The Blockade of Tumoral IL1β-Mediated Signaling in Normal Colonic Fibroblasts Sensitizes Tumor Cells to Chemotherapy and Prevents Inflammatory CAF Activation

Heterotypic interactions between newly transformed cells and normal surrounding cells define tumor’s fate in incipient carcinomas. Once homeostasis has been lost, normal resident fibroblasts become carcinoma-associated fibroblasts, conferring protumorogenic properties on these normal cells. Here we describe the IL1β-mediated interplay between cancer cells and normal colonic myofibroblasts (NCFs), which bestows differential sensitivity to cytotoxic drugs on tumor cells. We used NCFs, their conditioned media (CM), and cocultures with tumor cells to characterize the IL1β-mediated crosstalk between both cell types. We silenced IL1β in tumor cells to demonstrate that such cells do not exert an influence on NCFs inflammatory phenotype. Our results shows that IL1β is overexpressed in cocultured tumor cells. IL1β enables paracrine signaling in myofibroblasts, converting them into inflammatory-CAFs (iCAF). IL1β-stimulated-NCF-CM induces migration and differential sensitivity to oxaliplatin in colorectal tumor cells. Such chemoprotective effect has not been evidenced for TGFβ1-driven NCFs. IL1β induces the loss of a myofibroblastic phenotype in NCFs and acquisition of iCAF traits. In conclusion, IL1β-secreted by cancer cells modify surrounding normal fibroblasts to confer protumorogenic features on them, particularly tolerance to cytotoxic drugs. The use of IL1β-blocking agents might help to avoid the iCAF traits acquisition and consequently to counteract the protumorogenic actions these cells.

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Differential sensitivity of AS-30D rat hepatoma cells and normal hepatocytes to anoxic cell damage

AJP Cell Physiology ◽

10.1152/ajpcell.1992.262.6.c1384 ◽

1992 ◽

Vol 262 (6) ◽

pp. C1384-C1387 ◽

Cited By ~ 5

Author(s):

C. E. Kobryn ◽

G. Fiskum

Keyword(s):

Tumor Cells ◽

Cell Damage ◽

Metabolic Stress ◽

Metastatic Potential ◽

Cell Types ◽

Hepatoma Cells ◽

Differential Sensitivity ◽

Trypan Blue Exclusion ◽

Lactate Dehydrogenase Release

A substantial fraction of cells present within hard tumors experience extremely hypoxic and hypoglycemic conditions that can lead to phenotypic alterations such as increased metastatic potential and chemotherapeutic drug resistance. Little is known regarding the influence of anoxic aglycemia on tumor cell energy metabolism and viability, and no direct comparisons have been made between the effects of this form of metabolic stress on tumor cells and their tissue of origin. In this study, the effects of in vitro aglycemic incubation under N2 (with or without iodoacetate) on trypan blue exclusion, lactate dehydrogenase release, cell surface blebbing, ATP levels, and mitochondrial respiratory capacity of rat AS-30D ascites hepatoma cells and normal hepatocytes were measured. Under anoxic-aglycemic conditions, the period of incubation during which 50% viability was lost was 2 h for hepatocytes and 6-8 h for AS-30D cells. In contrast, the rate of anoxia-induced loss of ATP was comparable for the two cell types, and mitochondrial damage was actually accelerated in the tumor cells. These findings suggest that tumor cells are more resistant to anoxic cell death because of their greater ability to withstand deenergization and subcellular injury.

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Spatial transcriptomics reveals the architecture of the tumor/microenvironment interface

10.1101/2020.11.05.368753 ◽

2020 ◽

Author(s):

