Modeling tumor microenvironments using custom-designed biomaterial scaffolds

Defined by its potential for self-renewal, differentiation and tumorigenicity, cancer stem cells (CSCs) are considered responsible for drug resistance and relapse. To understand the behavior of CSC, the effects of the microenvironment in each tissue are a matter of great concerns for scientists in cancer biology. However, there are many complicated obstacles in the mimicking the microenvironment of CSCs even with current advanced technology. In this context, novel biomaterials have widely been assessed as in vitro platforms for their ability to mimic cancer microenvironment. These efforts should be successful to identify and characterize various CSCs specific in each type of cancer. Therefore, extracellular matrix scaffolds made of biomaterial will modulate the interactions and facilitate the investigation of CSC associated with biological phenomena simplifying the complexity of the microenvironment. In this review, we summarize latest advances in biomaterial scaffolds, which are exploited to mimic CSC microenvironment, and their chemical and biological requirements with discussion. The discussion includes the possible effects on both cells in tumors and microenvironment to propose what the critical factors are in controlling the CSC microenvironment focusing the future investigation. Our insights on their availability in drug screening will also follow the discussion.

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Cardiac tissue engineering, biomaterial scaffolds, and their fabrication techniques

Polymers for Advanced Technologies ◽

10.1002/pat.5273 ◽

2021 ◽

Author(s):

Marjan Roshandel ◽

Farid Dorkoosh

Keyword(s):

Tissue Engineering ◽

Cardiac Tissue ◽

Cardiac Tissue Engineering ◽

Biomaterial Scaffolds

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Artificial Tumor Microenvironments in Neuroblastoma

Cancers ◽

10.3390/cancers13071629 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1629

Author(s):

Colin H. Quinn ◽

Andee M. Beierle ◽

Elizabeth A. Beierle

Keyword(s):

Extracellular Matrix ◽

Three Dimensional ◽

Therapeutic Interventions ◽

3D Bioprinting ◽

Culture Studies ◽

In Vivo Models ◽

Novel Treatments ◽

Tumor Microenvironments ◽

Novel Approach

In the quest to advance neuroblastoma therapeutics, there is a need to have a deeper understanding of the tumor microenvironment (TME). From extracellular matrix proteins to tumor associated macrophages, the TME is a robust and diverse network functioning in symbiosis with the solid tumor. Herein, we review the major components of the TME including the extracellular matrix, cytokines, immune cells, and vasculature that support a more aggressive neuroblastoma phenotype and encumber current therapeutic interventions. Contemporary treatments for neuroblastoma are the result of traditional two-dimensional culture studies and in vivo models that have been translated to clinical trials. These pre-clinical studies are costly, time consuming, and neglect the study of cofounding factors such as the contributions of the TME. Three-dimensional (3D) bioprinting has become a novel approach to studying adult cancers and is just now incorporating portions of the TME and advancing to study pediatric solid. We review the methods of 3D bioprinting, how researchers have included TME pieces into the prints, and highlight present studies using neuroblastoma. Ultimately, incorporating the elements of the TME that affect neuroblastoma responses to therapy will improve the development of innovative and novel treatments. The use of 3D bioprinting to achieve this aim will prove useful in developing optimal therapies for children with neuroblastoma.

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A co-delivery nanoplatform for Lignan-derived compound and perfluorocarbon tuning IL-25 secretion and oxygen level in tumor microenvironments for meliorative tumor radiotherapy

Nanoscale ◽

10.1039/d1nr03738b ◽

2021 ◽

Author(s):

Zhenyu Duan ◽

Qiang Luo ◽

Lei Gu ◽

Xiaoling Li ◽

Hongyan Zhu ◽

...

Keyword(s):

Therapeutic Efficacy ◽

Glycolic Acid ◽

Treatment Technique ◽

Oxygen Level ◽

Tumor Microenvironments ◽

Hypoxic Environment ◽

Control Tumor ◽

Tumor Metastases ◽

Localized Treatment

A hypoxic environment in tumors hampers the therapeutic efficacy of radiotherapy. Moreover, radiotherapy, a localized treatment technique, can barely control tumor metastases. Herein, poly(lactic co-glycolic acid) was used to encapsulate...

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Poorly Differentiated and Anaplastic Thyroid Cancer: Insights into Genomics, Microenvironment and New Drugs

Cancers ◽

10.3390/cancers13133200 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3200

Author(s):

Alessandro Prete ◽

Antonio Matrone ◽

Carla Gambale ◽

Liborio Torregrossa ◽

Elisa Minaldi ◽

...

Keyword(s):

Overall Survival ◽

Thyroid Cancer ◽

Median Overall Survival ◽

Clinical Problem ◽

Anaplastic Thyroid Cancer ◽

New Drugs ◽

Poor Survival ◽

Tumor Microenvironments ◽

Genetic Features ◽

Poorly Differentiated

PDTC and ATC present median overall survival of 6 years and 6 months, respectively. In spite of their rarity, patients with PDTC and ATC represent a significant clinical problem, because of their poor survival and the substantial inefficacy of classical therapies. We reviewed the newest findings about genetic features of PDTC and ATC, from mutations occurring in DNA to alterations in RNA. Therefore, we describe their tumor microenvironments (both immune and not-immune) and the interactions between tumor and neighboring cells. Finally, we recapitulate how this upcoming evidence are changing the treatment of PDTC and ATC.

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TRPM2 Oxidation Activates Two Distinct Potassium Channels in Melanoma Cells through Intracellular Calcium Increase

International Journal of Molecular Sciences ◽

10.3390/ijms22168359 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8359

Author(s):

Loretta Ferrera ◽

Raffaella Barbieri ◽

Cristiana Picco ◽

Paolo Zuccolini ◽

Alessia Remigante ◽

...

