Concise review: The role of cancer-derived exosomes in tumorigenesis and immune cell modulation

Exosomes are subcellular entities which were first discovered in the 1980s. Over the past decade, scientists have discovered that they carry components of genetic information that allow for cell-cell communication and cell targeting. Exosomes secreted by cancer cells are termed cancer-derived exosomes (CDEs), and play an important role in tumor formation and progression. Specifically, CDEs mediate the communication between cancer cells, as well as between cancer cells and other cells in the tumor microenvironment, including cancer-associated fibroblasts, endothelial cells, mesenchymal stem cells, and effector immune cells. Additionally, through the vascular system and body fluids, CDEs can modulate response to drugs, increase angiogenesis, stimulate proliferation, promote invasion and metastasis, and facilitate escape from immune surveillance. This review will discuss the relationship between cancer cells and other cells (particularly immune cells), as mediated through CDEs, as well as the subsequent impact on tumorigenesis and immunomodulation. Understanding the role of CDEs in tumorigenesis and immune cell modulation will help advance their utilization in the diagnosis, prognosis, and treatment of cancer.

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Cancer Stem Cells: Emerging Key Players in Immune Evasion of Cancers

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.692940 ◽

2021 ◽

Vol 9 ◽

Author(s):

Martina Mang Leng Lei ◽

Terence Kin Wah Lee

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Immune Cells ◽

Immune Surveillance ◽

Suppressor Cells ◽

Tumor Infiltrating Lymphocytes ◽

Treg Cells ◽

Undifferentiated Cancer

Cancer stem cells (CSCs) are subpopulations of undifferentiated cancer cells within the tumor bulk that are responsible for tumor initiation, recurrence and therapeutic resistance. The enhanced ability of CSCs to give rise to new tumors suggests potential roles of these cells in the evasion of immune surveillance. A growing body of evidence has described the interplay between CSCs and immune cells within the tumor microenvironment (TME). Recent data have shown the pivotal role of some major immune cells in driving the expansion of CSCs, which concurrently elicit evasion of the detection and destruction of various immune cells through a number of distinct mechanisms. Here, we will discuss the role of immune cells in driving the stemness of cancer cells and provide evidence of how CSCs evade immune surveillance by exerting their effects on tumor-associated macrophages (TAMs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), T-regulatory (Treg) cells, natural killer (NK) cells, and tumor-infiltrating lymphocytes (TILs). The knowledge gained from the interaction between CSCs and various immune cells will provide insight into the mechanisms by which tumors evade immune surveillance. In conclusion, CSC-targeted immunotherapy emerges as a novel immunotherapy strategy against cancer by disrupting the interaction between immune cells and CSCs in the TME.

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The Role of Platelets in Cancer Pathophysiology: Focus on Malignant Glioma

Cancers ◽

10.3390/cancers11040569 ◽

2019 ◽

Vol 11 (4) ◽

pp. 569 ◽

Cited By ~ 9

Author(s):

Sascha Marx ◽

Yong Xiao ◽

Marcel Baschin ◽

Maximilian Splittstöhser ◽

Robert Altmann ◽

...

Keyword(s):

Malignant Glioma ◽

Immune Cells ◽

Potential Role ◽

Immune Cell ◽

Malignant Gliomas ◽

Cell Communication ◽

Distant Metastases ◽

Sphingosine 1 Phosphate ◽

The Central Nervous System

The link between thrombocytosis and malignancy has been well known for many years and its associations with worse outcomes have been reported mainly for solid tumors. Besides measuring platelet count, it has become popular to assess platelet function in the context of malignant diseases during the last decade. Malignant gliomas differ tremendously from malignancies outside the central nervous system because they virtually never form distant metastases. This review summarizes the current understanding of the platelet–immune cell communication and its potential role in glioma resistance and progression. Particularly, we focus on platelet-derived proinflammatory modulators, such as sphingosine-1-phosphate (S1P). The multifaceted interaction with immune cells puts the platelet into an interesting perspective regarding the recent advances in immunotherapeutic approaches in malignant glioma.

