scholarly journals Applicability of Drug Response Metrics for Cancer Studies using Biomaterials

2018 ◽  
Author(s):  
Elizabeth A. Brooks ◽  
Sualyneth Galarza ◽  
Maria F. Gencoglu ◽  
R. Chase Cornelison ◽  
Jennifer M. Munson ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Stromal Cells ◽  
Best Practice ◽  
Drug Response ◽  
Tissue Culture Polystyrene ◽  
Culture Cells ◽  
3D Geometry ◽  
Cancer Studies

AbstractBioengineers have built increasingly sophisticated models of the tumor microenvironment in which to study cell-cell interactions, mechanisms of cancer growth and metastasis, and to test new potential therapies. These models allow researchers to culture cells in conditions that include features of thein vivotumor microenvironment (TME) implicated in regulating cancer progression, such as ECM stiffness, integrin binding to the ECM, immune and stromal cells, growth factor and cytokine depots, and a 3D geometry more representative of the TME than tissue culture polystyrene (TCPS). These biomaterials could be particularly useful for drug screening applications to make better predictions of efficacy, offering better translation to preclinicalin vivomodels and clinical trials. However, it can be challenging to compare drug response reports across different platforms and conditions in the current literature. This is, in part, as a result of inconsistent reporting and use of drug response metrics, and vast differences in cell growth rates across a large variety of biomaterial design. This perspective paper attempts to clarify the definitions of drug response measurements used in the field, and presents examples in which these measurements can and cannot be applied. We suggest as best practice to include appropriate controls, always measure the growth rate of cells in the absence of drug, and follow our provided “decision tree” matrix when reporting drug response metrics.

scholarly journals Applicability of drug response metrics for cancer studies using biomaterials

2019 ◽  
Vol 374 (1779) ◽  
pp. 20180226 ◽  
Author(s):  
Elizabeth A. Brooks ◽  
Sualyneth Galarza ◽  
Maria F. Gencoglu ◽  
R. Chase Cornelison ◽  
Jennifer M. Munson ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Best Practice ◽  
Drug Response ◽  
Three Dimensional ◽  
Tumour Microenvironment ◽  
Tissue Culture Polystyrene ◽  
Culture Cells ◽  
Interdisciplinary Approaches ◽  
Improper Use

Bioengineers have built models of the tumour microenvironment (TME) in which to study cell–cell interactions, mechanisms of cancer growth and metastasis, and to test new therapies. These models allow researchers to culture cells in conditions that include features of the in vivo TME implicated in regulating cancer progression, such as extracellular matrix (ECM) stiffness, integrin binding to the ECM, immune and stromal cells, growth factor and cytokine depots, and a three-dimensional geometry more representative of the in vivo TME than tissue culture polystyrene (TCPS). These biomaterials could be particularly useful for drug screening applications to make better predictions of efficacy, offering better translation to preclinical models and clinical trials. However, it can be challenging to compare drug response reports across different biomaterial platforms in the current literature. This is, in part, a result of inconsistent reporting and improper use of drug response metrics, and vast differences in cell growth rates across a large variety of biomaterial designs. This study attempts to clarify the definitions of drug response measurements used in the field, and presents examples in which these measurements can and cannot be applied. We suggest as best practice to measure the growth rate of cells in the absence of drug, and follow our ‘decision tree’ when reporting drug response metrics. This article is part of a discussion meeting issue ‘Forces in cancer: interdisciplinary approaches in tumour mechanobiology’.

scholarly journals Diet, Obesity, and Cancer Progression: Are Adipocytes the Link?

