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

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.

scholarly journals When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Katrin Schlie ◽  
Jaeline E. Spowart ◽  
Luke R. K. Hughson ◽  
Katelin N. Townsend ◽  
Julian J. Lum
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Patient Treatment ◽  
Low Oxygen ◽  
Tumor Environment ◽  
And Function ◽  
The Impact

Hypoxia is a signature feature of growing tumors. This cellular state creates an inhospitable condition that impedes the growth and function of all cells within the immediate and surrounding tumor microenvironment. To adapt to hypoxia, cells activate autophagy and undergo a metabolic shift increasing the cellular dependency on anaerobic metabolism. Autophagy upregulation in cancer cells liberates nutrients, decreases the buildup of reactive oxygen species, and aids in the clearance of misfolded proteins. Together, these features impart a survival advantage for cancer cells in the tumor microenvironment. This observation has led to intense research efforts focused on developing autophagy-modulating drugs for cancer patient treatment. However, other cells that infiltrate the tumor environment such as immune cells also encounter hypoxia likely resulting in hypoxia-induced autophagy. In light of the fact that autophagy is crucial for immune cell proliferation as well as their effector functions such as antigen presentation and T cell-mediated killing of tumor cells, anticancer treatment strategies based on autophagy modulation will need to consider the impact of autophagy on the immune system.

scholarly journals Search for receptors in immune cells that bind cancer cell antigens and their activation in silent cases

2019 ◽  
Author(s):  
Wenfa Ng
Keyword(s):  
Immune System ◽  
Amino Acid ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Host Cells ◽  
Immune Receptor

The immune checkpoint plays an important role in keeping immune cells in check for protecting tissues and organs from attack by the body’s own immune system. Similar concepts also apply in how cancer cells managed to fool immune cells through the surface display of particular antigens that mimic those exhibited by normal body cells. Specifically, cancer cells display antigens that bind to receptors on immune cells that subsequently prevent an attack on the cancer cells. Such binding between cancer antigens and immune cell receptors can be prevented through the use of checkpoint inhibitors antibodies specific for particular receptors on immune cells; thereby, unleashing immune cells to mount an immune response against cancer cells. While demonstrating good remissions in many patients where tumours shrunk substantially after administration of checkpoint inhibitors, cases exist where an overactivated immune system cause harm to organs and tissues culminating in multiple organ failure. Analysis of such toxicity effects of checkpoint inhibitors revealed that generic nature of targeted immune receptor plays a pivotal role in determining extent of side effects. Specifically, if the target immune receptor participates in checkpoints that prevent immune cells from attacking host cells, unleashing such receptors in cancer therapy may have untoward effects on patient’s health. Hence, the goal should be the selection of immune cell receptor specific to cancer cell antigens and which does not bind antigens or ligands displayed by the body’s cells. Such receptors would provide ideal targets for the development of checkpoint inhibitor antibodies for unleashing immune cells against cancer cells. To search for non-generic receptors that bind cancer cell antigens only, a combined computational and experimental approach could be used where ensemble of surface antigens on cancer cells and available receptors on immune cells could be profiled by biochemical assays. Downstream purification of ligands and receptors would provide for both structural elucidation and amino acid sequencing useful for bioinformatic search of homologous sequences. Knowledge of the antigens’ and receptors’ structures and amino acid sequence would subsequently serve as inputs to computational algorithms that models molecular docking events between receptor and antigen. This paves the way for heterologous expression of putative ligand and receptor in cell lines cultured in co-culture format for assessing binding between ligand and receptor, and more importantly, its physiological effects. Ability of immune receptor to bind to ligands on normal cells could also be assessed. Similar co-culture studies could be conducted with cancer cells and different immune cell types to check for reproducibility of observed effect in cell lines. Finally, antibodies could be raised for candidate receptors whose inhibition would not result in systemic attack of immune cells on host cells.

scholarly journals Search for receptors in immune cells that bind cancer cell antigens and their activation in silent cases

2019 ◽  
Author(s):  
Wenfa Ng
Keyword(s):  
Immune System ◽  
Amino Acid ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Host Cells ◽  
Immune Receptor

