scholarly journals DDR2 controls breast tumor stiffness and metastasis by regulating integrin mediated mechanotransduction in CAFs

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Samantha VH Bayer ◽  
Whitney R Grither ◽  
Audrey Brenot ◽  
Priscilla Y Hwang ◽  
Craig E Barcus ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Lung Metastases ◽  
Tumor Stroma ◽  
Collagen Fibers ◽  
Tumor Aggressiveness ◽  
Biomechanical Changes ◽  
Tumor Stiffness ◽  
Collagen Receptor ◽  
Fiber Organization

Biomechanical changes in the tumor microenvironment influence tumor progression and metastases. Collagen content and fiber organization within the tumor stroma are major contributors to biomechanical changes (e., tumor stiffness) and correlated with tumor aggressiveness and outcome. What signals and in what cells control collagen organization within the tumors, and how, is not fully understood. We show in mouse breast tumors that the action of the collagen receptor DDR2 in CAFs controls tumor stiffness by reorganizing collagen fibers specifically at the tumor-stromal boundary. These changes were associated with lung metastases. The action of DDR2 in mouse and human CAFs, and tumors in vivo, was found to influence mechanotransduction by controlling full collagen-binding integrin activation via Rap1-mediated Talin1 and Kindlin2 recruitment. The action of DDR2 in tumor CAFs is thus critical for remodeling collagen fibers at the tumor-stromal boundary to generate a physically permissive tumor microenvironment for tumor cell invasion and metastases.

scholarly journals The MEMIC: An ex vivo system to model the complexity of the tumor microenvironment

2021 ◽  
Author(s):  
Libuše Janská ◽  
Libi Anandi ◽  
Nell C. Kirchberger ◽  
Zoran S. Marinkovic ◽  
Logan T. Schachtner ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Ex Vivo ◽  
Tumor Stroma ◽  
Stem Cell Differentiation ◽  
Blood Stream ◽  
Direct Access ◽  
Ex Vivo Model

There is an urgent need for accurate, scalable, and cost-efficient experimental systems to model the complexity of the tumor microenvironment. Here, we detail how to fabricate and use the Metabolic Microenvironment Chamber (MEMIC) – a 3D-printed ex vivo model of intratumoral heterogeneity. A major driver of the cellular and molecular diversity in tumors is the accessibility to the blood stream that provides key resources such as oxygen and nutrients. While some tumor cells have direct access to these resources, many others must survive under progressively more ischemic environments as they reside further from the vasculature. The MEMIC is designed to simulate the differential access to nutrients and allows co-culturing different cell types, such as tumor and immune cells. This system is optimized for live imaging and other microscopy-based approaches, and it is a powerful tool to study tumor features such as the effect of nutrient scarcity on tumor-stroma interactions. Due to its adaptable design and full experimental control, the MEMIC provide insights into the tumor microenvironment that would be difficult to obtain via other methods. As a proof of principle, we show that cells sense gradual changes in metabolite concentration resulting in multicellular spatial patterns of signal activation and cell proliferation. To illustrate the ease of studying cell-cell interactions in the MEMIC, we show that ischemic macrophages reduce epithelial features in neighboring tumor cells. We propose the MEMIC as a complement to standard in vitro and in vivo experiments, diversifying the tools available to accurately model, perturb, and monitor the tumor microenvironment, as well as to understand how extracellular metabolites affect other processes such as wound healing and stem cell differentiation.

scholarly journals Developing preclinical models of neuroblastoma: driving therapeutic testing

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Kimberly J. Ornell ◽  
Jeannine M. Coburn
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Therapeutics ◽  
Tumor Stroma ◽  
In Vitro Models ◽  
Preclinical Models ◽  
In Vivo Models ◽  
Therapeutic Development ◽  
Potential Applications

