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.

Immune cells and Notch1 signaling appear to drive the epithelial to mesenchymal transition in the development of adenomyosis in mice

2021 ◽  
Author(s):  
M Bourdon ◽  
P Santulli ◽  
L Doridot ◽  
M Jeljeli ◽  
C Chêne ◽  
...  
Keyword(s):  
Immune Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Target Genes ◽  
Immune Cell ◽  
Control Group ◽  
Aberrant Expression ◽  
M1 Macrophages ◽  
Mesenchymal Transition ◽  
Cell Markers ◽  
Notch1 Signaling

Abstract The epithelial to mesenchymal transition has been implicated in the development of adenomyosis, along with dysregulated immune responses. Inflammation potentially induces Notch signaling, that could promote this epithelial to mesenchymal transition. The objective of this study was to investigate the involvement of immune cells and Notch1-mediated epithelial to mesenchymal transition in the development of adenomyosis. Adenomyosis was induced in 18 CD-1 mice by neonatal oral administration of tamoxifen (TAM group), while 18 neonates received vehicle only (Control group). Their uteri were sampled at 30,60 or 90 days of age. Immune cell markers (Cd45, Ly6c1, Cd86, Arginine1, Cd19, Cd4, Cd8), Notch1 and its target genes (Hey1, Hey2, Hes1, Hes5), and biomarkers of epithelial to mesenchymal transition (E-Cadherin, Vimentin, Tgfb, Snail1, Slug, Snail3) were analyzed by quantitative RT-PCR and immunohistochemistry. Activated-Notch1 protein was measured by western blot. Aberrant expression of immune cell markers was observed in the uteri of mice as they developed adenomyosis. The expression of inflammatory cell markers, notably M1 macrophages and natural killer cells, was increased from Day 30 in the TAM group compared to controls, followed by an increase in the Cd4 marker (T-cells) at Day 60. Conversely, expression of the Cd19 marker (B-cells) was significantly reduced at all of the stages studied. Notch1 signaling was also highly activated compared to controls at Day 30 and Day 60. Concomitantly, the levels of several markers for epithelial to mesenchymal transition were also higher. Therefore, the activation of Notch1 coincides with aberrant expression of immune and epithelial to mesenchymal transition markers in the early development of adenomyosis.

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 CXC Chemokines as Therapeutic Targets and Prognostic Biomarkers in Skin Cutaneous Melanoma Microenvironment

2021 ◽  
Vol 11 ◽  
Author(s):  
Xuezhi Zhou ◽  
Manjuan Peng ◽  
Ye He ◽  
Jingjie Peng ◽  
Xuan Zhang ◽  
...  
Keyword(s):  
Immune Cells ◽  
Cutaneous Melanoma ◽  
Immune Cell ◽  
Gene Activation ◽  
Skin Tumor ◽  
Pathological Stage ◽  
Normal Tissues ◽  
The World ◽  
Cxc Chemokine ◽  
The Relationship

BackgroundSkin Cutaneous Melanoma (SKCM) is a tumor of the epidermal melanocytes induced by gene activation or mutation. It is the result of the interaction between genetic, constitutional, and environmental factors. SKCM is highly aggressive and is the most threatening skin tumor. The incidence of the disease is increasing year by year, and it is the main cause of death in skin tumors around the world. CXC chemokines in the tumor microenvironment can regulate the transport of immune cells and the activity of tumor cells, thus playing an anti-tumor immunological role and affecting the prognosis of patients. However, the expression level of CXC chemokine in SKCM and its effect on prognosis are still unclear.MethodOncomine, UALCAN, GEPIA, STRING, GeneMANIA, cBioPortal, TIMER, TRRUST, DAVID 6.8, and Metascape were applied in our research.ResultThe transcription of CXCL1, CXCL5, CXCL8, CXCL9, CXCL10, and CXCL13 in SKCM tissues were significantly higher than those in normal tissues. The pathological stage of SKCM patients is closely related to the expression of CXCL4, CXCL9, CXCL10, CXCL11, CXCL12, and CXCL13. The prognosis of SKCM patients with low transcription levels of CXCL4, CXCL9, CXCL10, CXCL11, and CXCL13 is better. The differential expression of CXC chemokines is mainly associated with inflammatory response, immune response, and cytokine mediated signaling pathways. Our data indicate that the key transcription factors of CXC chemokines are RELA, NF-κB1 and SP1. The targets of CXC chemokines are mainly LCK, LYN, SYK, MAPK2, MAPK12, and ART. The relationship between CXC chemokine expression and immune cell infiltration in SKCM was closed.ConclusionsOur research provides a basis for screening SKCM biomarkers, predicting prognosis, and choosing immunotherapy.