2013 ◽  
Vol 6 ◽  
pp. LPI.S10871 ◽  
Author(s):  
Paul Toren ◽  
Benjamin C. Mora ◽  
Vasundara Venkateswaran
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Tumor Biology ◽  
Model Systems ◽  
In Vivo Model ◽  
Diet Induced Obesity ◽  
Breast And Prostate Cancer ◽  
Obesity And Cancer

Obesity has been linked to more aggressive characteristics of several cancers, including breast and prostate cancer. Adipose tissue appears to contribute to paracrine interactions in the tumor microenvironment. In particular, cancer-associated adipocytes interact reciprocally with cancer cells and influence cancer progression. Adipokines secreted from adipocytes likely form a key component of the paracrine signaling in the tumor microenvironment. In vitro coculture models allow for the assessment of specific adipokines in this interaction. Furthermore, micronutrients and macronutrients present in the diet may alter the secretion of adipokines from adipocytes. The effect of dietary fat and specific fatty acids on cancer progression in several in vivo model systems and cancer types is reviewed. The more common approaches of caloric restriction or diet-induced obesity in animal models establish that such dietary changes modulate tumor biology. This review seeks to explore available evidence regarding how diet may modulate tumor characteristics through changes in the role of adipocytes in the tumor microenvironment.

scholarly journals TLR4 signaling drives mesenchymal stromal cells commitment to promote tumor microenvironment transformation in multiple myeloma

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Cesarina Giallongo ◽  
Daniele Tibullo ◽  
Giuseppina Camiolo ◽  
Nunziatina L. Parrinello ◽  
Alessandra Romano ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Immune Escape ◽  
In Vivo Model ◽  
Th2 Response ◽  
Tlr4 Signaling

Abstract Inflammation represents a key feature and hallmark of tumor microenvironment playing a major role in the interaction with mesenchymal stromal cells (MSC) in cancer progression. The aim of the present study was to investigate the crosstalk between MSCs and myeloma cells (MM) in the pro-inflammatory microenvironment promoting immune evasion and tumor growth. MSC were collected from patients with diagnosis of MGUS (n = 10), smoldering myeloma (n = 7), multiple myeloma at diagnosis (n = 16), relapse (n = 5) or refractory (n = 3), and from age-matched healthy controls (HC, n = 10) and cultured with peripheral blood mononucleated cells (PBMC) from healthy volunteer donors. Similarly to MM, we showed that MSC from smoldering multiple myeloma (SMM) patients activated neutrophils and conferred an immunosuppressive and pro-angiogenic phenotype. Furthermore, co-cultures of plasma cells (PC) and HC-MSC suggested that such activation is driven by MM cells through the switching into a pro-inflammatory phenotype mediated by toll-like receptor 4 (TLR4). These results were further confirmed using a zebrafish as an immunocompetent in vivo model, showing the role of MM–MSC in supporting PCs engraftment and Th2 response. Such effect was abolished following inhibition of TLR4 signaling in MM–MSC before co-injection with PC. Moreover, the addition of a TLR4 inhibitor in the co-culture of HC-MSC with MM cells prevented the activation of the pro-tumor activity in PC-educated MSC. In conclusion, our study provides evidence that TLR4 signaling plays a key role in MSC transformation by inducing a pro-tumor phenotype associated with a permissive microenvironment allowing immune escape and tumor growth.

scholarly journals MAPKAP Kinase-2 Drives Expression of Angiogenic Factors by Tumor-Associated Macrophages in a Model of Inflammation-Induced Colon Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Lucia Suarez-Lopez ◽  
Yi Wen Kong ◽  
Ganapathy Sriram ◽  
Jesse C. Patterson ◽  
Samantha Rosenberg ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Chronic Inflammation ◽  
Cancer Progression ◽  
Tumor Angiogenesis ◽  
Cell Types ◽  
Adoptive Cell Transfer ◽  
Tumor Associated Macrophages

Chronic inflammation increases the risk for colorectal cancer through a variety of mechanisms involving the tumor microenvironment. MAPK-activated protein kinase 2 (MK2), a major effector of the p38 MAPK stress and DNA damage response signaling pathway, and a critical regulator of pro-inflammatory cytokine production, has been identified as a key contributor to colon tumorigenesis under conditions of chronic inflammation. We have previously described how genetic inactivation of MK2 in an inflammatory model of colon cancer results in delayed tumor progression, decreased tumor angiogenesis, and impaired macrophage differentiation into a pro-tumorigenic M2-like state. The molecular mechanism responsible for the impaired angiogenesis and tumor progression, however, has remained contentious and poorly defined. Here, using RNA expression analysis, assays of angiogenesis factors, genetic models, in vivo macrophage depletion and reconstitution of macrophage MK2 function using adoptive cell transfer, we demonstrate that MK2 activity in macrophages is necessary and sufficient for tumor angiogenesis during inflammation-induced cancer progression. We identify a critical and previously unappreciated role for MK2-dependent regulation of the well-known pro-angiogenesis factor CXCL-12/SDF-1 secreted by tumor associated-macrophages, in addition to MK2-dependent regulation of Serpin-E1/PAI-1 by several cell types within the tumor microenvironment.