The immune checkpoint plays an important role in keeping immune cells in check for protecting tissues and organs from attack by the body’s own immune system. Similar concepts also apply in how cancer cells managed to fool immune cells through the surface display of particular antigens that mimic those exhibited by normal body cells. Specifically, cancer cells display antigens that bind to receptors on immune cells that subsequently prevent an attack on the cancer cells. Such binding between cancer antigens and immune cell receptors can be prevented through the use of checkpoint inhibitors antibodies specific for particular receptors on immune cells; thereby, unleashing immune cells to mount an immune response against cancer cells. While demonstrating good remissions in many patients where tumours shrunk substantially after administration of checkpoint inhibitors, cases exist where an overactivated immune system cause harm to organs and tissues culminating in multiple organ failure. Analysis of such toxicity effects of checkpoint inhibitors revealed that generic nature of targeted immune receptor plays a pivotal role in determining extent of side effects. Specifically, if the target immune receptor participates in checkpoints that prevent immune cells from attacking host cells, unleashing such receptors in cancer therapy may have untoward effects on patient’s health. Hence, the goal should be the selection of immune cell receptor specific to cancer cell antigens and which does not bind antigens or ligands displayed by the body’s cells. Such receptors would provide ideal targets for the development of checkpoint inhibitor antibodies for unleashing immune cells against cancer cells. To search for non-generic receptors that bind cancer cell antigens only, a combined computational and experimental approach could be used where ensemble of surface antigens on cancer cells and available receptors on immune cells could be profiled by biochemical assays. Downstream purification of ligands and receptors would provide for both structural elucidation and amino acid sequencing useful for bioinformatic search of homologous sequences. Knowledge of the antigens’ and receptors’ structures and amino acid sequence would subsequently serve as inputs to computational algorithms that models molecular docking events between receptor and antigen. This paves the way for heterologous expression of putative ligand and receptor in cell lines cultured in co-culture format for assessing binding between ligand and receptor, and more importantly, its physiological effects. Ability of immune receptor to bind to ligands on normal cells could also be assessed. Similar co-culture studies could be conducted with cancer cells and different immune cell types to check for reproducibility of observed effect in cell lines. Finally, antibodies could be raised for candidate receptors whose inhibition would not result in systemic attack of immune cells on host cells.

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

2020 ◽  
Vol 7 (12) ◽  
pp. 4158-4169
Author(s):  
Nhi Thao Huynh ◽  
Khuong Duy Pham ◽  
Nhat Chau Truong
Keyword(s):  
Cancer Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Vascular System ◽  
Immune Surveillance ◽  
Cell Communication ◽  
Tumor Formation ◽  
Concise Review ◽  
The Relationship

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.

scholarly journals Chemokine Pathways in Cutaneous Melanoma: Their Modulation by Cancer and Exploitation by the Clinician

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5625
Author(s):  
Rebecca Adams ◽  
Bernhard Moser ◽  
Sophia N. Karagiannis ◽  
Katie E. Lacy
Keyword(s):  
Immune Cells ◽  
Cutaneous Melanoma ◽  
Epithelial To Mesenchymal Transition ◽  
Immune Cell ◽  
Metastatic Potential ◽  
Mesenchymal Transition ◽  
Emerging Therapies ◽  
Dense Cell ◽  
Chemokine Signalling ◽  
Melanoma Therapy

The incidence of cutaneous malignant melanoma is rising globally and is projected to continue to rise. Advances in immunotherapy over the last decade have demonstrated that manipulation of the immune cell compartment of tumours is a valuable weapon in the arsenal against cancer; however, limitations to treatment still exist. Cutaneous melanoma lesions feature a dense cell infiltrate, coordinated by chemokines, which control the positioning of all immune cells. Melanomas are able to use chemokine pathways to preferentially recruit cells, which aid their growth, survival, invasion and metastasis, and which enhance their ability to evade anticancer immune responses. Aside from this, chemokine signalling can directly influence angiogenesis, invasion, lymph node, and distal metastases, including epithelial to mesenchymal transition-like processes and transendothelial migration. Understanding the interplay of chemokines, cancer cells, and immune cells may uncover future avenues for melanoma therapy, namely: identifying biomarkers for patient stratification, augmenting the effect of current and emerging therapies, and designing specific treatments to target chemokine pathways, with the aim to reduce melanoma pathogenicity, metastatic potential, and enhance immune cell-mediated cancer killing. The chemokine network may provide selective and specific targets that, if included in current therapeutic regimens, harbour potential to improve outcomes for patients.

scholarly journals Tissues and Tumor Microenvironment (TME) in 3D: Models to Shed Light on Immunosuppression in Cancer

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 831
Author(s):  
Teresa Ho ◽  
Rasha Msallam
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Cell ◽  
3D Models ◽  
Genetic Alterations ◽  
Experimental Models ◽  
Model Systems ◽  
Patient Specific ◽  
Great Promise ◽  
The Impact