scholarly journals Lamins in Lung Cancer: Biomarkers and Key Factors for Disease Progression through miR-9 Regulation?

Cells ◽  
2018 ◽  
Vol 7 (7) ◽  
pp. 78 ◽  
Author(s):  
Julien Guinde ◽  
Diane Frankel ◽  
Sophie Perrin ◽  
Valérie Delecourt ◽  
Nicolas Lévy ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Tumor Development ◽  
Nuclear Lamina ◽  
Metastatic Potential ◽  
Disease Diagnosis ◽  
Carcinoma Cells ◽  
Scaffolding Protein ◽  
Mesenchymal Transition ◽  
Cancer Subtypes

Lung cancer represents the primary cause of cancer death in the world. Malignant cells identification and characterization are crucial for the diagnosis and management of patients with primary or metastatic cancers. In this context, the identification of new biomarkers is essential to improve the differential diagnosis between cancer subtypes, to select the most appropriate therapy, and to establish prognostic correlations. Nuclear abnormalities are hallmarks of carcinoma cells and are used as cytological diagnostic criteria of malignancy. Lamins (divided into A- and B-types) are localized in the nuclear matrix comprising nuclear lamina, where they act as scaffolding protein, involved in many nuclear functions, with regulatory effects on the cell cycle and differentiation, senescence and apoptosis. Previous studies have suggested that lamins are involved in tumor development and progression with opposite results concerning their prognostic role. This review provides an overview of lamins expression in lung cancer and the relevance of these findings for disease diagnosis and prognosis. Furthermore, we discuss the link between A-type lamins expression in lung carcinoma cells and nuclear deformability, epithelial to mesenchymal transition, and metastatic potential, and which mechanisms could regulate A-type lamins expression in lung cancer, such as the microRNA miR-9.

scholarly journals Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1058 ◽  
Author(s):  
Gener ◽  
Rafael ◽  
Seras-Franzoso ◽  
Perez ◽  
Pindado ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Distant Metastases ◽  
Metastatic Potential ◽  
Phenotypic Change ◽  
Primary Tumors ◽  
Mesenchymal Transition

Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by the presence of cancer stem cells (CSC) within a tumor. The difficulty in targeting this subpopulation derives from their dynamic interconversion process, where CSC can differentiate to non-CSC, which in turn de-differentiate into cells with CSC properties. Using fluorescent CSC models driven by the expression of ALDH1A 1(aldehyde dehydrogenase 1A1), we confirmed this dynamic phenotypic change in MDA-MB-231 breast cancer cells and to identify Serine/Threonine Kinase 2 (AKT2) as an important player in the process. To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines. Our results revealed that AKT2 inhibition effectively prevents non-CSC reversion through mesenchymal to epithelial transition, reducing invasion and colony formation ability of both, non-CSC and CSC. Further, AKT2 inhibition reduced CSC survival in low attachment conditions. Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potential.

scholarly journals Dual-procedural separation of CTCs in cutaneous melanoma provides useful information for both molecular diagnosis and prognosis