AbstractDespite advances in cancer therapeutics, particularly in the area of immuno-oncology, successful treatment of neuroblastoma (NB) remains a challenge. NB is the most common cancer in infants under 1 year of age, and accounts for approximately 10% of all pediatric cancers. Currently, children with high-risk NB exhibit a survival rate of 40–50%. The heterogeneous nature of NB makes development of effective therapeutic strategies challenging. Many preclinical models attempt to mimic the tumor phenotype and tumor microenvironment. In vivo mouse models, in the form of genetic, syngeneic, and xenograft mice, are advantageous as they replicated the complex tumor-stroma interactions and represent the gold standard for preclinical therapeutic testing. Traditional in vitro models, while high throughput, exhibit many limitations. The emergence of new tissue engineered models has the potential to bridge the gap between in vitro and in vivo models for therapeutic testing. Therapeutics continue to evolve from traditional cytotoxic chemotherapies to biologically targeted therapies. These therapeutics act on both the tumor cells and other cells within the tumor microenvironment, making development of preclinical models that accurately reflect tumor heterogeneity more important than ever. In this review, we will discuss current in vitro and in vivo preclinical testing models, and their potential applications to therapeutic development.

scholarly journals Rectal Tumor Stiffness Quantified by In Vivo Tomoelastography and Collagen Content Estimated by Histopathology Predict Tumor Aggressiveness

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiaxi Hu ◽  
Jing Guo ◽  
Yigang Pei ◽  
Ping Hu ◽  
Mengsi Li ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
High Risk ◽  
Magnetic Resonance ◽  
Rectal Tumor ◽  
Collagen Content ◽  
Tumor Aggressiveness ◽  
Rectal Tumors ◽  
Tumor Stages ◽  
Tumor Stiffness

PurposeTo investigate the significance of collagen in predicting the aggressiveness of rectal tumors in patients, examined in vivo based on tomoelastography quantified stiffness and ex vivo by histologically measured collagen volume fraction (CVF).Experimental Design170 patients with suspected rectal cancer were prospectively enrolled and underwent preoperative magnetic resonance imaging (MRI) and rectal tomoelastography, a technique based on multifrequency magnetic resonance elastography. Histopathologic analysis identified eighty patients with rectal cancer who were divided into subgroups by tumor-node (TN) stage, prognostic stage, and risk level. Rectal tumor stiffness was correlated with histopathologic CVF. Area-under-the-curve (AUC) and contingency analysis were used to evaluate the performance of rectal stiffness in distinguishing tumor stages which was compared to standard clinical MRIResultsIn vivo tomoelastography revealed that rectal tumor stiffened significantly with increased TN stage (p<0.05). Tumors with poorly differentiated status, perineural and lymphovascular invasion also displayed higher stiffness than well-to-moderately differentiated, noninvasive tumors (all p<0.05). Similar to in vivo stiffness, CVF indicated an abnormally high collagen content in tumors with perineural invasion and poor differentiation status. CVF was also positively correlated with stiffness (p<0.05). Most importantly, both stiffness (AUROC: 0.82) and CVF (AUROC: 0.89) demonstrated very good diagnostic accuracy in detecting rectal tumors that have high risk for progressing to an aggressive state with poorer prognosis.ConclusionIn human rectal carcinomas, overexpression of collagen is correlated with increased tissue stiffness and high risk for tumor advancing more aggressively. In vivo tomoelastography quantifies rectal tumor stiffness which improves the diagnostic performance of standard MRI in the assessment of lymph nodes metastasis. Therefore, in vivo stiffness mapping by tomoelastography can predict rectal tumor aggressiveness and add diagnostic value to MRI.

scholarly journals A humanized single-chain antibody against beta 3 integrin inhibits pulmonary metastasis by preferentially fragmenting activated platelets in the tumor microenvironment

Blood ◽  
2012 ◽  
Vol 120 (14) ◽  
pp. 2889-2898 ◽  
Author(s):  
Wei Zhang ◽  
Suying Dang ◽  
Tao Hong ◽  
Jian Tang ◽  
Jing Fan ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Molecular Mechanisms ◽  
Time Window ◽  
Lung Metastases ◽  
Pulmonary Nodules ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Activated Platelets