Miranda V. Hunter ◽

Reuben Moncada ◽

Joshua M. Weiss ◽

Itai Yanai ◽

Richard M. White

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Tumor Cells ◽

Cell Types ◽

Human Melanoma ◽

Zebrafish Model ◽

Interface Cell ◽

Ets Family

SUMMARYDuring tumor progression, cancer cells come into contact with new cell types in the microenvironment, but it is unclear how tumor cells adapt to new environments. Here, we integrate spatial transcriptomics and scRNA-seq to characterize tumor/microenvironment interactions during the initial steps of invasion. Using a zebrafish model of melanoma, we identify a unique “interface” cell state at the tumor/microenvironment boundary. This interface is composed of specialized tumor and microenvironment cells that upregulate a common set of cilia genes, and cilia proteins are enriched only where the tumor contacts the microenvironment. Cilia gene expression is regulated by ETS-family transcription factors, which normally act to suppress cilia genes outside of the interface. An ETS-driven interface is conserved across ten patient samples, suggesting it is a conserved feature of human melanoma. Our results demonstrate the power of spatial transcriptomic approaches in uncovering mechanisms that allow tumors to invade into the microenvironment.

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Mesenchymal stem cells carry and transport clusters of cancer cells

10.1101/2021.02.11.430875 ◽

2021 ◽

Author(s):

Jana Zarubova ◽

Mohammad Mahdi Hasani-Sadrabadi ◽

Sam CP Norris ◽

Andrea M Kasko ◽

Song Li

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cell Migration ◽

Tumor Cell ◽

Cancer Cells ◽

Tumor Cells ◽

Cancer Cell ◽

Cell Types ◽

Cell Clusters ◽

Different Cell Types

AbstractCell clusters that collectively migrate from primary tumors appear to be far more potent in forming distant metastases than single cancer cells. A better understanding of collective cell migration phenomenon and the involvement of different cell types during this process is needed. Here, we utilize a micropatterned surface composed of a thousand of low-adhesive microwells to screen motility of spheroids containing different cell types by analyzing their ability to move from the bottom to the top of the microwells. Mesenchymal stem cells (MSCs) spheroid migration was efficient in contrast to cancer cell only spheroids. In spheroids with both cell types mixed together, MSCs were able to carry the low-motile cancer cells during migration. As the percentage of MSCs increased in the spheroids, more migrating spheroids were detected. Extracellular vesicles secreted by MSCs also contributed to the pro-migratory effect exerted by MSCs. However, the transport of cancer cells was more efficient when MSCs were physically present in the cluster. Similar results were obtained when cell clusters were encapsulated within a micropatterned hydrogel, where collective migration was guided by micropatterned matrix stiffness. These results suggest that stromal cells facilitate the migration of cancer cell clusters, which is contrary to the general belief that malignant cells metastasize independently.SignificanceDuring metastasis, tumor cells may migrate as a cluster, which exhibit higher metastatic capacity compared to single cells. However, whether and how non-cancer cells contained in tumor cluster regulate it’s migration is not clear. Here, we utilize two unique approaches to study collective tumor cell migration in vitro: first, in low-adhesive microwells and second, in micropatterned hydrogels to analyze migration in 3D microenvironment. Our results indicate that MSCs in tumor cell clusters could play an important role in the dissemination of cancer cells by actively transporting low-motile cancer cells. In addition, MSC-released paracrine factors also increase the motility of tumor cells. These findings reveal a new mechanism of cancer cell migration and may lead to new approaches to suppress metastases.

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MAPK Signaling Is Required for Generation of Tunneling Nanotube-Like Structures in Ovarian Cancer Cells

Cancers ◽

10.3390/cancers13020274 ◽

2021 ◽

Vol 13 (2) ◽

pp. 274

Author(s):

