scholarly journals A Signaling View into the Inflammatory Tumor Microenvironment

Immuno ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 91-118
Author(s):  
Joana F. S. Pereira ◽  
Peter Jordan ◽  
Paulo Matos
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Chromosomal Abnormalities ◽  
Current Knowledge ◽  
Genetic Alterations ◽  
Malignant Progression ◽  
Membrane Receptors ◽  
Surrounding Tissue ◽  
Inflammatory Microenvironment

The development of tumors requires an initiator event, usually exposure to DNA damaging agents that cause genetic alterations such as gene mutations or chromosomal abnormalities, leading to deregulated cell proliferation. Although the mere stochastic accumulation of further mutations may cause tumor progression, it is now clear that an inflammatory microenvironment has a major tumor-promoting influence on initiated cells, in particular when a chronic inflammatory reaction already existed before the initiated tumor cell was formed. Moreover, inflammatory cells become mobilized in response to signals emanating from tumor cells. In both cases, the microenvironment provides signals that initiated tumor cells perceive by membrane receptors and transduce via downstream kinase cascades to modulate multiple cellular processes and respond with changes in cell gene expression, metabolism, and morphology. Cytokines, chemokines, and growth factors are examples of major signals secreted by immune cells, fibroblast, and endothelial cells and mediate an intricate cell-cell crosstalk in an inflammatory microenvironment, which contributes to increased cancer cell survival, phenotypic plasticity and adaptation to surrounding tissue conditions. Eventually, consequent changes in extracellular matrix stiffness and architecture, coupled with additional genetic alterations, further fortify the malignant progression of tumor cells, priming them for invasion and metastasis. Here, we provide an overview of the current knowledge on the composition of the inflammatory tumor microenvironment, with an emphasis on the major signals and signal-transducing events mediating different aspects of stromal cell-tumor cell communication that ultimately lead to malignant progression.

scholarly journals Tumor Microenvironment and Cell Fusion

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Erhui Jiang ◽  
Tinglin Yan ◽  
Zhi Xu ◽  
Zhengjun Shang
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cell Fusion ◽  
Direct Interaction ◽  
Tumor Stem Cell ◽  
Migration And Invasion ◽  
Future Research ◽  
Microenvironmental Factors ◽  
Cell Cell

Cell fusion is a highly regulated biological process that occurs under both physiological and pathological conditions. The cellular and extracellular environment is critical for the induction of the cell–cell fusion. Aberrant cell fusion is initiated during tumor progression. Tumor microenvironment is a complex dynamic system formed by the interaction between tumor cells and their surrounding cells. Cell–cell fusion mediates direct interaction between tumor cells and their surrounding cells and is associated with tumor initiation and progression. Various microenvironmental factors affect cell fusion in tumor microenvironment and generate hybrids that acquire genomes of both parental cells and exhibit novel characteristics, such as tumor stem cell-like properties, radioresistance, drug resistance, immune evasion, and enhanced migration and invasion abilities, which are closely related to the initiation, invasion, and metastasis of tumor. The phenotypic characteristics of hybrids are based on the phenotypes of parental cells, and the fusion of tumor cells with diverse types of microenvironmental fusogenic cells is concomitant with phenotypic heterogeneity. This review highlights the types of fusogenic cells in tumor microenvironment that can fuse with tumor cells and their specific significance and summarizes the various microenvironmental factors affecting tumor cell fusion. This review may be used as a reference to develop strategies for future research on tumor cell fusion and the exploration of cell fusion-based antitumor therapies.

scholarly journals From Genetic Alterations to Tumor Microenvironment: The Ariadne’s String in Pancreatic Cancer

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 309 ◽  
Author(s):  
Chiara Bazzichetto ◽  
Fabiana Conciatori ◽  
Claudio Luchini ◽  
Francesca Simionato ◽  
Raffaela Santoro ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Myeloid Cells ◽  
Genetic Alterations ◽  
Molecular Characteristics ◽  
Precision Oncology ◽  
Cancer Type ◽  
Tumor Type ◽  
Driver Genes

The threatening notoriety of pancreatic cancer mainly arises from its negligible early diagnosis, highly aggressive progression, failure of conventional therapeutic options and consequent very poor prognosis. The most important driver genes of pancreatic cancer are the oncogene KRAS and the tumor suppressors TP53, CDKN2A, and SMAD4. Although the presence of few drivers, several signaling pathways are involved in the oncogenesis of this cancer type, some of them with promising targets for precision oncology. Pancreatic cancer is recognized as one of immunosuppressive phenotype cancer: it is characterized by a fibrotic-desmoplastic stroma, in which there is an intensive cross-talk between several cellular (e.g., fibroblasts, myeloid cells, lymphocytes, endothelial, and myeloid cells) and acellular (collagen, fibronectin, and soluble factors) components. In this review; we aim to describe the current knowledge of the genetic/biological landscape of pancreatic cancer and the composition of its tumor microenvironment; in order to better direct in the intrinsic labyrinth of this complex tumor type. Indeed; disentangling the genetic and molecular characteristics of cancer cells and the environment in which they evolve may represent the crucial step towards more effective therapeutic strategies