Abstract Platelets play a supportive role in tumor metastasis. Impairment of platelet function within the tumor microenvironment may provide a clinically useful approach to inhibit metastasis. We developed a novel humanized single-chain antibody (scFv Ab) against integrin GPIIIa49-66 (named A11) capable of lysing activated platelets. In this study, we investigate the effect of A11 on the development of pulmonary metastases. In the Lewis lung carcinoma (LLC) metastatic model, A11 decreases the mean number of surface nodules and mean volume of pulmonary nodules. It protects against lung metastases in a time window that extended 4 hours before and 4 hours after the IV injection of LLCs. Coinjection of GPIIIa49-66 albumin reverses the antimetastatic activity of A11 in the B16 melanoma model, consistent with the pathophysiologic relevance of the platelet GPIIIa49-66 epitope. Significantly, A11 had no effect on angiogenesis using both in vitro and in vivo assays. The underlying molecular mechanisms are a combination of inhibition of each of the following interactions: between activated platelets and tumor cells, platelets and endothelial cells, and platelets and monocytes, as well as disaggregation of an existing platelet/tumor thrombus. Our observations may provide a novel antimetastatic strategy through lysing activated platelets in the tumor microenvironment using humanized anti–GPIIIa49-66 scFv Ab.

scholarly journals 936 Stromal remodeling regulates dendritic cell abundance in the tumor microenvironment

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A982-A982
Author(s):  
Athanasios Papadas ◽  
Gauri Deb ◽  
Adam Officer ◽  
Chelsea Hope ◽  
Philip Emmerich ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Cell Fate ◽  
Tumor Stroma ◽  
Matrix Remodeling ◽  
Dependent Manner ◽  
Cancer Society ◽  
Cellular Models ◽  
Cancer Types

BackgroundStimulatory dendritic cells (SDC), enriched within the Batf3-DC lineage (also known as conventional type 1 DC, cDC1), engage in productive interactions with CD8+ effectors along tumor-stroma boundaries. This puzzling pattern of T-cell-DC localization has been interpreted as ”tumor-exclusion”, limiting anti-tumor immunity. To understand this paradox, we hypothesized that dynamic matrix remodeling at the invasive margin generates unique activation and cell-fate cues critical for Batf3-DC homeostasis.MethodsWe studied immunocompetent tumor models of lung carcinoma, breast carcinoma, melanoma and multiple myeloma. For mechanistic experiments, we generated novel Vcan-targeted models through CRISPR-Cas9 targeting. We delineated DC subsets through multi-parametric flow cytometry and tumor immune contexture through mass cytometry. Batf3-DC cellular models included MutuDC1940 immortalized DC and iCD103 primary cells. TCGA data were mined for human validation.ResultsWe find that CD8+ T cells massively infiltrate tumor matrices undergoing robust matrix proteoglycan versican (VCAN) proteolysis, an essential organ-sculpting modification in development and adult tissue-plane forging. Across 7591 samples from 20 TCGA cancer types, a significant-positive correlation between VCAN substrate expression and Batf3-DC score was observed, suggesting that the VCAN pathway may regulate Batf3-DC across several cancer types. Experimental Vcan depletion in the tumor microenvironment was detrimental for Batf3-DC. Batf3-DC abundance was restored through the VCAN N-terminal fragment (matrikine) versikine, physiologically generated through ADAMTS protease activity in remodeled stroma. In addition to Batf3-DC expansion, versikine resulted in G-MDSC contraction as well as the emergence of an atypical innate lymphoid (NK/ILC1) subset expressing cytotoxicity receptors, low IFNgamma and robust pro-survival GM-CSF. Despite broad intratumoral IRF8 induction (10-100-fold), adoptive transfer of pre-DC into versikine-replete microenvironments did not influence their differentiation choice between Batf3-DC and cDC2. Instead, versikine delivered a distinct Batf3-DC activation signal characterized by non-TLR maturation as well as downregulation of TGFbeta and Wnt signaling. In vivo, versikine promoted Batf3-DC abundance through NK cells but independently of stromal TLR2 or CD44. Versikine sensitized immune-evasive tumors to STING agonist immunotherapy in a Batf3-DC dependent manner and promoted antigen-specific CD8+ responses. Versikine-DC signatures correlated with CD8+ T cell scores in human lung cancers.ConclusionsWe demonstrate that dynamic extracellular matrix remodeling controls Batf3-DC abundance in the tumor microenvironment. N-terminal proteolysis of the matrix proteoglycan versican (VCAN), releases a bioactive fragment (matrikine), versikine, that is remarkably necessary and sufficient for Batf3-DC accumulation. Versikine orchestrates a multi-lineage network that regulates Batf3-DC activation and survival at matrix-remodeling interfaces. Therapeutic harnessing of matrix-Batf3-DC cross-talk sensitizes immune-evasive tumors to immunotherapy.AcknowledgementsWe acknowledge support by the National Cancer Institute (R01CA252937 and U01CA196406), the American Cancer Society (127508-RSG-15-045-01-LIB), the Leukemia and Lymphoma Society (6551–18), the UW Trillium Myeloma Fund and the Robert J. Shillman Foundation.Ethics ApprovalLaboratory animal work was performed under IACUC-approved protocols #M5476 and #S19109 in the University of Wisconsin-Madison and University of California, San Diego respectively.