Jennifer M. Cole ◽

Richard Dahl ◽

Karen D. Cowden Dahl

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Cell Types ◽

Therapy Resistance ◽

Mapk Signaling ◽

Conditioned Media ◽

Ovarian Cancer Cells ◽

Tunneling Nanotubes ◽

Tunneling Nanotube

Ovarian cancer (OC) cells survive in the peritoneal cavity in a complex microenvironment composed of diverse cell types. The interaction between tumor cells and non-malignant cells is crucial to the success of the metastatic process. Macrophages activate pro-metastatic signaling pathways in ovarian cancer cells (OCCs), induce tumor angiogenesis, and orchestrate a tumor suppressive immune response by releasing anti-inflammatory cytokines. Understanding the interaction between immune cells and tumor cells will enhance our ability to combat tumor growth and dissemination. When co-cultured with OCCs, macrophages induce projections consistent with tunneling nanotubes (TnTs) to form between OCCs. TnTs mediate transfer of material between cells, thus promoting invasiveness, angiogenesis, proliferation, and/or therapy resistance. Macrophage induction of OCC TnTs occurs through a soluble mediator as macrophage-conditioned media potently induced TnT formation in OCCs. Additionally, EGFR-induced TnT formation in OCCs through MAPK signaling may occur. In particular, inhibition of ERK and RSK prevented EGFR-induced TnTs. TnT formation in response to macrophage-conditioned media or EGFR signaling required MAPK signaling. Collectively, these studies suggest that inhibition of ERK/RSK activity may dampen macrophage-OCC communication and be a promising therapeutic strategy.

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Lactate in Sarcoma Microenvironment: Much More than just a Waste Product

Cells ◽

10.3390/cells9020510 ◽

2020 ◽

Vol 9 (2) ◽

pp. 510

Author(s):

Maria Letizia Taddei ◽

Laura Pietrovito ◽

Angela Leo ◽

Paola Chiarugi

Keyword(s):

Cancer Cells ◽

Tumor Cells ◽

Environmental Changes ◽

Malignant Tumors ◽

Waste Product ◽

Tumor Stroma ◽

Cell Types ◽

Extracellular Proteins ◽

Strong Acidity ◽

Current Therapies

Sarcomas are rare and heterogeneous malignant tumors relatively resistant to radio- and chemotherapy. Sarcoma progression is deeply dependent on environmental conditions that sustain both cancer growth and invasive abilities. Sarcoma microenvironment is composed of different stromal cell types and extracellular proteins. In this context, cancer cells may cooperate or compete with stromal cells for metabolic nutrients to sustain their survival and to adapt to environmental changes. The strict interplay between stromal and sarcoma cells deeply affects the extracellular metabolic milieu, thus altering the behavior of both cancer cells and other non-tumor cells, including immune cells. Cancer cells are typically dependent on glucose fermentation for growth and lactate is one of the most heavily increased metabolites in the tumor bulk. Currently, lactate is no longer considered a waste product of the Warburg metabolism, but novel signaling molecules able to regulate the behavior of tumor cells, tumor-stroma interactions and the immune response. In this review, we illustrate the role of lactate in the strong acidity microenvironment of sarcoma. Really, in the biological context of sarcoma, where novel targeted therapies are needed to improve patient outcomes in combination with current therapies or as an alternative treatment, lactate targeting could be a promising approach to future clinical trials.

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Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies

Cancers ◽

10.3390/cancers13194904 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4904

Author(s):

Khiyam Hussain ◽

Mark S. Cragg ◽

Stephen A. Beers

Keyword(s):

Small Molecules ◽

Tumor Cells ◽

Tumor Targeting ◽

Immune Cell ◽

Cell Types ◽

Tumor Immune Evasion ◽

Surface Molecules ◽

Inflammatory Phenotype ◽

New Strategies ◽

Antitumor Antibody

Among the diverse tumor resident immune cell types, tumor-associated macrophages (TAMs) are often the most abundant, possess an anti-inflammatory phenotype, orchestrate tumor immune evasion and are frequently associated with poor prognosis. However, TAMs can also be harnessed to destroy antibody-opsonized tumor cells through the process of antibody-dependent cellular phagocytosis (ADCP). Clinically important tumor-targeting monoclonal antibodies (mAb) such as Rituximab, Herceptin and Cetuximab, function, at least in part, by inducing macrophages to eliminate tumor cells via ADCP. For IgG mAb, this is mediated by antibody-binding activating Fc gamma receptors (FcγR), with resultant phagocytic activity impacted by the level of co-engagement with the single inhibitory FcγRIIb. Approaches to enhance ADCP in the tumor microenvironment include the repolarization of TAMs to proinflammatory phenotypes or the direct augmentation of ADCP by targeting so-called ‘phagocytosis checkpoints’. Here we review the most promising new strategies targeting the cell surface molecules present on TAMs, which include the inhibition of ‘don’t eat me signals’ or targeting immunostimulatory pathways with agonistic mAb and small molecules to augment tumor-targeting mAb immunotherapies and overcome therapeutic resistance.

