bims-tuchim 2021-05-09 papers

bims-tuchim

Biomed News

on Tumor-on-chip models

Issue of 2021–05–09
seventeen papers selected by
Philipp Albrecht, Friedrich Schiller University

Antitumor effects of iPSC-based cancer vaccine in pancreatic cancer.
Organotypic-liver slide culture systems to explore the role of extracellular vesicles in pancreatic cancer metastatic behavior and guide new therapeutic approaches.
Visualizing Extracellular Vesicles and Their Function in 3D Tumor Microenvironment Models.
Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression.
A thermo-responsive collagen-nanocellulose hydrogel for the growth of intestinal organoids.
3D heterospecies spheroids of pancreatic stroma and cancer cells demonstrate key phenotypes of pancreatic ductal adenocarcinoma.
Transforming a well into a chip: A modular 3D-printed microfluidic chip.
Direct laser writing for cardiac tissue engineering: a microfluidic heart on a chip with integrated transducers.
Personalized Models of Heterogenous 3D Epithelial Tumor Microenvironments: Ovarian Cancer as a Model.
Single-cell dissection of cellular components and interactions shaping the tumor immune phenotypes in ovarian cancer.
Hypoxia-sensing CAR T cells provide safety and efficacy in treating solid tumors.
High-Yield Human Induced Pluripotent Stem Cell-Derived Monocytes and Macrophages Are Functionally Comparable With Primary Cells.
Bioscaffold-based study of glioblastoma cell behavior and drug delivery for tumor therapy.
Nano drug delivery system reconstruct tumor vasculature for the tumor vascular normalization.
Development of a Decellularized Porcine Esophageal Matrix for Potential Applications in Cancer Modeling.
Breast cancer organoids from malignant pleural effusion-derived tumor cells as an individualized medicine platform.
Analysis of Tumor Microenvironment Characteristics in Bladder Cancer: Implications for Immune Checkpoint Inhibitor Therapy.

Stem Cell Reports. 2021 May 05. pii: S2213-6711(21)00199-5. [Epub ahead of print]

Antitumor effects of iPSC-based cancer vaccine in pancreatic cancer.

Xiaoming Ouyang, Yu Liu, Yang Zhou, Jing Guo, Tzu-Tang Wei, Chun Liu, Bomi Lee, Binbin Chen, Angela Zhang, Kerriann M Casey, Lin Wang, Nigel G Kooreman, Aida Habtezion, Edgar G Engleman, Joseph C Wu.

  Induced pluripotent stem cells (iPSCs) and cancer cells share cellular similarities and transcriptomic profiles. Here, we show that an iPSC-based cancer vaccine, comprised of autologous iPSCs and CpG, stimulated cytotoxic antitumor CD8+ T cell effector and memory responses, induced cancer-specific humoral immune responses, reduced immunosuppressive CD4+ T regulatory cells, and prevented tumor formation in 75% of pancreatic ductal adenocarcinoma (PDAC) mice. We demonstrate that shared gene expression profiles of "iPSC-cancer signature genes" and others are overexpressed in mouse and human iPSC lines, PDAC cells, and multiple human solid tumor types compared with normal tissues. These results support further studies of iPSC vaccination in PDAC in preclinical and clinical models and in other cancer types that have low mutational burdens.

Keywords:  cancer vaccine; iPSC; iPSC-based cancer vaccine; pancreatic ductal adenocarcinoma; tumor-associated antigens

DOI:  https://doi.org/10.1016/j.stemcr.2021.04.004
Expert Opin Drug Metab Toxicol. 2021 May 04.

Organotypic-liver slide culture systems to explore the role of extracellular vesicles in pancreatic cancer metastatic behavior and guide new therapeutic approaches.

I Gede Putu Supadmanaba, Annalisa Comandatore, Luca Morelli, Elisa Giovannetti, Tonny Lagerweij.