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Role of Interleukin-34 in Cancer

Cancers ◽

10.3390/cancers12010252 ◽

2020 ◽

Vol 12 (1) ◽

pp. 252 ◽

Cited By ~ 4

Author(s):

Eleonora Franzè ◽

Carmine Stolfi ◽

Edoardo Troncone ◽

Patrizio Scarozza ◽

Giovanni Monteleone

Keyword(s):

Cancer Cells ◽

Immune Cells ◽

Multiple Roles ◽

Cancer Cell Proliferation ◽

Potential Therapeutic Target ◽

Wide Range ◽

Tumor Growth And Metastasis ◽

The Relationship ◽

And Diffusion

Cross-talk between cancer cells and the immune cells occurring in the tumor microenvironment is crucial in promoting signals that foster tumor growth and metastasis. Both cancer cells and immune cells secrete various interleukins (IL), which, either directly or indirectly, stimulate cancer-cell proliferation, survival, and diffusion, as well as contribute to sculpt the immune microenvironment, thereby amplifying tumorigenic stimuli. IL-34, a cytokine produced by a wide range of cells, has been initially involved in the control of differentiation, proliferation, and survival of myeloid cells. More recent studies documented the overexpression of IL-34 in several cancers, such as hepatocarcinoma, osteosarcoma, multiple myeloma, colon cancer, and lung cancer, and showed that tumor cells can produce and functionally respond to this cytokine. In this review, we summarize the multiple roles of IL-34 in various cancers, with the aim to better understand the relationship between the expression of this cytokine and cancer behavior and to provide new insights for exploring a new potential therapeutic target.

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Interplay of Immunometabolism and Epithelial–Mesenchymal Transition in the Tumor Microenvironment

International Journal of Molecular Sciences ◽

10.3390/ijms22189878 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9878

Author(s):

Ming-Yu Chou ◽

Muh-Hwa Yang

Keyword(s):

Tumor Microenvironment ◽

Immune Cells ◽

Tumor Metastasis ◽

Epithelial Mesenchymal Transition ◽

Immune Surveillance ◽

Metabolic Reprogramming ◽

Mesenchymal Transition ◽

Regulatory Loop ◽

The Relationship

Epithelial–mesenchymal transition (EMT) and metabolic reprogramming in cancer cells are the key hallmarks of tumor metastasis. Since the relationship between the two has been well studied, researchers have gained increasing interest in the interplay of cancer cell EMT and immune metabolic changes. Whether the mutual influences between them could provide novel explanations for immune surveillance during metastasis is worth understanding. Here, we review the role of immunometabolism in the regulatory loop between tumor-infiltrating immune cells and EMT. We also discuss the challenges and perspectives of targeting immunometabolism in cancer treatment.

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Pannexin Channel Regulation of Cell Migration: Focus on Immune Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.750480 ◽

2021 ◽

Vol 12 ◽

Author(s):

Paloma A. Harcha ◽

Tamara López-López ◽

Adrián G. Palacios ◽

Pablo J. Sáez

Keyword(s):

Cell Migration ◽

Immune Cells ◽

Immune Cell ◽

Adenine Nucleotide ◽

Cell Communication ◽

Negative Regulator ◽

General Mechanism ◽

Current Evidence ◽

Inflammatory Conditions

The role of Pannexin (PANX) channels during collective and single cell migration is increasingly recognized. Amongst many functions that are relevant to cell migration, here we focus on the role of PANX-mediated adenine nucleotide release and associated autocrine and paracrine signaling. We also summarize the contribution of PANXs with the cytoskeleton, which is also key regulator of cell migration. PANXs, as mechanosensitive ATP releasing channels, provide a unique link between cell migration and purinergic communication. The functional association with several purinergic receptors, together with a plethora of signals that modulate their opening, allows PANX channels to integrate physical and chemical cues during inflammation. Ubiquitously expressed in almost all immune cells, PANX1 opening has been reported in different immunological contexts. Immune activation is the epitome coordination between cell communication and migration, as leukocytes (i.e., T cells, dendritic cells) exchange information while migrating towards the injury site. In the current review, we summarized the contribution of PANX channels during immune cell migration and recruitment; although we also compile the available evidence for non-immune cells (including fibroblasts, keratinocytes, astrocytes, and cancer cells). Finally, we discuss the current evidence of PANX1 and PANX3 channels as a both positive and/or negative regulator in different inflammatory conditions, proposing a general mechanism of these channels contribution during cell migration.