2020 ◽  
Vol 12 ◽  
pp. 175883592090541 ◽  
Author(s):  
Marco Tucci ◽  
Stella D’Oronzo ◽  
Francesco Mannavola ◽  
Claudia Felici ◽  
Domenica Lovero ◽  
...  
Keyword(s):  
Cutaneous Melanoma ◽  
Epithelial To Mesenchymal Transition ◽  
Stage Iv ◽  
Digital Pcr ◽  
Isolated Cells ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Diagnosis And Prognosis ◽  
Mutational Status ◽  
Magnetic Sorting

Background: Circulating tumor cells (CTCs) have recently emerged as a new dynamic soluble marker for several malignancies including cutaneous melanoma (CM) and are suitable for prognostic evaluations and treatment monitoring. However, to date many limitations still hamper the wide-scale application of CTCs in CM setting, including the lack of standardized methods as well as both low levels and heterogeneity of these cells. Methods: We developed a protocol for CTC detection in CM based on immune-magnetic sorting to deplete CD45-, CD31- or CD34-positive cells, followed by dielectrophoretic DEPArray separation according to cell morphology and immunophenotype. To this end, we explored the expression of melanoma stem cell antigens (CD271, ABCB5, and RANK) and the epithelial-to-mesenchymal transition markers (N-Cad, -CD44, and -MCAM/CD146) on CTCs from 17 stage IV CM patients, and investigated their BRAF mutational status by droplet digital PCR. Results: The number of CTCs isolated from CM patients ranged from 2 to 91 cells (38 ± 6.4) with respect to healthy donors ( p < 0.0002). To confirm the melanoma origin of isolated cells, we observed an 80% agreement between their BRAFV600 mutational status and matched primary tumors. The characterization of the immune phenotype of isolated cells revealed high interindividual and intraindividual heterogeneity that was found to correlate with the clinical outcome. Conclusions: The dual-step protocol of immune-magnetic sorting and subsequent dielectrophoretic DEPArray separation, turned out to be a suitable method to isolate viable CTCs from stage IV melanoma patients and enabled quantitative and qualitative analyses on these cells, which may deserve prospective evaluation for potential use in the clinical practice.

scholarly journals Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 137
Author(s):  
Zhi-Jian Han ◽  
Yang-Bing Li ◽  
Lu-Xi Yang ◽  
Hui-Juan Cheng ◽  
Xin Liu ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Immune Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Checkpoint Inhibitors ◽  
Lymphatic Vessels ◽  
Cell Types ◽  
Mesenchymal Transition ◽  
Development Of Resistance ◽  
Immunosuppressive Cells

In humans, Interleukin-8 (IL-8 or CXCL8) is a granulocytic chemokine with multiple roles within the tumor microenvironment (TME), such as recruiting immunosuppressive cells to the tumor, increasing tumor angiogenesis, and promoting epithelial-to-mesenchymal transition (EMT). All of these effects of CXCL8 on individual cell types can result in cascading alterations to the TME. The changes in the TME components such as the cancer-associated fibroblasts (CAFs), the immune cells, the extracellular matrix, the blood vessels, or the lymphatic vessels further influence tumor progression and therapeutic resistance. Emerging roles of the microbiome in tumorigenesis or tumor progression revealed the intricate interactions between inflammatory response, dysbiosis, metabolites, CXCL8, immune cells, and the TME. Studies have shown that CXCL8 directly contributes to TME remodeling, cancer plasticity, and the development of resistance to both chemotherapy and immunotherapy. Further, clinical data demonstrate that CXCL8 could be an easily measurable prognostic biomarker in patients receiving immune checkpoint inhibitors. The blockade of the CXCL8-CXCR1/2 axis alone or in combination with other immunotherapy will be a promising strategy to improve antitumor efficacy. Herein, we review recent advances focusing on identifying the mechanisms between TME components and the CXCL8-CXCR1/2 axis for novel immunotherapy strategies.

scholarly journals Integrative Transcriptomic, Proteomic and Functional Analysis Reveals ATP1B3 as a Diagnostic and Potential Therapeutic Target in Hepatocellular Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Shanshan Lu ◽  
Shenglan Cai ◽  
Xiaozhen Peng ◽  
Ruochan Cheng ◽  
Yiya Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Functional Analysis ◽  
Prognostic Factor ◽  
Epithelial To Mesenchymal Transition ◽  
Immune Cell ◽  
Prognostic Significance ◽  
Independent Prognostic Factor ◽  
Mesenchymal Transition ◽  
Immune Infiltration ◽  
Geo Database