   INTRODUCTION: Recent studies suggested that extracellular vesicles (EVs) play a role both in the metastatic niche formation and in the progression of several tumors, including pancreatic cancer. In particular, the effects of EVs on metastasis should be studied in model systems that take into account both the tumor cells and the metastatic site/tumor microenvironment. Studies with labeled EVs or EV-secreting cells in ex vivo models will reflect the physiological and pathological functions of EVs. The organotypic-tissue slide culture systems can fulfill such a role.
AREAS COVERED: This review provides an overview of available organotypic-culture slide systems. We specifically focus on the assay system of liver culture-slides in combination with pancreatic tumors which can be modulated to test the efficacy of new therapeutic approaches.
EXPERT OPINION: The intercellular exchange of EVs has emerged as a biologically relevant phenomenon to drive cancer metastasis. However, further models need to be developed to better elucidate the functional roles of EVs. The use of novel organotypic slide culture systems provides the opportunity to explore the role of EVs in the metastatic behavior of pancreatic cancer, decreasing the use of costly and cumbersome organoid or animal models.

Keywords:  extracellular vesicles; metastasis; organotypic-tissue slide culture systems; pancreatic cancer; preclinical models; tumor microenvironment

DOI:  https://doi.org/10.1080/17425255.2021.1925646
Int J Mol Sci. 2021 Apr 30. pii: 4784. [Epub ahead of print]22(9):

Visualizing Extracellular Vesicles and Their Function in 3D Tumor Microenvironment Models.

Evran E Ural, Victoria Toomajian, Ehsanul Hoque Apu, Mladen Veletic, Ilangko Balasingham, Nureddin Ashammakhi, Masamitsu Kanada, Christopher H Contag.

  Extracellular vesicles (EVs) are cell-derived nanostructures that mediate intercellular communication by delivering complex signals in normal tissues and cancer. The cellular coordination required for tumor development and maintenance is mediated, in part, through EV transport of molecular cargo to resident and distant cells. Most studies on EV-mediated signaling have been performed in two-dimensional (2D) monolayer cell cultures, largely because of their simplicity and high-throughput screening capacity. Three-dimensional (3D) cell cultures can be used to study cell-to-cell and cell-to-matrix interactions, enabling the study of EV-mediated cellular communication. 3D cultures may best model the role of EVs in formation of the tumor microenvironment (TME) and cancer cell-stromal interactions that sustain tumor growth. In this review, we discuss EV biology in 3D culture correlates of the TME. This includes EV communication between cell types of the TME, differences in EV biogenesis and signaling associated with differing scaffold choices and in scaffold-free 3D cultures and cultivation of the premetastatic niche. An understanding of EV biogenesis and signaling within a 3D TME will improve culture correlates of oncogenesis, enable molecular control of the TME and aid development of drug delivery tools based on EV-mediated signaling.

Keywords:  cell-to-matrix interactions; extracellular vesicles (EVs); scaffold; three-dimensional (3D) cell culture models; tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/ijms22094784
Cancer Lett. 2021 May 04. pii: S0304-3835(21)00173-7. [Epub ahead of print]

Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression.

Chika Iwamoto, Kenoki Ohuchida, Tomohiko Shinkawa, Sho Okuda, Yoshiki Otsubo, Takashi Okumura, Akiko Sagara, Kazuhiro Koikawa, Yohei Ando, Koji Shindo, Naoki Ikenaga, Kohei Nakata, Taiki Moriyama, Yoshihiro Miyasaka, Takao Ohtsuka, Masatoshi Eto, Koichi Akashi, Masafumi Nakamura.

  Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic reaction caused by cancer-associated fibroblasts (CAFs), which provokes treatment resistance. CAFs are newly proposed to be heterogeneous populations with different functions within the PDAC microenvironment. The most direct sources of CAFs are resident tissue fibroblasts and mesenchymal stem cells, however, the origins and functions of CAF subtypes remain unclear. Here, we established allogeneic bone marrow (BM) transplantation models using spontaneous PDAC mice, and then investigated what subtype cells derived from BM modulate the tumor microenvironment and affect the behavior of pancreatic cancer cells (PCCs). BM-derived multilineage hematopoietic cells were engrafted in recipient pancreas, and accumulated at the invasive front and central lesion of PDAC. We identified BM macrophages-derived CAFs in tumors. BM-derived macrophages treated with PCC-conditioned media expressed CAF markers. BM-derived macrophages led the local invasion of PCCs in vitro and enhanced the tumor invasive growth in vivo. Our data suggest that BM-derived cells are recruited to the pancreas during carcinogenesis and that the specific subpopulation of BM-derived macrophages partially converted into CAF-like cells, acted as leading cells, and facilitated pancreatic cancer progression. The control of the conversion of BM-derived macrophages into CAF-like cells may be a novel therapeutic strategy to suppress tumor growth.

Keywords:  BM-derived macrophages; Bone marrow transplantation; CAF-like cells; Tumor microenvironment; Tumor progression

DOI:  https://doi.org/10.1016/j.canlet.2021.04.013
Mater Sci Eng C Mater Biol Appl. 2021 May;pii: S0928-4931(21)00190-9. [Epub ahead of print]124 112051

A thermo-responsive collagen-nanocellulose hydrogel for the growth of intestinal organoids.

Rodrigo Curvello, Diana Alves, Helen E Abud, Gil Garnier.

  Three-dimensional (3D) cell culture systems include bioengineered microenvironments that mimic the complexity of human tissues and organs in vitro. Robust biological models, like organoids and spheroids, rely on biomaterials to emulate the biochemical and biomechanical properties found in the extracellular matrix (ECM). Collagen (COL) is the main protein component of the ECM and has been used to generate fibrous matrices for 3D cell culture. Whilst neat COL gels are commonly blended with inert polymers to improve their poor mechanical properties, whether nanocellulose (NC) fibers interact or can develop some synergic bioactive effect to support organoid systems has never been demonstrated. Here, we investigate collagen-nanocellulose (COL-NC) hydrogels as a thermo-responsive matrix for the formation and growth of intestinal organoids. Cellulose nanofibres grafted with fibronectin-like adhesive sites form a porous network with type I collagen, presenting a sol-gel transition and viscoelastic profile similar to those of standard animal-based matrices. Crypts embedded in COL-NC form organoids with evidence of epithelial budding. Cell viability and metabolic activity are preserved as well as the expression of key cell markers. The stiffness of COL-NC hydrogels is shown to be a determinant element for the formation and development organoids. COL-NC hydrogels provide an affordable, performant thermo-responsive and sustainable matrix for organoid growth.

Keywords:  Collagen; Hydrogel; Nanocellulose; Organoids; Stiffness; Thermo-responsive

DOI:  https://doi.org/10.1016/j.msec.2021.112051
Transl Oncol. 2021 May 01. pii: S1936-5233(21)00099-1. [Epub ahead of print]14(7): 101107

3D heterospecies spheroids of pancreatic stroma and cancer cells demonstrate key phenotypes of pancreatic ductal adenocarcinoma.

Xinyuan Liu, Beate Gündel, Xidan Li, Jianping Liu, Anthony Wright, Matthias Löhr, Gustav Arvidsson, Rainer Heuchel.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, partly due to the dense desmoplasia and a lack of suitable model systems to study. In the present work, we developed a 3D heterospecies spheroid model to study the microenvironmental interactions between tumor cells and stellate cells which can also be employed to test therapeutic regimens. We set up monospheroids and heterospheroids made up from murine pancreatic stellate cells (mPSCs) and human PDAC cells (Panc1), which allowed for direct isolation of mRNA from a mixed cell population followed by an in silico separation of the RNA-seq reads. Global transcript level changes for cells in heterospheroids versus monospheroids were calculated, followed by gene set enrichment analysis and molecular subtype analysis. We observed an apparent shift of Panc1 from the classical to the squamous/basal-like phenotype upon co-culture with mPSCs. Moreover, mPSCs acquired a different cancer-associated fibroblast-related phenotype upon co-culture with Panc1. We analyzed the tumor cell-specific chemosensitivities towards gemcitabine, paclitaxel and SN38 and compared these to published pharmacotranscriptomic signatures. In conclusion, our heterospecies spheroid model reflected key aspects of PDAC and facilitated the study of intercellular interactions between tumor and stroma while additionally proving to be a good model for studying therapeutic responses.

