well as bioprinted models, and
discuss how they have been utilized to address major
challenges in the process of drug discovery, such as chemoresistance,
intratumor heterogeneity, drug toxicity, etc. We also
present the potential of these platform technologies for use in
high-throughput drug screening approaches as a replacements
of conventional assays. Within each section, we will
provide our perspectives on advantages of the discussed
platform technologies.
more »
« less
- Award ID(s):
- 1914680
- NSF-PAR ID:
- 10253499
- Date Published:
- Journal Name:
- Annals of Biomedical Engineering
- ISSN:
- 0090-6964
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
null (Ed.)Heterogeneity is a hallmark of all cancers. Tumor heterogeneity is found at different levels — interpatient, intrapatient, and intratumor heterogeneity. All of them pose challenges for clinical treatments. The latter two scenarios can also increase the risk of developing drug resistance. Although the existence of tumor heterogeneity has been known for two centuries, a clear understanding of its origin is still elusive, especially at the level of intratumor heterogeneity (ITH). The coexistence of different subpopulations within a single tumor has been shown to play crucial roles during all stages of carcinogenesis. Here, using concepts from evolutionary game theory and public goods game, often invoked in the context of the tragedy of commons, we explore how the interactions among subclone populations influence the establishment of ITH. By using an evolutionary model, which unifies several experimental results in distinct cancer types, we develop quantitative theoretical models for explaining data from in vitro experiments involving pancreatic cancer as well as in vivo data in glioblastoma multiforme. Such physical and mathematical models complement experimental studies, and could optimistically provide new ideas for the design of efficacious therapies for cancer patients.more » « less
-
Three-dimensional (3D) tumor spheroid models have gained increased recognition as important tools in cancer research and anti-cancer drug development. However, currently available imaging approaches employed in high-throughput screening drug discovery platforms e.g. bright field, phase contrast, and fluorescence microscopies, are unable to resolve 3D structures deep inside (>50 μm) tumor spheroids. In this study, we established a label-free, non-invasive optical coherence tomography (OCT) imaging platform to characterize 3D morphological and physiological information of multicellular tumor spheroids (MCTS) growing from ~250 μm up to ~600 μm in height over 21 days. In particular, tumor spheroids of two cell lines glioblastoma (U-87 MG) and colorectal carcinoma (HCT 116) exhibited distinctive evolutions in their geometric shapes at late growth stages. Volumes of MCTS were accurately quantified using a voxel-based approach without presumptions of their geometries. In contrast, conventional diameter-based volume calculations assuming perfect spherical shape resulted in large quantification errors. Furthermore, we successfully detected necrotic regions within these tumor spheroids based on increased intrinsic optical attenuation, suggesting a promising alternative of label-free viability tests in tumor spheroids. Therefore, OCT can serve as a promising imaging modality to characterize morphological and physiological features of MCTS, showing great potential for high-throughput drug screening.more » « less
-
more » « less
Abstract Cancer immunotherapy, or the utilization of a patient's own immune system to treat cancer, has shifted the paradigm of cancer treatment. Despite meaningful responses being observed in multiple studies, currently available immunotherapy platforms have only proven effective to a small subset of patients. To address this, nanoparticles have been utilized as a novel carrier for immunotherapeutic drugs, achieving robust anti‐tumor effects with increased adaptive and durable responses. Specifically, dendrimer nanoparticles have attracted a great deal of scientific interest due to their versatility in various therapeutic applications, resulting from their unique physicochemical properties and chemically well‐defined architecture. This review offers a comprehensive overview of dendrimer‐based immunotherapy technologies, including their formulations, biological functionalities, and therapeutic applications. Common formulations include: (1) modulators of cytokine secretion of immune cells (adjuvants); (2) facilitators of the recognition of tumorous antigens (vaccines); (3) stimulators of immune effectors to selectively attack cells expressing specific antigens (antibodies); and (4) inhibitors of immune‐suppressive responses (immune checkpoint inhibitors). On‐going works and prospects of dendrimer‐based immunotherapies are also discussed. Overall, this review provides a critical overview on rapidly growing dendrimer‐based immunotherapy technologies and serves as a guideline for researchers and clinicians who are interested in this field.
This article is categorized under:
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Therapeutic Approaches and Drug Discovery > Emerging Technologies
-
Patient derived organoids have emerged as robust preclinical models for screening anti-cancer therapeutics. Current 2D culturing methods do not provide physiological responses to therapeutics, therefore 3D models are being developed to better reproduce physiological responses. 3D culturing however often requires large initial cell populations and one week to one month to grow tumors ready for therapeutic testing. As a solution a 3D culturing system has been developed capable of producing physiologically relevant tumors in an expedited fashion while only requiring a small number of initial cancer cells. A bi-layer microfluidic system capable of facilitating active convective nutrient supply to populations of cancer cells facilitates expedited growth of cancer cells when starting with populations as small as 8 cells. The system has been shown to function well with adherent and non-adherent cell types by expediting cell growth by a factor ranging from 1.27 to 4.76 greater than growth under static conditions. Utilizing such an approach has enable to formation of tumors ready for therapeutic screening within 3 days and the ability to perform therapeutic screening within the microfluidic system is demonstrated. A mathematical model has been developed which allows for adjustments to be made to the dynamic delivery of nutrients in order to efficiently use culture media without excessive waste. We believe this work to be the first attempt to grow cancers in an expedited fashion utilizing only a convective nutrient supply within a microfluidic system which also facilitates on-device therapeutic screening. The developed microfluidic system and cancer growth method have the potential to offer improved drug screening for patients in clinical settings.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1007/s10439-020-02704-9