Biological and biomedical applications of collagenous biomaterials

1990 ◽  
Vol 48 (3) ◽  
pp. 856-857
Author(s):  
Yasushi P. Kato ◽  
Michael G. Dunn ◽  
Frederick H. Silver ◽  
Arthur J. Wasserman
Keyword(s):  
Biomedical Applications ◽  
Soft Tissues ◽  
Collagen Fibers ◽  
Bone Collagen ◽  
Cover Slip ◽  
Fibroblast Migration ◽  
Cellular Expression ◽  
Defect Repair

Collagenous biomaterials have been used for growing cells in vitro as well as for augmentation and replacement of hard and soft tissues. The substratum used for culturing cells is implicated in the modulation of phenotypic cellular expression, cellular orientation and adhesion. Collagen may have a strong influence on these cellular parameters when used as a substrate in vitro. Clinically, collagen has many applications to wound healing including, skin and bone substitution, tendon, ligament, and nerve replacement. In this report we demonstrate two uses of collagen. First as a fiber to support fibroblast growth in vitro, and second as a demineralized bone/collagen sponge for radial bone defect repair in vivo.For the in vitro study, collagen fibers were prepared as described previously. Primary rat tendon fibroblasts (1° RTF) were isolated and cultured for 5 days on 1 X 15 mm sterile cover slips. Six to seven collagen fibers, were glued parallel to each other onto a circular cover slip (D=18mm) and the 1 X 15mm cover slip populated with 1° RTF was placed at the center perpendicular to the collagen fibers. Fibroblast migration from the 1 x 15mm cover slip onto and along the collagen fibers was measured daily using a phase contrast microscope (Olympus CK-2) with a calibrated eyepiece. Migratory rates for fibroblasts were determined from 36 fibers over 4 days.

Facilitated migration of cells from a transected peripheral nerve over collagen fibers: in vivo observations

1989 ◽  
Vol 47 ◽  
pp. 888-889
Author(s):  
Arthur J. Wasserman ◽  
Azam Rizvi ◽  
George Zazanis ◽  
Frederick H. Silver
Keyword(s):  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Collagen Gel ◽  
Collagen Fibers ◽  
Control Group ◽  
Guide Tube ◽  
Sprague Dawley ◽  
Silicone Tube ◽  
Thin Sections

In cases of peripheral nerve damage the gap between proximal and distal stumps can be closed by suturing the ends together, using a nerve graft, or by nerve tubulization. Suturing allows regeneration but does not prevent formation of painful neuromas which adhere to adjacent tissues. Autografts are not reported to be as good as tubulization and require a second surgical site with additional risks and complications. Tubulization involves implanting a nerve guide tube that will provide a stable environment for axon proliferation while simultaneously preventing formation of fibrous scar tissue. Supplementing tubes with a collagen gel or collagen plus extracellular matrix factors is reported to increase axon proliferation when compared to controls. But there is no information regarding the use of collagen fibers to guide nerve cell migration through a tube. This communication reports ultrastructural observations on rat sciatic nerve regeneration through a silicone nerve stent containing crosslinked collagen fibers.Collagen fibers were prepared as described previously. The fibers were threaded through a silicone tube to form a central plug. One cm segments of sciatic nerve were excised from Sprague Dawley rats. A control group of rats received a silicone tube implant without collagen while an experimental group received the silicone tube containing a collagen fiber plug. At 4 and 6 weeks postoperatively, the implants were removed and fixed in 2.5% glutaraldehyde buffered by 0.1 M cacodylate containing 1.5 mM CaCl2 and balanced by 0.1 M sucrose. The explants were post-fixed in 1% OSO4, block stained in 1% uranyl acetate, dehydrated and embedded in Epon. Axons were counted on montages prepared at a total magnification of 1700x. Montages were viewed through a dissecting microscope. Thin sections were sampled from the proximal, middle and distal regions of regenerating sciatic plugs.