Keywords:  Cancer associated fibroblasts; Co-culture; Pancreatic cancer; Spheroids; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.tranon.2021.101107
APL Bioeng. 2021 Jun;5(2): 026103

Transforming a well into a chip: A modular 3D-printed microfluidic chip.

Rossana Rauti, Adi Ess, Baptiste Le Roi, Yevgeniy Kreinin, Mark Epshtein, Netanel Korin, Ben M Maoz.

Organ-on-a-Chip platforms provide rich opportunities to observe interactions between different cell types under in vivo-like conditions, i.e., in the presence of flow. Yet, the costs and know-how required for the fabrication and implementation of these platforms restrict their accessibility. This study introduces and demonstrates a novel Insert-Chip: a microfluidic device that provides the functionality of an Organ-on-a-Chip platform, namely, the capacity to co-culture cells, expose them to flow, and observe their interactions-yet can easily be integrated into standard culture systems (e.g., well plates or multi-electrode arrays). The device is produced using stereolithograpy 3D printing and is user-friendly and reusable. Moreover, its design features overcome some of the measurement and imaging challenges characterizing standard Organ-on-a-Chip platforms. We have co-cultured endothelial and epithelial cells under flow conditions to demonstrate the functionality of the device. Overall, this novel microfluidic device is a promising platform for the investigation of biological functions, cell-cell interactions, and response to therapeutics.

DOI: https://doi.org/10.1063/5.0039366
Lab Chip. 2021 May 04. 21(9): 1724-1737

Direct laser writing for cardiac tissue engineering: a microfluidic heart on a chip with integrated transducers.

Rachael K Jayne, M Çağatay Karakan, Kehan Zhang, Noelle Pierce, Christos Michas, David J Bishop, Christopher S Chen, Kamil L Ekinci, Alice E White.

We have developed a microfluidic platform for engineering cardiac microtissues in highly-controlled microenvironments. The platform is fabricated using direct laser writing (DLW) lithography and soft lithography, and contains four separate devices. Each individual device houses a cardiac microtissue and is equipped with an integrated strain actuator and a force sensor. Application of external pressure waves to the platform results in controllable time-dependent forces on the microtissues. Conversely, oscillatory forces generated by the microtissues are transduced into measurable electrical outputs. We demonstrate the capabilities of this platform by studying the response of cardiac microtissues derived from human induced pluripotent stem cells (hiPSC) under prescribed mechanical loading and pacing. This platform will be used for fundamental studies and drug screening on cardiac microtissues.

DOI: https://doi.org/10.1039/d0lc01078b
Acta Biomater. 2021 Apr 30. pii: S1742-7061(21)00285-3. [Epub ahead of print]

Personalized Models of Heterogenous 3D Epithelial Tumor Microenvironments: Ovarian Cancer as a Model.

Eric N Horst, Michael E Bregenzer, Pooja Mehta, Catherine S Snyder, Taylor Repetto, Yang Yang-Hartwich, Geeta Mehta.