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The role of the organic anion transporting polypeptide OATP4A1 in immunactivation in colorectal cancer and inflammatory colon disease.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.481 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 481-481

Author(s):

Christoph Alexander Ausch ◽

Simone Zotter ◽

Maidah Scheikh ◽

Heike Bauer ◽

Marina Mollik ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Immune Cells ◽

Immune Cell ◽

Organic Anion ◽

Staining Intensity ◽

Image Analysis System ◽

Cellular Markers

481 Background: OATP-transporter proteins, such as OATP4A1, present influence cancer progression by providing compounds (hormones, prostaglandins, cyclic nucleotides, second messenger proteins, drugs) which either inhibit or stimulate tumor cells growth. Therefore, OATP expression in cancer cells and in the stroma, i.e., the microenvironment surrounding the epithelial cells can become a critical parameter. Methods: OATP4A1 was investigated in paraffin-embedded specimens from 148 patients with colorectal cancer and 20 with diverticulitis by immunohistochemistry (IHC) on an automatic quantitative microscopic image analysis system (TissuesFaxs). With the Histoquest program, the immunoreactive score (IRS), was calculated from the degree of the staining intensity and the number of OATP4A1-positive cells. To identify OATP4A1+-cells, double-immunofluorescence staining (IF) was done with antibodies against appropriate cellular markers. Results: OATP4A1 was located in the membrane and cytosol of colon cancer cells and immune cells, while membranous OATP4A1staining was seen in normal mucosa. OATP4A1 levels were higher in cancer cells in patients without tumor recurrence for up to 5 years (NR) than in patients with an early relapse (R) having IRS of 4391±231 and 3026±373 (Mean±SEM), respectively. Highest OATP4A1 levels were observed in immune cells in the tumors of Rs (IRS, 5712 ±254, while in NRs they were lower (IRS: 3549±358; p=0.05). In both groups, OATP4A1 levels in stroma cells were low (288±54 vs. 611±82). OATP4A1 expressing immune cell subtypes in cancer and diverticulitis sections were identified as CD45+ leukocytes, CD3+ T- and CD20+ B-cells, CD68+ macrophages, CD34+precursor cells. OATP4A1 was not detectable in Conclusions: High levels of OATP4A1 in immune cells in malignant and non-malignant colon disease suggest a role of the transporter in the activation of the immune system in malignant and non-malignant colon disease. Whether OATP4A1 might be a therapeutical target has to be established.

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The Role of Cytokines in Interactions of Mesenchymal Stem Cells and Breast Cancer Cells

Current Stem Cell Research & Therapy ◽

10.2174/1574888x15666201022111942 ◽

2020 ◽

Vol 15 ◽

Author(s):

Hariharan Jayaraman ◽

Nalinkanth V. Ghone ◽

Ranjith Kumaran R ◽

Himanshu Dashora

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Cell Communication ◽

Extra Cellular Matrix ◽

Cytokine Signaling ◽

Cellular Matrix

: Mesenchymal stem cells because of its high proliferation, differentiation, regenerative capacity, and ease of availability have been a popular choice in cytotherapy. Mesenchymal Stem Cells (MSCs) have a natural tendency to home in a tumor microenvironment and acts against it, owing to the similarity of the latter to an injured tissue environment. Several studies have confirmed the recruitment of MSCs by tumor through various cytokine signaling that brings about phenotypic changes to cancer cells, thereby promoting migration, invasion, and adhesion of cancer cells. The contrasting results on MSCs as a tool for cancer cytotherapy may be due to the complex cell to cell interaction in the tumor microenvironment, which involves various cell types such as cancer cells, immune cells, endothelial cells, and cancer stem cells. Cell to cell communication can be simple or complex and it is transmitted through various cytokines among multiple cell phenotypes, mechano-elasticity of the extra-cellular matrix surrounding the cancer cells, and hypoxic environments. In this article, the role of the extra-cellular matrix proteins and soluble mediators that acts as communicators between mesenchymal stem cells and cancer cells has been reviewed specifically for breast cancer, as it is the leading member of cancer malignancies. The comprehensive information may be beneficial in finding a new combinatorial cytotherapeutic strategy using MSCs by exploiting the cross-talk between mesenchymal stem cells and cancer cells for treating breast cancer.

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Potential of Mesenchymal Stem Cells in Anti-Cancer Therapies

Current Stem Cell Research & Therapy ◽

10.2174/1574888x15666200310171547 ◽

2020 ◽

Vol 15 (6) ◽

pp. 482-491 ◽

Cited By ~ 1

Author(s):

Milena Kostadinova ◽

Milena Mourdjeva

Keyword(s):