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Ultrastructural Changes in Three Different Mammalian Cells Following Ultraviolet Laser Irradiation

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100095017 ◽

1972 ◽

Vol 30 ◽

pp. 350-351

Author(s):

K. Shankar Narayan ◽

Kailash C. Gupta ◽

Tohru Okigaki

Keyword(s):

Ultraviolet Light ◽

Mammalian Cells ◽

Biological Effects ◽

Survival Rates ◽

Chinese Hamster ◽

Cell Types ◽

Differential Sensitivity ◽

Ultrastructural Changes ◽

Ultraviolet Laser

The biological effects of short-wave ultraviolet light has generally been described in terms of changes in cell growth or survival rates and production of chromosomal aberrations. Ultrastructural changes following exposure of cells to ultraviolet light, particularly at 265 nm, have not been reported.We have developed a means of irradiating populations of cells grown in vitro to a monochromatic ultraviolet laser beam at a wavelength of 265 nm based on the method of Johnson. The cell types studies were: i) WI-38, a human diploid fibroblast; ii) CMP, a human adenocarcinoma cell line; and iii) Don C-II, a Chinese hamster fibroblast cell strain. The cells were exposed either in situ or in suspension to the ultraviolet laser (UVL) beam. Irradiated cell populations were studied either "immediately" or following growth for 1-8 days after irradiation.Differential sensitivity, as measured by survival rates were observed in the three cell types studied. Pattern of ultrastructural changes were also different in the three cell types.

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Role of exosomes in diagnosis and therapy of prostate cancer

I P Pavlov Russian Medical Biological Herald ◽

10.23888/pavlovj2020283399-405 ◽

2020 ◽

Vol 28 (3) ◽

pp. 399-405

Author(s):

Fabrizio Fontana ◽

Olga A. Babenko

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Biological Fluids ◽

Diagnosis And Treatment ◽

Diagnosis And Therapy ◽

The Future ◽

Important Direction ◽

Potential Biomarkers

Aim of this letter is to attract the attention of journal readers to the study of exosomes as an important direction in the development of Oncology, in particular, in the diagnosis and treatment of prostate cancer. Exosomes are produced by tumor cells and regulate proliferation, metastasis, and the development of chemoresistance. Their extraction from biological fluids allows further use of these vesicles as potential biomarkers of prostate cancer. In the future, exosomes can be successfully used in the delivery of drugs and other anti-tumor substances to cancer cells.

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Recent Advances on Therapeutic Peptides for Breast Cancer Treatment

Current Protein and Peptide Science ◽

10.2174/1389203721999201117123616 ◽

2020 ◽

Vol 21 ◽

Author(s):

Samad Beheshtirouy ◽

Farhad Mirzaei ◽

Shirin Eyvazi ◽

Vahideh Tarhriz

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Breast Cancer Cells ◽

Specific Binding ◽

High Specificity ◽

The Novel ◽

Anti Cancer ◽

Therapeutic Peptides ◽

Low Toxicity

: Breast cancer is a heterogeneous malignancy which is the second cause of mortality among women in the world. Increasing the resistance to anti-cancer drugs in breast cancer cells persuades researchers to search the novel therapies approaches for the treatment of the malignancy. Among the novel methods, therapeutic peptides which target and disrupt tumor cells have been of great interest. Therapeutic peptides are short amino acids monomer chains with high specificity to bind and modulate a protein interaction of interest. Several advantages of peptides such as specific binding on tumor cells surface, low molecular weight and low toxicity on normal cells make the peptides as an appealing therapeutic agents against solid tumors, particularly breast cancer. Also, National Institutes of Health (NIH) describes therapeutic peptides as suitable candidate for the treatment of drug-resistant breast cancer. In this review, we attempt to review the different therapeutic peptides against breast cancer cells which can be used in treatment and diagnosis of the malignancy. Meanwhile, we presented an overview of peptide vaccines which have been developed for the treatment of breast cancer.

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