  Intractable human diseases such as cancers, are context dependent, unique to both the individual patient and to the specific tumor microenvironment. However, conventional cancer treatments are often nonspecific, targeting global similarities rather than unique drivers. This limits treatment efficacy across heterogeneous patient populations and even at different tumor locations within the same patient. Ultimately, this poor efficacy can lead to poor clinical outcomes and the development of treatment-resistant relapse. To prevent this and improve outcomes, it is necessary to be selective when choosing a patient's optimal adjuvant treatment. In this review, we posit the use of personalized, tumor-specific disease models (TSM) as tools to achieve this remarkable feat. First, using ovarian cancer as a model disease, we outline the heterogeneity and complexity of both the cellular and extracellular components in the tumor microenvironment. Then we examine the advantages and disadvantages of contemporary cancer models and the rationale for personalized TSM. We discuss how to generate TSM through careful and detailed analysis of patient biopsies with contemporary analysis techniques and utilizing the resultant data to construct precision 3D models in vitro. Finally, we provide clinically relevant applications of these versatile personalized cancer models to highlight their potential impact. These models have utility towards a myriad of fundamental cancer biology and translational studies. Importantly, these approaches can be extended to other carcinomas, facilitating the discovery of new therapeutics that more effectively target the unique aspects of each individual patient's TME. STATEMENT OF SIGNIFICANCE: : In this article, we have presented the case for the application of biomaterials in developing personalized models of complex diseases such as cancers. Personalized biomaterials-based models could bring about breakthrough in the promise of precision medicine. The critical components of the diverse tumor microenvironments, that lead to treatment failures, include cellular- and extracellular matrix- heterogeneity, and biophysical signals to the cells. Therefore, we have described these dynamic components of the tumor microenvironments, and have highlighted how contemporary biomaterials that can be utilized to create personalized in vitro models of cancers. We have also described the application of the personalized biomaterials-based models to carefully characterize the dynamic patterns of patients' disease, and predict effective therapies that can produce durable responses, limit relapses and treat any minimal residual disease.

Keywords:  Biomaterial; Cancer stem-like cells; Cancers; Chemoresistance; Extracellular matrix; Immune cells; Mechanics; Mechanobiology; Ovarian cancers; Personalized; Predict relapse; Residual disease; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.actbio.2021.04.041
Cancer Cell. 2021 Apr 27. pii: S1535-6108(21)00212-9. [Epub ahead of print]

Single-cell dissection of cellular components and interactions shaping the tumor immune phenotypes in ovarian cancer.

Milena Hornburg, Mélanie Desbois, Shan Lu, Yinghui Guan, Amy A Lo, Susan Kaufman, Ashley Elrod, Alina Lotstein, Teresa M DesRochers, Jose L Munoz-Rodriguez, Xingwei Wang, Jennifer Giltnane, Oleg Mayba, Shannon J Turley, Richard Bourgon, Anneleen Daemen, Yulei Wang.

  Distinct T cell infiltration patterns, i.e., immune infiltrated, excluded, and desert, result in different responses to cancer immunotherapies. However, the key determinants and biology underpinning these tumor immune phenotypes remain elusive. Here, we provide a high-resolution dissection of the entire tumor ecosystem through single-cell RNA-sequencing analysis of 15 ovarian tumors. Immune-desert tumors are characterized by unique tumor cell-intrinsic features, including metabolic pathways and low antigen presentation, and an enrichment of monocytes and immature macrophages. Immune-infiltrated and -excluded tumors differ markedly in their T cell composition and fibroblast subsets. Furthermore, our study reveals chemokine receptor-ligand interactions within and across compartments as potential mechanisms mediating immune cell infiltration, exemplified by the tumor cell-T cell cross talk via CXCL16-CXCR6 and stromal-immune cell cross talk via CXCL12/14-CXCR4. Our data highlight potential molecular mechanisms that shape the tumor immune phenotypes and may inform therapeutic strategies to improve clinical benefit from cancer immunotherapies.

Keywords:  CXCL16; Granzyme K; desert; excluded; fibroblasts; immune phenotype; infiltrated; ovarian cancer; single-cell RNA-seq; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2021.04.004
Cell Rep Med. 2021 Apr 20. 2(4): 100227

Hypoxia-sensing CAR T cells provide safety and efficacy in treating solid tumors.