Immunosuppression in cancer has emerged as a major hurdle to immunotherapy efforts. Immunosuppression can arise from oncogene-induced signaling within the tumor as well as from tumor-associated immune cells. Understanding various mechanisms by which the tumor can undermine and evade therapy is critical in improving current cancer immunotherapies. While mouse models have allowed for the characterization of key immune cell types and their role in tumor development, extrapolating these mechanisms to patients has been challenging. There is need for better models to unravel the effects of genetic alterations inherent in tumor cells and immune cells isolated from tumors on tumor growth and to investigate the feasibility of immunotherapy. Three-dimensional (3D) organoid model systems have developed rapidly over the past few years and allow for incorporation of components of the tumor microenvironment such as immune cells and the stroma. This bears great promise for derivation of patient-specific models in a dish for understanding and determining the impact on personalized immunotherapy. In this review, we will highlight the significance of current experimental models employed in the study of tumor immunosuppression and evaluate current tumor organoid-immune cell co-culture systems and their potential impact in shedding light on cancer immunosuppression.

scholarly journals Shaping Immune Responses in the Tumor Microenvironment of Ovarian Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Luo ◽  
Jing Xu ◽  
Jianhua Yu ◽  
Ping Yi
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Cancer Cells ◽  
Disease Progression ◽  
Immune Cells ◽  
Biomarker Discovery ◽  
Immune Cell ◽  
Ovarian Cancer Cells ◽  
Cancer Tumor

Reciprocal signaling between immune cells and ovarian cancer cells in the tumor microenvironment can alter immune responses and regulate disease progression. These signaling events are regulated by multiple factors, including genetic and epigenetic alterations in both the ovarian cancer cells and immune cells, as well as cytokine pathways. Multiple immune cell types are recruited to the ovarian cancer tumor microenvironment, and new insights about the complexity of their interactions have emerged in recent years. The growing understanding of immune cell function in the ovarian cancer tumor microenvironment has important implications for biomarker discovery and therapeutic development. This review aims to describe the factors that shape the phenotypes of immune cells in the tumor microenvironment of ovarian cancer and how these changes impact disease progression and therapy.

scholarly journals Cell Programmed Nutrient Partitioning in the Tumor Microenvironment

2020 ◽  
Author(s):  
BI Reinfeld ◽  
MZ Madden ◽  
MM Wolf ◽  
A Chytil ◽  
JE Bader ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Glucose Uptake ◽  
Cancer Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Specific Cell ◽  
Mtorc1 Signaling ◽  
Nutrient Partitioning ◽  
Glutamine Uptake

The tumor microenvironment (TME) includes transformed cancer and infiltrating immune cells1,2. Cancer cells can consume large quantities of glucose through Warburg metabolism3,4 that can be visualized with positron emission tomography (PET). While infiltrating immune cells also rely on glucose, disruptions to metabolism can contribute to tumor immunological evasion5–9. How immune cell metabolism is programmed or restrained by competition with cancer cells for nutrients, remains uncertain. Here we used PET tracers to measure the accessibility of glucose and glutamine to cell subsets in the TME. Surprisingly, myeloid cells including macrophages were the greatest consumers of intra-tumoral glucose, followed by T cells and cancer cells. Cancer cells, in contrast, had the highest glutamine uptake. This distinct nutrient partitioning was programmed through selective mTORC1 signaling and glucose or glutamine-related gene expression. Inhibition of glutamine uptake enhanced glucose uptake across tumor resident cell types and shifted macrophage phenotype, demonstrating glucose is not limiting in the TME. Thus, cancer cells are not the only cells in tumors which exhibit high glucose uptake in vivo and instead preferentially utilize glutamine over other cell types. We observe that intrinsic cellular programs can play a major role in the use of some nutrients. Together, these data argue cell selective partitioning of glucose and glutamine can be exploited to develop therapies and imaging strategies to alter the metabolic programs of specific cell populations in the TME.

Hippo/YAP Signaling Choreographs The Tumor Immune Microenvironment to Promote Triple Negative Breast Cancer Progression Via TAZ/IL-34 Axis

2021 ◽  
Author(s):  
Zheng Wang ◽  
Fan Wang ◽  
Xin-Yuan Ding ◽  
Tian-En Li ◽  
Hao-Yu Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Immune Cells ◽  
Triple Negative ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Hippo Pathway ◽  
Immune Microenvironment