scholarly journals Regeneration linked miRNA modify tumor phenotype and can enforce multi-lineage growth arrest in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Siamak Salehi ◽  
Oliver D. Tavabie ◽  
Augusto Villanueva ◽  
Julie Watson ◽  
David Darling ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Inhibition ◽  
Tumor Aggressiveness ◽  
Novel Treatment ◽  
Tumor Phenotype ◽  
Aggressive Tumor ◽  
In Vivo Growth ◽  
Regulation Of Regeneration

AbstractRegulated cell proliferation is an effector mechanism of regeneration, whilst dysregulated cell proliferation is a feature of cancer. We have previously identified microRNA (miRNA) that regulate successful and failed human liver regeneration. We hypothesized that these regulators may directly modify tumor behavior. Here we show that inhibition of miRNAs -503 and -23a, alone or in combination, enhances tumor proliferation in hepatocyte and non-hepatocyte derived cancers in vitro, driving more aggressive tumor behavior in vivo. Inhibition of miRNA-152 caused induction of DNMT1, site-specific methylation with associated changes in gene expression and in vitro and in vivo growth inhibition. Enforced changes in expression of two miRNA recapitulating changes observed in failed regeneration led to complete growth inhibition of multi-lineage cancers in vivo. Our results indicate that regulation of regeneration and tumor aggressiveness are concordant and that miRNA-based inhibitors of regeneration may constitute a novel treatment strategy for human cancers.

scholarly journals Loss of PR55α promotes proliferation and metastasis by activating MAPK/AKT signaling in hepatocellular carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
JiangSheng Zhao ◽  
GuoFeng Chen ◽  
Jingqi Li ◽  
Shiqi Liu ◽  
Quan Jin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle Progression ◽  
Lung Metastases ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Signal Pathways ◽  
And Migration ◽  
Healthy Liver

Abstract Background PR55α plays important roles in oncogenesis and progression of numerous malignancies. However, its role in hepatocellular carcinoma (HCC) is unclear. This study aims to characterize the functions of PR55α in HCC. Methods PR55α expressions in HCC tissues and paired healthy liver samples were evaluated using Western blot and tissue microarray immunohistochemistry. We knocked down the expression of PR55α in SMMC-7721 and LM3 cell lines via small interfering and lentivirus. In vitro cell counting, colony formation, migration and invasion assays were performed along with in vivo xenograft implantation and lung metastases experiments. The potential mechanisms involving target signal pathways were investigated by RNA-sequencing. Results PR55α expression level was suppressed in HCC tissues in comparison to healthy liver samples. Decreased PR55α levels were correlated with poorer prognosis (P = 0.0059). Knockdown of PR55α significantly promoted cell proliferation and migration, induced repression of the cell cycle progression and apoptosis in vitro while accelerating in vivo HCC growth and metastasis. Mechanistic analysis indicated that PR55α silencing was involved with MAPK/AKT signal pathway activation and resulted in increased phosphorylation of both AKT and ERK1/2. Conclusions This study identifies PR55α to be a candidate novel therapeutic target in the treatment of HCC.

scholarly journals Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer

2021 ◽  
Vol 9 (1) ◽  
pp. e001341
Author(s):  
Chunxiao Li ◽  
Xiaofei Xu ◽  
Shuhua Wei ◽  
Ping Jiang ◽  
Lixiang Xue ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
Tumor Immunotherapy ◽  
Therapeutic Strategies ◽  
Preclinical Studies ◽  
Future Prospects ◽  
Tumor Associated Macrophages

Macrophages are the most important phagocytes in vivo. However, the tumor microenvironment can affect the function and polarization of macrophages and form tumor-associated macrophages (TAMs). Usually, the abundance of TAMs in tumors is closely associated with poor prognosis. Preclinical studies have identified important pathways regulating the infiltration and polarization of TAMs during tumor progression. Furthermore, potential therapeutic strategies targeting TAMs in tumors have been studied, including inhibition of macrophage recruitment to tumors, functional repolarization of TAMs toward an antitumor phenotype, and other therapeutic strategies that elicit macrophage-mediated extracellular phagocytosis and intracellular destruction of cancer cells. Therefore, with the increasing impact of tumor immunotherapy, new antitumor strategies to target TAMs are now being discussed.

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