The role of serpins in tumor cell migration

2015 ◽  
Vol 396 (3) ◽  
pp. 205-213 ◽  
Author(s):  
Yolanda Fortenberry
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Serine Proteases ◽  
Proteolytic Enzymes ◽  
Cysteine Proteases ◽  
Malignant Cell ◽  
Genetic Alterations ◽  
Primary Site ◽  
Tumor Cell Migration

Abstract Tumor cells are characterized by uncontrolled cell growth at a primary site that is caused by genetic alterations. Tumor cells that metastasize from their primary site to distant locations are commonly referred to as malignant. Cell migration is a critical step in this process. The ability of tumor cells to migrate and invade is partly controlled by proteolytic enzymes. These enzymes are secreted by either the tumor cells themselves or adjacent cells. They represent all classes of proteases, including serine and cysteine proteases. Serine proteases, in particular urokinase plasminogen activator (uPA), initiate a proteolytic cascade that culminates in degrading components of the extracellular matrix (ECM). Some serine proteases are controlled by a superfamily of proteins known as serpins. This minireview provides an overview of serpins that are vital in regulating tumor cell migration and progressing cancer.

scholarly journals Formation of the Immunosuppressive Microenvironment of Classic Hodgkin Lymphoma and Therapeutic Approaches to Counter It

2019 ◽  
Vol 20 (10) ◽  
pp. 2416 ◽  
Author(s):  
Donatella Aldinucci ◽  
Cinzia Borghese ◽  
Naike Casagrande
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
T Cell Exhaustion ◽  
Normal Cells ◽  
Cell Exhaustion ◽  
Classic Hodgkin Lymphoma

Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed–Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They evade antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation and “educate” (i.e. reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies are being developed to target not only tumor cells but also the tumor microenvironment. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.

scholarly journals Jacalin-Activated Macrophages Exhibit an Antitumor Phenotype

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Cláudia Danella Polli ◽  
Luciana Pereira Ruas ◽  
Luciana Chain Veronez ◽  
Thais Herrero Geraldino ◽  
Fabiana Rossetto de Morais ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Human Colon ◽  
Inos Mrna ◽  
Activated Macrophages ◽  
Proinflammatory Activity ◽  
Carcinogenic Process ◽  
Ht 29 ◽  
Mcf 7

Tumor-associated macrophages (TAMs) have an ambiguous and complex role in the carcinogenic process, since these cells can be polarized into different phenotypes (proinflammatory, antitumor cells or anti-inflammatory, protumor cells) by the tumor microenvironment. Given that the interactions between tumor cells and TAMs involve several players, a better understanding of the function and regulation of TAMs is crucial to interfere with their differentiation in attempts to skew TAM polarization into cells with a proinflammatory antitumor phenotype. In this study, we investigated the modulation of macrophage tumoricidal activities by the lectin jacalin. Jacalin bound to macrophage surface and induced the expression and/or release of mainly proinflammatory cytokines via NF-κB signaling, as well as increased iNOS mRNA expression, suggesting that the lectin polarizes macrophages toward the antitumor phenotype. Therefore, tumoricidal activities of jacalin-stimulated macrophages were evaluated. High rates of tumor cell (human colon, HT-29, and breast, MCF-7, cells) apoptosis were observed upon incubation with supernatants from jacalin-stimulated macrophages. Taken together, these results indicate that jacalin, by exerting a proinflammatory activity, can direct macrophages to an antitumor phenotype. Deep knowledge of the regulation of TAM functions is essential for the development of innovative anticancer strategies.

Isolation of circulating tumor cells in colon cancer patients by size and chromosomal abnormalities.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22058-e22058 ◽  
Author(s):  
Ignacio Matos ◽  
Rebeca Lozano ◽  
Emilio Fonseca ◽  
Jesus MariÂa Hernandez ◽  
Arantxa Amores ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Chromosomal Abnormalities ◽  
Genetic Alterations ◽  
Automated System ◽  
Circulating Cells ◽  
Trisomy 3 ◽  
The Difference ◽  
Chromosomal Changes