Abstract Background: Growing evidence suggests that the bidirectional interactions between cancer cells and their surrounding environment namely the tumor microenvironment (TME), contributes to cancer progression, metastasis, and resistance to treatment. Intense investigation of Hippo pathway, which controls multiple central cellular function to tumorigenesis, was focused on cancer cells. However, the role of Hippo pathway in modulating tumor–stromal interactions in triple negative breast cancer remains largely unknow. This study therefore focused on revealing effects of Hippo-YAP/TAZ signaling to immune microenvironment.Methods: The correlation between Hippo/YAP signaling and the abundance of immune cells were estimated by Immune Cell Abundance Identifier. Clinical TNBC samples from 120 patients were analyzed to assess the correlation between TAZ expression and disease prognosis as well as tumor-infiltrating immune cells. Inflammatory immune profiles, bioinformatics analysis and chromatin immunoprecipitation were performed to identify the expression of immune-related genes that were regulated by TAZ. An in vitro co-culture system was applied to investigate the crosstalk between TNBC cells and tumor-associated macrophages (TAMs) modulated by the TAZ/interleukin 34 (IL-34) axis. In vivo tumor growth and metastasis models were used to evaluate the pro-tumor functions of TAZ, IL-34, and TAMs as well as the antitumor efficacy of anti-PD-L1 and IL-34/colony-stimulating factor 1 receptor (CSF-1R) blockade.Results: In TNBC patients, high activity of Hippo pathway was correlated with decreased number of T cells, upregulated TAM infiltration, and poor prognosis. TAZ could directly regulate IL-34 and PD-L1 expression and promote IL-34 secretion in TNBC cells, leading to increased TAM infiltration and distant metastasis. TAM-derived transforming growth factor beta 1 (TGF-β1) could also induce TAZ expression in TNBC cells, thus forming a positive feedback loop between TNBC cells and TAMs. Furthermore, targeting the TAZ/IL-34 axis through its CSF-1R inhibitor could dramatically decrease TAM infiltration and significantly improve anti-PD-L1 efficacy in inhibiting metastasis in TNBC.Conclusions: Activity of Hippo pathway was associated with worse disease outcomes in TNBC and could increase TAM infiltration through the TAZ/IL-34 axis, leading to an immunosuppressive microenvironment and impairing the treatment efficacy of anti-PD-L1. Thus, the TAZ/IL-34 axis can serve as a novel target for TNBC patients.

Integrated DNA and RNA sequencing to reveal early drivers of metastasis in gastric cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16096-e16096
Author(s):  
Jieyun Zhang ◽  
Fatao Liu ◽  
Ya'nan Yang ◽  
Xiaoling Weng ◽  
Yue Yang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Exome Sequencing ◽  
Distant Metastasis ◽  
Immune Cell ◽  
Immune Escape ◽  
Target Therapy ◽  
Metastatic Potential ◽  
Driver Mutations ◽  
Immunosuppressive Microenvironment

e16096 Background: Gastric cancer (GC) is the second cause of cancer-related death and metastasis is an important cause of death. Considering difficulties in searching for metastatic driver mutations, we tried a novel strategy to identify early drivers in primary gastric tumors. In this study, we conducted an integrative genomic analysis on GC patients and identified early drivers that lead to metastases. Methods: Tumors and matched normal tissues from 400 Chinese GC patients were characterized by whole-exome sequencing (WES), transcriptome sequencing and targeted exome sequencing (TES), especially the comparative analysis results between higher metastatic potential (HMP) group with T1 stage and lymph-node metastases, and lower metastatic potential (LMP) group without lymph-nodes or distant metastases. Functional experiments on candidate driver mutations were applied in GC cell lines to explore their roles in metastasis and immune escape. Results: HMP group presented higher mutation load and heterogeneity, enrichment in immunosuppressive signaling, lower tumor purity, more stromal and immune cell infiltration than LMP group. We identified 262 differentially expressed mRNA, lncRNA and miRNA between HMP and LMP group (with more than twice proportion of 2-fold increased or decreased tumor than normal tissue in HMP than LMP group, and with significantly 2-fold higher or lower in HMP tumors than LMP tumors). 168 candidate prometastatic mutations were found by WES and 8 were selected for following TES to detect their association with distant metastasis. We found that four candidate mutations were related to distant metastasis and mutated TP53 and MADCAM1 were significantly associated with poor metastasis-free survival. It’s worth noting that though with low mutational rate, MADCAM1 mutations were only observed in patients with metastasis within three years after surgery or at diagnosis. We demonstrated that MADCAM1-mutated proteins act as GOF mutants and could not only directly promote cancer cells migration, but also could trigger tumor metastasis by establishing complicated immunosuppressive microenvironment, including promoting PD-L1-mediated immune escape and reprogramming tumor-associated macrophages (TAMs). Conclusions: Our results showed that the GCs with different metastatic potential are distinguishable at the genetic level. A number of potential metastatic driver mutations was revealed in this study including known cancer-associated genes TP53. We also discovered some novel driver mutations, such as MADCAM1. The results indicate driver mutations in early-onset metastatic GC could promote metastasis not only by directly empower cancer cells to disseminate but also by establishing an immunosuppressive microenvironment. This study increased the understanding of molecular landscape of GC patients and provided possibility for future target therapy.

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