scholarly journals C-Myc Driven Tolerogenic Tumor Microenvironment (TME) in Mantle Cell Lymphoma (MCL) Is Overcome By Bromodomain Inhibition

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 777-777
Author(s):  
Fengdong Cheng ◽  
Yuan Ren ◽  
Jie Chen ◽  
Zi Wang ◽  
Tao Li ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Cell Lymphoma ◽  
Ex Vivo ◽  
Checkpoint Blockade ◽  
Programmed Death ◽  
Mantle Cell

Abstract Remarkable clinical efficacy and durable responses to antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway have been observed in patients with multiple cancers, including classical Hodgkin lymphomas (cHL). However, the responses in the majority of Non-Hodgkin lymphoma patients, including mantle cell lymphoma (MCL), treated with anti- PD1/PDL1 antibodies have been modest to date. It has been postulated that the immune suppressive nature of the tumor microenvironment (TME) may play a role in limiting the efficacy of checkpoint blockade strategies. As such, identification of critical molecules in TME required for driving response and resistance is key to improve lymphoma immunotherapy. We have therefore generated in vivo and ex-vivo MCL lymphoma-stroma co-culture models and capitalize this model with primary human MCL cells as well. First, we found that co-injection of murine Fc-muMCL1 cells with stromal cells significantly promote lymphoma growthas compared to Fc-muMCL1 cells injected alone. This aggressive growth was associated with less tumor infiltrating cytotoxic T-cells in the TME. Second, to identify the tolerogenic mechanism(s) that drive immunosuppression in TME, we co-cultured MCL cells with stroma cells ex-vivo and found an increased translation and transcription of PD-L1 via upregulation of c-Myc. Furthermore, co-culture of patient primary lymphoma cells with stromal cell dramatically increases PD-L1 expression in both stromal cells and lymphoma cells. Tumor infiltrating T cells also induce PD-L1 expression in stromal cells. Of note, just by knocking down c-Myc in stromal cell we were able to block co-culture-induced PD-L1 expression, highlighting a critical role for c-Myc in driving this tolerogenic process in the TME. In lieu of the above findings, next we treated murine MCL in vitro with a bromodomain inhibitor (JQ1) and observed a significant decrease in c-Myc/PD-L1 expression which was associated with increased immunogenicity of malignant B-cells leading to a better T-cell activation. More importantly, treatment of MCL-bearing mice with a combination of a bromodomain inhibitor with anti-PD1 antibody resulted in enhanced inhibition of MCL growth, increased effector memory T cells and improved function of tumor infiltrating T cells in vivo. No such effects were observed in MCL-bearing mice treated with either agent alone. Taken together, we have identified the c-Myc/PD-L1 axis in stromal cells that by creating a tolerogenic/immunosuppressive TME imposes a significant barrier to the efficacy of checkpoint blockade therapy in lymphomas. This barrier seems not to be unsurmountable since the addition of a bromodomain inhibitor augmented the efficacy of checkpoint blockade by inducing a more immunogenic TME in MCL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Organotypic Modeling of the Tumor Landscape

2020 ◽  
Vol 8 ◽  
Author(s):  
Maria M. Haykal ◽  
Clara Nahmias ◽  
Christine Varon ◽  
Océane C. B. Martin
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Complex Disease ◽  
Epithelial Tumor ◽  
Stromal Compartment ◽  
Culture Models ◽  
Potential Benefits