e22058 Background: Determining the number of circulating tumor cells (CTCs) in patients with metastatic colorectal cancer (CRC) has shown to be a prognostic factor, recent studies have proven the existence of EpCAM and cytokeratin negative CTCs. These cells present morphological and genetic alterations. Our study is based on an algorithm determined by the selection of the size of the cells and the genetic alterations detected by FISH which enables the isolation of CTCs in CRC patients by an automated system of fluorescence. Methods: Patients with metastatic CRC with normal blood differential and healthy controls between June 2011 and June 2012 were chosen. The objective was to show the differences between the quantification of morphogenetically altered cells in peripheral blood obtained from control and patients. The selected cells were over 7 micra in size and presented two or more genetic alterations. A combination of four probe sets was used: centromeric probe for CEP3, CEP7 and CEP17 and LSI p16INK4A 9p21.3. Fluorescent signals in specimens were quantified using an automated fluorescent system (Metafer) that is capable of scanning and classifying hundreds of cells under fluorescent illumination and allows for detection of cells according to nuclear size > 7 um and FISH pattern based on the algorithm that we have developed. Results: We selected 28 healthy individuals and 45 patients with CRC. In all the cases, 1,000 cells were analyzed in each individual. Only 30 cells >7 micra being found in the controls out of the 28,000 cells analyzed (0.1%). In the case of the patients, 640 cells were found (1.42%), the difference becoming statistically relevant after the T-test (p=0.003). None of the controls presented cells with two or more genetic alterations and over 7 micra in size, whereas 38% of the patients presented these characteristics despite having received treatment. The most frequent chromosomal changes were trisomy 3 and 17 (26% and 18%, respectively). Conclusions: This method allows us to select genetically abnormal circulating cells in a simple and automatic way. This opens the door for future studies to analyze the prognostic factor and the response rate to treatment under this method.

Thrombin Control Mechanisms and Thrombin Targets in Cancer Biology

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-17-SCI-17
Author(s):  
Jay L. Degen ◽  
Joseph S. Palumbo
Keyword(s):  
Tumor Cell ◽  
Tissue Factor ◽  
Tumor Cells ◽  
Cancer Biology ◽  
Malignant Progression ◽  
Wild Type ◽  
Hemostatic System ◽  
System Components ◽  
Hemostatic Factors

Abstract SCI-17 A link between hemostasis and cancer has been recognized for more than a century, but the last decade has seen substantial strides in understanding the mechanisms by which hemostatic system components actively contribute to the malignant phenotype. The expression of procoagulants, such as tissue factor (TF), by tumor cells has been shown to be a poor prognostic factor in clinical studies and a crucial determinant of metastasis in animal models. While TF expressed by tumor cells likely plays a multifaceted role in cancer biology, a substantial body of evidence indicates that tumor cell-associated and circulating hemostatic system components (e.g., prothrombin, fibrinogen, platelets) play a cooperative role in supporting metastasis. The capacity of tumor cells to generate thrombin has been proposed to support metastasis through several mechanisms, including tumor cell proliferation, stable adhesion, regulation of apoptosis, and escape from innate immune surveillance mechanisms. More recently, the fundamental importance of endothelial regulators of thrombin activity in metastasis was established through studies of tumor dissemination in mice expressing mutant forms of thrombomodulin (TM). Mice expressing a TM derivative with reduced thrombin affinity (TMPro) exhibited a profoundly prometastatic phenotype relative to wild-type (WT) mice. The TMPro mutation was shown to support metastasis by promoting the survival of tumor cell emboli newly localized to the lung. The impact of the TMPro mutation on metastasis was dependent on tumor cell-associated tissue factor, prothrombin, thrombin function, and platelets. In contrast, mice expressing a mutant form of TM lacking the lectin-like domain (TMLed) that were shown previously to have altered immune function but normal thrombin affinity, exhibited metastatic potential comparable to wild-type mice. These studies further highlight the importance of the hemostatic system in metastasis and demonstrate that apart from tumor cell-associated and circulating procoagulants, TM-mediated regulation of hemostatic function strongly influences tumor cell metastatic success. In addition, recent studies of inflammation-driven cancer have revealed that the role of hemostatic factors in tumor biology is not limited to later phases of malignant progression, such as metastasis. Fibrin(ogen)-mediated regulation of leukocyte function was shown to support tumor development and tumor proliferation in a murine model of inflammation-driven colon cancer. Recent advances in our understanding of the role of hemostatic factors in cancer biology demonstrate that this system of proteins can be important in multiple phases of malignant progression, and underscore the potential utility of targeting selected coagulation factors as a novel adjunct therapy in the treatment of cancer. Disclosures: Palumbo: Novo Nordisk Corporation: Research Funding.