The Na+/K+-ATPase (NKA), has been proposed as a signal transducer involving various pathobiological processes, including tumorigenesis. However, the clinical relevance of NKA in hepatocellular carcinoma (HCC) has not been well studied. This study revealed the upregulation of mRNA of ATP1A1, ATP1B1, and ATP1B3 in HCC using TCGA, ICGC, and GEO database. Subsequently, ATP1B3 was demonstrated as an independent prognostic factor of overall survival (OS) of HCC. To investigate the potential mechanisms of ATP1B3 in HCC, we analyzed the co-expression network using LinkedOmics and found that ATP1B3 co-expressed genes were associated with immune-related biological processes. Furthermore, we found that ATP1B3 was correlated immune cell infiltration and immune-related cytokines expression in HCC. The protein level of ATP1B3 was also validated as a prognostic significance and was correlated with immune infiltration in HCC using two proteomics datasets. Finally, functional analysis revealed that ATP1B3 was increased in HCC cells and tissues, silenced ATP1B3 repressed HCC cell proliferation, migration, and promoted HCC cell apoptosis and epithelial to mesenchymal transition (EMT). In conclusion, these findings proved that ATP1B3 could be an oncogene and it was demonstrated as an independent prognostic factor and correlated with immune infiltration in HCC, revealing new insights into the prognostic role and potential immune regulation of ATP1B3 in HCC progression and provide a novel possible therapeutic strategy for HCC.

scholarly journals EBV latent membrane proteins promote hybrid epithelial-mesenchymal and extreme mesenchymal states of nasopharyngeal carcinoma cells for tumorigenicity

2021 ◽  
Vol 17 (8) ◽  
pp. e1009873
Author(s):  
Nannan Zhu ◽  
Xiaoting Xu ◽  
Yan Wang ◽  
Musheng Zeng ◽  
Yan Yuan
Keyword(s):  
Stem Cells ◽  
Nasopharyngeal Carcinoma ◽  
Cancer Stem Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Vasculogenic Mimicry ◽  
Metastatic Potential ◽  
Carcinoma Cells ◽  
Tumor Xenograft ◽  
Additional Function ◽  
Mesenchymal Transition

EBV-encoded LMPs are consistently detected in nasopharyngeal carcinoma (NPC). Recent evidence suggests potential roles of LMP1 and LMP2A in Epithelial-to-mesenchymal transition (EMT) process in NPC. EMT engages in the generation and maintenance of cancer stem cells (CSCs) and confers on cancer cells increased tumor-initiating and metastatic potential, and higher resistance to anticancer therapies. However, how LMP1 and LMP2A regulate the EMT process to generate cells with different EMT states and its implications for tumor progression remain unclear. Here we report that LMP1 and LMP2A promote EMT that drives NPC cells from the epithelial-like state (CD104+, CD44low) to epithelial-mesenchymal hybrid (E/M) state (CD104+, CD44high). Furthermore, LMP2A possesses an additional function in stabilizing LMP1 and increasing the level of LMP1 in NPC cells. The elevated LMP1 further forces the EMT to generate extreme-mesenchymal (xM) state cells (CD104-, CD44high). To define the tumorigenic features of cancer stem cells at different states in the EMT spectrum, E, E/M and xM subpopulations were isolated and tested for tumorigenic capability in a tumor xenograft animal model. We found that the cells with E/M phenotypes possess the highest tumor initiating capacity. However, the xM subpopulation exhibits increased vasculogenic mimicry, a hallmark of metastatic cancers. Taken together, coordinated action of LMP1 and LMP2A generates an array of intermediate subpopulations in the EMT spectrum that are responsible for distinct tumorigenic features of NPC such as tumor-initiation, vasculogenesis, and metastasis.

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