Cancer is a complex disease and it is now clear that not only epithelial tumor cells play a role in carcinogenesis. The tumor microenvironment is composed of non-stromal cells, including endothelial cells, adipocytes, immune and nerve cells, and a stromal compartment composed of extracellular matrix, cancer-associated fibroblasts and mesenchymal cells. Tumorigenesis is a dynamic process with constant interactions occurring between the tumor cells and their surroundings. Even though all connections have not yet been discovered, it is now known that crosstalk between actors of the microenvironment drives cancer progression. Taking into account this complexity, it is important to develop relevant models to study carcinogenesis. Conventional 2D culture models fail to represent the entire tumor microenvironment properly and the use of animal models should be decreased with respect to the 3Rs rule. To this aim, in vitro organotypic models have been significantly developed these past few years. These models have different levels of complexity and allow the study of tumor cells alone or in interaction with the microenvironment actors during the multiple stages of carcinogenesis. This review depicts recent insights into organotypic modeling of the tumor and its microenvironment all throughout cancer progression. It offers an overview of the crosstalk between epithelial cancer cells and their microenvironment during the different phases of carcinogenesis, from the early cell autonomous events to the late metastatic stages. The advantages of 3D over classical 2D or in vivo models are presented as well as the most promising organotypic models. A particular focus is made on organotypic models used for studying cancer progression, from the less complex spheroids to the more sophisticated body-on-a-chip. Last but not least, we address the potential benefits of these models in personalized medicine which is undoubtedly a domain paving the path to new hopes in terms of cancer care and cure.

scholarly journals 3D Bioprinting of Model Tissues That Mimic the Tumor Microenvironment

Micromachines ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 535
Author(s):  
Florina Bojin ◽  
Andreea Robu ◽  
Maria Iulia Bejenariu ◽  
Valentin Ordodi ◽  
Emilian Olteanu ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Mononuclear Cells ◽  
Lattice Models ◽  
Cell Types ◽  
Cancer Drug ◽  
Peripheral Blood Mononuclear ◽  
Metropolis Monte Carlo

The tumor microenvironment (TME) influences cancer progression. Therefore, engineered TME models are being developed for fundamental research and anti-cancer drug screening. This paper reports the biofabrication of 3D-printed avascular structures that recapitulate several features of the TME. The tumor is represented by a hydrogel droplet uniformly loaded with breast cancer cells (106 cells/mL); it is embedded in the same type of hydrogel containing primary cells—tumor-associated fibroblasts isolated from the peritumoral environment and peripheral blood mononuclear cells. Hoechst staining of cryosectioned tissue constructs demonstrated that cells remodeled the hydrogel and remained viable for weeks. Histological sections revealed heterotypic aggregates of malignant and peritumoral cells; moreover, the constituent cells proliferated in vitro. To investigate the interactions responsible for the experimentally observed cellular rearrangements, we built lattice models of the bioprinted constructs and simulated their evolution using Metropolis Monte Carlo methods. Although unable to replicate the complexity of the TME, the approach presented here enables the self-assembly and co-culture of several cell types of the TME. Further studies will evaluate whether the bioprinted constructs can evolve in vivo in animal models. If they become connected to the host vasculature, they may turn into a fully organized TME.

scholarly journals Metalloproteinases in Ovarian Cancer

2021 ◽  
Vol 22 (7) ◽  
pp. 3403
Author(s):  
Preston Carey ◽  
Ethan Low ◽  
Elizabeth Harper ◽  
M. Sharon Stack
Keyword(s):  
Ovarian Cancer ◽  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Ovarian Cancer Cells ◽  
Age Related ◽  
The Matrix ◽  
Interaction Stress