Keyword(s):

Intracellular Calcium ◽

Expression Analysis ◽

Large Fraction ◽

Specific Inhibitor ◽

Metastatic Potential ◽

Melanoma Cells ◽

Bk Channels ◽

Current Increase ◽

Tumor Microenvironments ◽

Trpm2 Channel

Tumor microenvironments are often characterized by an increase in oxidative stress levels. We studied the response to oxidative stimulation in human primary (IGR39) or metastatic (IGR37) cell lines obtained from the same patient, performing patch-clamp recordings, intracellular calcium ([Ca2+]i) imaging, and RT-qPCR gene expression analysis. In IGR39 cells, chloramine-T (Chl-T) activated large K+ currents (KROS) that were partially sensitive to tetraethylammonium (TEA). A large fraction of KROS was inhibited by paxilline—a specific inhibitor of large-conductance Ca2+-activated BK channels. The TEA-insensitive component was inhibited by senicapoc—a specific inhibitor of the Ca2+-activated KCa3.1 channel. Both BK and KCa3.1 activation were mediated by an increase in [Ca2+]i induced by Chl-T. Both KROS and [Ca2+]i increase were inhibited by ACA and clotrimazole—two different inhibitors of the calcium-permeable TRPM2 channel. Surprisingly, IGR37 cells did not exhibit current increase upon the application of Chl-T. Expression analysis confirmed that the genes encoding BK, KCa3.1, and TRPM2 are much more expressed in IGR39 than in IGR37. The potassium currents and [Ca2+]i increase observed in response to the oxidizing agent strongly suggest that these three molecular entities play a major role in the progression of melanoma. Pharmacological targeting of either of these ion channels could be a new strategy to reduce the metastatic potential of melanoma cells, and could complement classical radio- or chemotherapeutic treatments.

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Multi-omic profiling of lung and liver tumor microenvironments of metastatic pancreatic cancer reveals site-specific immune regulatory pathways

Genome Biology ◽

10.1186/s13059-021-02363-6 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Won Jin Ho ◽

Rossin Erbe ◽

Ludmila Danilova ◽

Zaw Phyo ◽

Emma Bigelow ◽

...

Keyword(s):

Mouse Model ◽

Primary Tumors ◽

Regulatory Pathways ◽

Tumor Microenvironments ◽

Clinical Responses ◽

Cellular Pathways ◽

Autopsy Specimens ◽

Rapid Autopsy ◽

Insight Into ◽

Systemic Therapies

Abstract Background The majority of pancreatic ductal adenocarcinomas (PDAC) are diagnosed at the metastatic stage, and standard therapies have limited activity with a dismal 5-year survival rate of only 8%. The liver and lung are the most common sites of PDAC metastasis, and each have been differentially associated with prognoses and responses to systemic therapies. A deeper understanding of the molecular and cellular landscape within the tumor microenvironment (TME) metastasis at these different sites is critical to informing future therapeutic strategies against metastatic PDAC. Results By leveraging combined mass cytometry, immunohistochemistry, and RNA sequencing, we identify key regulatory pathways that distinguish the liver and lung TMEs in a preclinical mouse model of metastatic PDAC. We demonstrate that the lung TME generally exhibits higher levels of immune infiltration, immune activation, and pro-immune signaling pathways, whereas multiple immune-suppressive pathways are emphasized in the liver TME. We then perform further validation of these preclinical findings in paired human lung and liver metastatic samples using immunohistochemistry from PDAC rapid autopsy specimens. Finally, in silico validation with transfer learning between our mouse model and TCGA datasets further demonstrates that many of the site-associated features are detectable even in the context of different primary tumors. Conclusions Determining the distinctive immune-suppressive features in multiple liver and lung TME datasets provides further insight into the tissue specificity of molecular and cellular pathways, suggesting a potential mechanism underlying the discordant clinical responses that are often observed in metastatic diseases.

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Targeting the Ubiquitin Signaling Cascade in Tumor Microenvironment for Cancer Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms22020791 ◽

2021 ◽

Vol 22 (2) ◽

pp. 791

Author(s):

Qi Liu ◽

Bayonle Aminu ◽

Olivia Roscow ◽

Wei Zhang

Keyword(s):

Tumor Microenvironment ◽

Cancer Therapy ◽

Therapeutic Agents ◽

Biological Processes ◽

Post Translational Modification ◽

E3 Ligases ◽

Tumor Microenvironments ◽

Cellular Immune ◽

Ubiquitin Conjugating Enzymes ◽

Cellular Components

Tumor microenvironments are composed of a myriad of elements, both cellular (immune cells, cancer-associated fibroblasts, mesenchymal stem cells, etc.) and non-cellular (extracellular matrix, cytokines, growth factors, etc.), which collectively provide a permissive environment enabling tumor progression. In this review, we focused on the regulation of tumor microenvironment through ubiquitination. Ubiquitination is a reversible protein post-translational modification that regulates various key biological processes, whereby ubiquitin is attached to substrates through a catalytic cascade coordinated by multiple enzymes, including E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes and E3 ubiquitin ligases. In contrast, ubiquitin can be removed by deubiquitinases in the process of deubiquitination. Here, we discuss the roles of E3 ligases and deubiquitinases as modulators of both cellular and non-cellular components in tumor microenvironment, providing potential therapeutic targets for cancer therapy. Finally, we introduced several emerging technologies that can be utilized to develop effective therapeutic agents for targeting tumor microenvironment.

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