Paris Kosti, James W Opzoomer, Karen I Larios-Martinez, Rhonda Henley-Smith, Cheryl L Scudamore, Mary Okesola, Mustafa Y M Taher, David M Davies, Tamara Muliaditan, Daniel Larcombe-Young, Natalie Woodman, Cheryl E Gillett, Selvam Thavaraj, John Maher, James N Arnold.

  Utilizing T cells expressing chimeric antigen receptors (CARs) to identify and attack solid tumors has proven challenging, in large part because of the lack of tumor-specific targets to direct CAR binding. Tumor selectivity is crucial because on-target, off-tumor activation of CAR T cells can result in potentially lethal toxicities. This study presents a stringent hypoxia-sensing CAR T cell system that achieves selective expression of a pan-ErbB-targeted CAR within a solid tumor, a microenvironment characterized by inadequate oxygen supply. Using murine xenograft models, we demonstrate that, despite widespread expression of ErbB receptors in healthy organs, the approach provides anti-tumor efficacy without off-tumor toxicity. This dynamic on/off oxygen-sensing safety switch has the potential to facilitate unlimited expansion of the CAR T cell target repertoire for treating solid malignancies.

Keywords:  CAR T cells; HIF1α; HypoxiCAR; T cell; cancer; chimeric antigen receptor; cytokine release syndrome; hypoxia; immunotherapy; toxicity

DOI:  https://doi.org/10.1016/j.xcrm.2021.100227
Front Cell Dev Biol. 2021 ;9 656867

High-Yield Human Induced Pluripotent Stem Cell-Derived Monocytes and Macrophages Are Functionally Comparable With Primary Cells.

Di Cui, Alexandra Franz, Sophie A Fillon, Linda Jannetti, Timo Isambert, Katrin Fundel-Clemens, Heinrich J Huber, Coralie Viollet, Alexander Ghanem, Akira Niwa, Bernd Weigle, Stefan Pflanz.

  Macrophages are pivotal effectors of host immunity and regulators of tissue homeostasis. Understanding of human macrophage biology has been hampered by the lack of reliable and scalable models for cellular and genetic studies. Human induced pluripotent stem cell (hiPSC)-derived monocytes and macrophages, as an unlimited source of subject genotype-specific cells, will undoubtedly play an important role in advancing our understanding of macrophage biology and implication in human diseases. In this study, we present a fully optimized differentiation protocol of hiPSC-derived monocytes and granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF). We present characterization of iPSC-derived myeloid lineage cells at phenotypic, functional, and transcriptomic levels, in comparison with corresponding subsets of peripheral blood-derived cells. We also highlight the application of hiPSC-derived monocytes and macrophages as a gene-editing platform for functional validation in research and drug screening, and the study also provides a reference for cell therapies.

Keywords:  Crispr/Cas; differentiation; gene-editing; iPSC; macrophages; monocytes; myeloid

DOI:  https://doi.org/10.3389/fcell.2021.656867
Neurochem Int. 2021 May 01. pii: S0197-0186(21)00095-4. [Epub ahead of print] 105049

Bioscaffold-based study of glioblastoma cell behavior and drug delivery for tumor therapy.

Kimmy Tran, Ryan Brice, Li Yao.

  Glioblastoma multiforme (GBM) is a severe form of brain cancer with an average five-year survival rate of 6.7%. Current treatment strategies include surgical resection of the tumor area and lining the lesion site with therapeutics, which offer only a moderate impact on increasing survival rates. Drug-testing models based on the monolayer cell culture method may partially explain the lack of advancement in effective GBM treatment, because this model is limited in its ability to show heterogeneous cell-cell and cell-environment interactions as tumor cells in the in vivo state. The development of bioscaffold-based culture models is an important improvement in GBM research, preclinical trials, and targeted drug testing, through better mimicking of the heterogeneity of tumor environmental conditions. A major hurdle towards better GBM outcomes is in delivering medication across the blood-brain barrier (BBB), which normally prevents the crossing of materials into the treatment site. The delivery of therapeutics using bioscaffolds is a potential means of overcoming the BBB and could potentially facilitate long-lasting drug release. A number of natural and synthetic materials have been studied for their biodegradability, toxicity, distribution, and pharmaceutical stability, which are needed to determine the overall effectiveness and safety of glioblastoma treatment. This review summarizes advancements in the research of bioscaffold-based GBM cell growth systems and the potential of using bioscaffolds as a carrier for drug delivery.