Proteases play a crucial role in the progression and metastasis of ovarian cancer. Pericellular protein degradation and fragmentation along with remodeling of the extracellular matrix (ECM) is accomplished by numerous proteases that are present in the ovarian tumor microenvironment. Several proteolytic processes have been linked to cancer progression, particularly those facilitated by the matrix metalloproteinase (MMP) family. These proteases have been linked to enhanced migratory ability, extracellular matrix breakdown, and development of support systems for tumors. Several studies have reported the direct involvement of MMPs with ovarian cancer, as well as their mechanisms of action in the tumor microenvironment. MMPs play a key role in upregulating transcription factors, as well as the breakdown of structural proteins like collagen. Proteolytic mechanisms have been shown to enhance the ability of ovarian cancer cells to migrate and adhere to secondary sites allowing for efficient metastasis. Furthermore, angiogenesis for tumor growth and development of metastatic implants is influenced by upregulation of certain proteases, including MMPs. While proteases are produced normally in vivo, they can be upregulated by cancer-associated mutations, tumor–microenvironment interaction, stress-induced catecholamine production, and age-related pathologies. This review outlines the important role of proteases throughout ovarian cancer progression and metastasis.

scholarly journals Targeting neurons in the tumor microenvironment with bupivacaine nanoparticles reduces breast cancer progression and metastases

2021 ◽  
Author(s):  
Maya Kaduri ◽  
Mor Sela ◽  
Shaked Kagan ◽  
Maria Poley ◽  
Hanan Abumanhal-Masarweh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Opioid Analgesic ◽  
Neurite Growth

Neurons within the tumor microenvironment promote cancer progression, thus their local targeting has potential clinical benefits. We designed PEGylated lipid nanoparticles loaded with a non-opioid analgesic, bupivacaine, to target neurons within breast cancer tumors and suppress nerve-to-cancer crosstalk. In vitro, 100-nm nanoparticles were taken up readily by primary neurons, trafficking from the neuronal body and along the axons. We demonstrate that signaling between triple-negative breast cancer cells (4T1) and neurons involves secretion of cytokines stimulating neurite outgrowth. Reciprocally, neurons stimulated 4T1 proliferation, migration and survival through secretion of neurotransmitters. Bupivacaine curbs neurite growth and signaling with cancer cells, inhibiting cancer-cell viability. In vivo, bupivacaine-loaded nanoparticles administered intravenously, suppressed neurons in orthotopic triple-negative breast cancer tumors, inhibiting tumor growth and metastatic dissemination. Overall, our findings suggest that reducing nerve involvement in tumors is important for treating cancer.

scholarly journals An Omentum-inspired 3D PEG Hydrogel for Identifying ECM-drivers of Drug Resistant Ovarian Cancer

2019 ◽  
Author(s):  
Elizabeth A. Brooks ◽  
Maria F. Gencoglu ◽  
Daniel C. Corbett ◽  
Kelly R. Stevens ◽  
Shelly R. Peyton
Keyword(s):  
Ovarian Cancer ◽  
Drug Testing ◽  
Drug Response ◽  
Early Stage ◽  
Treatment Options ◽  
Tissue Culture Polystyrene ◽  
Pathology Reports ◽  
Additional Therapy

AbstractOvarian cancer (OvCa) is a challenging disease to treat due to poor screening techniques and late diagnosis. There is an urgent need for additional therapy options, as patients recur in 70% of cases. The limited availability of clinical treatment options could be a result of poor predictions in early stage drug screens on standard tissue culture polystyrene (TCPS). TCPS does not capture the mechanical and biochemical cues that cells experiencein vivo, which can impact how cells will respond to a drug. Therefore, anin vitromodel that captures some of the microenvironment features that the cells experiencein vivocould provide better insights into drug response. In this study, we formed 3D multicellular tumor spheroids (MCTS) in microwells, and encapsulated them in 3D omentum-inspired hydrogels. SKOV-3 MCTS were resistant to Paclitaxel in our 3D hydrogels compared to a monolayer on TCPS. Toward clinical application, we tested cells from patients (ovarian carcinoma ascites spheroids (OCAS)), and drug responses predicted by using the 3D omentum-inspired hydrogels correlated with the reported pathology reports of those same patients. Additionally, we observed the presence of collagen production around the encapsulated SKOV-3 MCTS, but not on TCPS. Our results demonstrated that our 3D omentum-inspired hydrogel is an improvedin vitrodrug testing platform to study OvCa drug response for patient-derived cells, and helped us identify collagen 3 as a potential driver of Paclitaxel resistance.

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