Cancer Cells ◽

Small Population ◽

Tumor Formation ◽

Bioactive Molecules ◽

Cancer Therapies ◽

New Methods ◽

Cycle Arrest ◽

Anti Cancer ◽

Blocking Mechanisms

Mesenchymal stem/stromal cells (MSCs) are localized throughout the adult body as a small population in the stroma of the tissue concerned. In injury, tissue damage, or tumor formation, they are activated and leave their niche to migrate to the site of injury, where they release a plethora of growth factors, cytokines, and other bioactive molecules. With the accumulation of data about the interaction between MSCs and tumor cells, the dualistic role of MSCs remains unclear. However, a large number of studies have demonstrated the natural anti-tumor properties inherent in MSCs, so this is the basis for intensive research for new methods using MSCs as a tool to suppress cancer cell development. This review focuses specifically on advanced approaches in modifying MSCs to become a powerful, precision- targeted tool for killing cancer cells, but not normal healthy cells. Suppression of tumor growth by MSCs can be accomplished by inducing apoptosis or cell cycle arrest, suppressing tumor angiogenesis, or blocking mechanisms mediating metastasis. In addition, the chemosensitivity of cancer cells may be increased so that the dose of the chemotherapeutic agent used could be significantly reduced.

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Platelets, immune cells and the coagulation cascade; friend or foe of the circulating tumour cell?

Molecular Cancer ◽

10.1186/s12943-021-01347-1 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Mark P. Ward ◽

Laura E. Kane ◽

Lucy A. Norris ◽

Bashir M. Mohamed ◽

Tanya Kelly ◽

...

Keyword(s):

Cancer Cells ◽

Immune Cells ◽

Immune Cell ◽

Circulatory System ◽

Morphological Characteristics ◽

Metastatic Potential ◽

Coagulation Cascade ◽

Molecular Profile ◽

Great Promise ◽

Liquid Biopsies

AbstractCancer cells that transit from primary tumours into the circulatory system are known as circulating tumour cells (CTCs). These cancer cells have unique phenotypic and genotypic characteristics which allow them to survive within the circulation, subsequently extravasate and metastasise. CTCs have emerged as a useful diagnostic tool using “liquid biopsies” to report on the metastatic potential of cancers. However, CTCs by their nature interact with components of the blood circulatory system on a constant basis, influencing both their physical and morphological characteristics as well as metastatic capabilities. These properties and the associated molecular profile may provide critical diagnostic and prognostic capabilities in the clinic. Platelets interact with CTCs within minutes of their dissemination and are crucial in the formation of the initial metastatic niche. Platelets and coagulation proteins also alter the fate of a CTC by influencing EMT, promoting pro-survival signalling and aiding in evading immune cell destruction. CTCs have the capacity to directly hijack immune cells and utilise them to aid in CTC metastatic seeding processes. The disruption of CTC clusters may also offer a strategy for the treatment of advance staged cancers. Therapeutic disruption of these heterotypical interactions as well as direct CTC targeting hold great promise, especially with the advent of new immunotherapies and personalised medicines. Understanding the molecular role that platelets, immune cells and the coagulation cascade play in CTC biology will allow us to identify and characterise the most clinically relevant CTCs from patients. This will subsequently advance the clinical utility of CTCs in cancer diagnosis/prognosis.

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Multifaceted Functions of Platelets in Cancer: From Tumorigenesis to Liquid Biopsy Tool and Drug Delivery System

International Journal of Molecular Sciences ◽

10.3390/ijms21249585 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9585

Author(s):

Melania Dovizio ◽

Patrizia Ballerini ◽

Rosa Fullone ◽

Stefania Tacconelli ◽

Annalisa Contursi ◽

...

Keyword(s):

Drug Delivery ◽

Cancer Cells ◽

Immune Cells ◽

Expression Patterns ◽

Cell Communication ◽

Antiplatelet Agents ◽

Cell Types ◽

Disease Monitoring ◽

Crucial Component ◽

Numerous Cell

Platelets contribute to several types of cancer through plenty of mechanisms. Upon activation, platelets release many molecules, including growth and angiogenic factors, lipids, and extracellular vesicles, and activate numerous cell types, including vascular and immune cells, fibroblasts, and cancer cells. Hence, platelets are a crucial component of cell–cell communication. In particular, their interaction with cancer cells can enhance their malignancy and facilitate the invasion and colonization of distant organs. These findings suggest the use of antiplatelet agents to restrain cancer development and progression. Another peculiarity of platelets is their capability to uptake proteins and transcripts from the circulation. Thus, cancer-patient platelets show specific proteomic and transcriptomic expression patterns, a phenomenon called tumor-educated platelets (TEP). The transcriptomic/proteomic profile of platelets can provide information for the early detection of cancer and disease monitoring. Platelet ability to interact with tumor cells and transfer their molecular cargo has been exploited to design platelet-mediated drug delivery systems to enhance the efficacy and reduce toxicity often associated with traditional chemotherapy. Platelets are extraordinary cells with many functions whose exploitation will improve cancer diagnosis and treatment.

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