Keywords:  3D cell culture; Glioblastoma; biomaterials; drug delivery; therapy

DOI:  https://doi.org/10.1016/j.neuint.2021.105049
J Drug Target. 2021 May 07. 1-46

Nano drug delivery system reconstruct tumor vasculature for the tumor vascular normalization.

Qiangwei Liang, Liyue Zhou, Yifan Li, Jinxia Liu, Yanhua Liu.

  The specific tumor microenvironment plays a crucial role in the occurrence and development of tumors. Among them, the abnormal structure and function of blood vessels in the tumor microenvironment are obvious characteristics of the tumor. Abnormal blood vessels with high leakage can lead to impaired blood perfusion and non-specific leakage of blood components into the surrounding interstitial spaces. They create a hypoxic and acidic microenvironment for tumors, which supports the occurrence of malignant tumors and increases the possibility of tumor cell invasion and metastasis. The formation of abnormal vascular also enhances immunosuppression and prevents the delivery of chemotherapy drugs to deeper tumors. Therefore, the normalization of tumor blood vessels is a very promising approach to improve anti-tumor efficacy, aiming to restore the structural integrity of vessels and improve drug delivery efficiency and anti-tumor immunity. In this review, we have summarized strategies to improve cancer treatment that via nano drug delivery technology regulates the normalization of tumor blood vessels. The treatment strategies related to the structure and function of tumor blood vessels such as angiogenesis factors, tumor-associated macrophages, tumor vascular endothelial cells, tumor-associated fibroblasts, and immune checkpoints in the tumor microenvironment were mainly discussed. The normalization of tumor blood vessels presents new opportunities and challenges for the more efficient delivery of nanoparticles to tumor tissues and cells and an innovative combination of treatments for cancer.

Keywords:  antitumor; nanoparticles; normalization; tumor blood vessel; tumor microenvironment

DOI:  https://doi.org/10.1080/1061186X.2021.1927056
Cells. 2021 Apr 29. pii: 1055. [Epub ahead of print]10(5):

Development of a Decellularized Porcine Esophageal Matrix for Potential Applications in Cancer Modeling.

Hersh Chaitin, Michael L Lu, Michael B Wallace, Yunqing Kang.

  Many decellularized extracellular matrix-derived whole organs have been widely used in studies of tissue engineering and cancer models. However, decellularizing porcine esophagus to obtain decellularized esophageal matrix (DEM) for potential biomedical applications has not been widely investigated. In this study a modified decellularization protocol was employed to prepare a porcine esophageal DEM for the study of cancer cell growth. The cellular removal and retention of matrix components in the porcine DEM were fully characterized. The microstructure of the DEM was observed using scanning electronic microscopy. Human esophageal squamous cell carcinoma (ESCC) and human primary esophageal fibroblast cells (FBCs) were seeded in the DEM to observe their growth. Results show that the decellularization process did not cause significant loss of mechanical properties and that blood ducts and lymphatic vessels in the submucosa layer were also preserved. ESCC and FBCs grew on the DEM well and the matrix did not show any toxicity to cells. When FBS and ESCC were cocultured on the matrix, they secreted more periostin, a protein that supports cell adhesion on matrix. This study shows that the modified decellularization protocol can effectively remove the cell materials and maintain the microstructure of the porcine esophageal matrix, which has the potential application of studying cell growth and migration for esophageal cancer models.

Keywords:  decellularization; decellularized extracellular matrix; esophageal cancer; tumor model

DOI:  https://doi.org/10.3390/cells10051055
In Vitro Cell Dev Biol Anim. 2021 May 05.