The Role of the Tumor Microenvironment in Lymphoid Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-46-SCI-46
Author(s):  
Christian Steidl
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Complex Function ◽  
Genetic Alterations ◽  
Immune Privilege ◽  
Lymphoid Cells ◽  
T Cell Subsets ◽  
Structural Genomic ◽  
Genomic Changes ◽  
Surface Molecules

Lymphoid cancers represent a heterogeneous group of neoplasms composed of malignant lymphoid cells with variable infiltration by non-neoplastic, mostly immune cells (tumor microenvironment). For some subtypes of lymphoid cancers, the contribution of the microenvironment to the histological appearance is widely recognized and used for pathological classification. Although microenvironment-related biology in lymphoid cancers has been primarily explored in a core set of lymphoma subtypes, the number of entities studied has recently accelerated. The pathogenic evolution of tumor microenvironments and in particular their composition and spatial distribution can be perceived as a complex function of 1) genetic alterations within the malignant cell population, 2) the extent and dependence on the molecular crosstalk involving cyto- and chemokines, and 3) host-specific factors. As a result, three major patterns of microenvironmental architecture can be distinguished termed "Re-education", "Recruitment" and "Effacement". Hodgkin lymphoma can serve as a paradigm for an extensive crosstalk between tumor cells and a quantitatively dominant tumor microenvironment. Importantly, related prognostic implications of tumor microenvironment composition (e.g. macrophage content, representation of T cell subsets) have been extensively studied in this disease. With focus on B cell lymphomas, this talk will highlight the emerging literature about genetic alterations in malignant lymphoma cells that provide the foundation for somatically acquired immune privilege and evasion from immune surveillance. The genomic changes discussed in this talk can be broadly categorized according to the effect that they exert on the tumor microenvironment: 1) Loss or down-regulation of (surface) molecules leading to decreased immunogenicity of tumor cells (e.g. mutations of B2M, CIITA); 2) Increased expression of surface molecules suppressing immune cell function (e.g. structural genomic changes of PDL1, PDL2); 3) Recruitment or induction of a regulatory cellular milieu (e.g. mutations in JAK-STAT and NFκB signaling pathways). The discovery of gene mutations underlying immune privilege, properties of the altered molecules, downstream functional consequences and clinical rationales for therapeutic intervention will be presented in the context of specific lymphoma subtypes. It will be discussed how precise description of genomic and molecular alterations underlying immune privilege might accelerate effective targeting of microenvironment-related biology in the clinical setting. Moreover, the development and clinical implementation of predictive biomarkers will be outlined that harbor the potential to inform on companion diagnostic approaches to accompany therapies such as immunological checkpoint inhibition. Disclosures No relevant conflicts of interest to declare.

scholarly journals Exosomes and Their Role in Cancer Progression

2021 ◽  
Vol 11 ◽  
Author(s):  
Yang Liu ◽  
Ke Shi ◽  
Yong Chen ◽  
Xianrui Wu ◽  
Zheng Chen ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Immune Escape ◽  
Research Progress ◽  
Chemotherapeutic Drugs ◽  
Other Substances

Exosomes from extracellular vesicles can activate or inhibit various signaling pathways by transporting proteins, lipids, nucleic acids and other substances to recipient cells. In addition, exosomes are considered to be involved in the development and progression of tumors from different tissue sources in numerous ways, including remodeling of the tumor microenvironment, promoting angiogenesis, metastasis, and invasion, and regulating the immune escape of tumor cells. However, the precise molecular mechanisms by which exosomes participate in these different processes remains unclear. In this review, we describe the research progress of tumor cell-derived exosomes in cancer progression. We also discuss the prospects of the application of exosomes combined with nanoengineered chemotherapeutic drugs in the treatment of cancer.

scholarly journals Tumor Dormancy and Interplay with Hypoxic Tumor Microenvironment

2019 ◽  
Vol 20 (17) ◽  
pp. 4305 ◽  
Author(s):  
Elena Butturini ◽  
Alessandra Carcereri de Prati ◽  
Diana Boriero ◽  
Sofia Mariotto
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Current Knowledge ◽  
Tumor Dormancy ◽  
Hypoxic Conditions ◽  
Cycle Arrest ◽  
Regulatory Machinery ◽  
Key Factor ◽  
Hypoxic Tumor

The tumor microenvironment is a key factor in disease progression, local resistance, immune-escaping, and metastasis. The rapid proliferation of tumor cells and the aberrant structure of the blood vessels within tumors result in a marked heterogeneity in the perfusion of the tumor tissue with regions of hypoxia. Although most of the tumor cells die in these hypoxic conditions, a part of them can adapt and survive for many days or months in a dormant state. Dormant tumor cells are characterized by cell cycle arrest in G0/G1 phase as well as a low metabolism, and are refractive to common chemotherapy, giving rise to metastasis. Despite these features, the cells retain their ability to proliferate when conditions improve. An understanding of the regulatory machinery of tumor dormancy is essential for identifying early cancer biomarkers and could provide a rationale for the development of novel agents to target dormant tumor cell populations. In this review, we examine the current knowledge of the mechanisms allowing tumor dormancy and discuss the crucial role of the hypoxic microenvironment in this process.

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