Breast cancer organoids from malignant pleural effusion-derived tumor cells as an individualized medicine platform.

Bo Pan, Dongyi Zhao, Yaqian Liu, Na Li, Chen Song, Ning Li, Xuelu Li, Zuowei Zhao.

  Malignant pleural effusion (MPE) presents a severe medical condition in patients with advanced breast cancer (BC). We applied organoid culture technology to culture preoperative puncture specimen and corresponding surgical specimen-derived tumor cells from early BC patients and pleural effusion-derived tumor cells from advanced BC patients with MPE to study whether in vitro models could predict therapies of clinical patients. We successfully expanded pleural effusion-derived tumor organoids from 1 advanced triple-negative breast cancer (TNBC) patient with MPE which had been continuously propagated for more than 3 months. The organoids matched the histological characteristics of primary BC and metastatic supraclavicular lymph nodes by H&E staining and retained negative expression of TNBC biomarkers: estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and positive expression of antigen Ki-67. Multiple mutations were detected from this advanced TNBC patient with MPE by high-throughput sequencing of metastatic supraclavicular lymph node and the plasma sample. We performed the 3D drug screening tests combined with the clinical medication situation of this patient. The pleural effusion-derived tumor organoids were sensitive to capecitabine (IC50 1.580 μmol) and everolimus (IC50 4.008 μmol) single-agent treatments. The sensitivity to capecitabine was consistent with the clinical treatment response of this patient for capecitabine and with the sequencing results that reported MTHFR gene polymorphism mutation and TYMS -6bp/-6bp polymorphism mutation indicating effectiveness to fluorouracil. Our results suggested that an effective platform for ex vivo pleural effusion-derived tumor organoids from advanced TNBC patients with MPE could be used to identify treatment options and explore the clinicopathological characteristics of these patients.

Keywords:  Drug sensitivity test; Individualized therapy; Organoid culture; Pleural effusion; Triple-negative breast cancer

DOI:  https://doi.org/10.1007/s11626-021-00563-9
Front Immunol. 2021 ;12 672158

Analysis of Tumor Microenvironment Characteristics in Bladder Cancer: Implications for Immune Checkpoint Inhibitor Therapy.

Xingyu Chen, Haotian Chen, Dong He, Yaxin Cheng, Yuxing Zhu, Mengqing Xiao, Hua Lan, Zhanwang Wang, Ke Cao.

  The tumor microenvironment (TME) plays a crucial role in cancer progression and recent evidence has clarified its clinical significance in predicting outcomes and efficacy. However, there are no studies on the systematic analysis of TME characteristics in bladder cancer. In this study, we comprehensively evaluated the TME invasion pattern of bladder cancer in 1,889 patients, defined three different TME phenotypes, and found that different subtypes were associated with the clinical prognosis and pathological characteristics of bladder cancer. We further explored the signaling pathways, cancer-immunity cycle, copy number, and somatic mutation differences among the different subtypes and used the principal component analysis algorithm to calculate the immune cell (IC) score, a tool for comprehensive evaluation of TME. Univariate and multivariate Cox regression analyses showed that ICscore is a reliable and independent prognostic biomarker. In addition, the use of anti-programmed death-ligand (PD-L1) treatment cohort, receiver operating characteristic (ROC) curve, Tumor Immune Dysfunction and Exclusion (TIDE), Subnetwork Mappings in Alignment of Pathways (SubMAP), and other algorithms confirmed that ICscore is a reliable prognostic biomarker for immune checkpoint inhibitor response. Patients with higher ICscore showed a significant therapeutic advantage in immunotherapy. In conclusion, this study improves our understanding of the characteristics of TME infiltration in bladder cancer and provides guidance for more effective personalized immunotherapy strategies.

Keywords:  bladder cancer; immune checkpoint; immunotherapy; tumor immune dysfunction and exclusion; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2021.672158