Exploring the oncostatin M (OSM) feed-forward signaling of glioblastoma via STAT3 in pan-cancer analysis

Abstract Background Oncostatin M (OSM) has been reported to be a key regulating factor in the process of tumor development. Previous studies have demonstrated both the promotion and inhibition effects of OSM in tumors, therefore inspiring controversies. However, no systematic assessment of OSM across various cancers is available, and the mechanisms behind OSM-related cancer progression remain to be elucidated. Methods Based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, we conducted a pan-cancer analysis on OSM to explore its tumor-related functions across cancers as well as its correlations with specific molecules, cells in the tumor microenvironment. Considering the results of pan-cancer analysis, we chose the specific tumor glioblastoma multiforme (GBM) to screen out the OSM-induced signaling pathways and intercellular communications in tumor progression. Wound scratch assay, invasion assay and qRT-PCR were performed to verify the biological effects of OSM on glioblastoma cells. Results Higher OSM level was found in most tumor tissues compared with corresponding normal tissues, and the enhanced OSM expression was observed to be strongly related to patients’ poor prognosis in several cancers. Moreover, the expression of OSM was associated with stromal and immune cell infiltration in the tumor microenvironment, and OSM-related immune checkpoint and chemokine co-expression were also observed. Our results suggested that OSM could communicate extensively with the tumor microenvironment. Taking GBM as an example, our study found that two critical signaling pathways in OSM-related tumor progression by KEGG enrichment analysis: Jak-STAT and NF-κB pathways. Single-cell RNA sequencing data analysis of GBM revealed that OSM was mainly secreted by microglia, and cell–cell interaction analysis proved that OSM-OSMR is an important pathway for OSM to stimulate malignant cells. In vitro, OSM treatment could facilitate the migration and invasion of glioblastoma cells, meanwhile promote the proneural-mesenchymal transition. The administration of STAT3 inhibitors effectively suppressed the OSM-mediated biological effects, which proved the key role of STAT3 in OSM signaling. Conclusion Taken together, our study provides a comprehensive understanding with regard to the tumor progression under the regulation of OSM. OSM seems to be closely related to chronic inflammation and tumor development in the tumor microenvironment. As an important inflammatory factor in the tumor microenvironment, OSM may serve as a potential immunotherapeutic target for cancer treatment, especially for GBM.

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The Molecular Mechanism of Epithelial–Mesenchymal Transition for Breast Carcinogenesis

Biomolecules ◽

10.3390/biom9090476 ◽

2019 ◽

Vol 9 (9) ◽

pp. 476 ◽

Cited By ~ 4

Author(s):

Chia-Jung Li ◽

Pei-Yi Chu ◽

Giou-Teng Yiang ◽

Meng-Yu Wu

Keyword(s):

Epithelial Cells ◽

Tumor Progression ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Transforming Growth Factor Β ◽

Inhibition Of Proliferation ◽

Mesenchymal Transition

The transforming growth factor-β (TGF-β) signaling pathway plays multiple regulatory roles in the tumorigenesis and development of cancer. TGF-β can inhibit the growth and proliferation of epithelial cells and induce apoptosis, thereby playing a role in inhibiting breast cancer. Therefore, the loss of response in epithelial cells that leads to the inhibition of cell proliferation due to TGF-β is a landmark event in tumorigenesis. As tumors progress, TGF-β can promote tumor cell invasion, metastasis, and drug resistance. At present, the above-mentioned role of TGF-β is related to the interaction of multiple signaling pathways in the cell, which can attenuate or abolish the inhibition of proliferation and apoptosis-promoting effects of TGF-β and enhance its promotion of tumor progression. This article focuses on the molecular mechanisms through which TGF-β interacts with multiple intracellular signaling pathways in tumor progression and the effects of these interactions on tumorigenesis.

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CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

Journal of Oncology ◽

10.1155/2019/9681698 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Alessandra Righetti ◽

Matteo Giulietti ◽

Berina Šabanović ◽

Giulia Occhipinti ◽

Giovanni Principato ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Microenvironment ◽

Stromal Cells ◽

Tumor Invasion ◽

Epithelial To Mesenchymal Transition ◽

Current Knowledge ◽

Tumor Development ◽

Physiological Role ◽

Mesenchymal Transition ◽

Splicing Isoforms

CXCL12 is a chemokine that acts through CXCR4 and ACKR3 receptors and plays a physiological role in embryogenesis and haematopoiesis. It has an important role also in tumor development, since it is released by stromal cells of tumor microenvironment and alters the behavior of cancer cells. Many studies investigated the roles of CXCL12 in order to understand if it has an anti- or protumor role. In particular, it seems to promote tumor invasion, proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in pancreatic cancer. Nevertheless, some evidence shows opposite functions; therefore research on CXCL12 is still ongoing. These discrepancies could be due to the presence of at least six CXCL12 splicing isoforms, each with different roles. Interestingly, three out of six variants have the highest levels of expression in the pancreas. Here, we report the current knowledge about the functions of this chemokine and then focus on pancreatic cancer. Moreover, we discuss the methods applied in recent studies in order to understand if they took into account the existence of the CXCL12 isoforms.

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Pan-Cancer Analysis Reveals that the SARS-CoV-2 Receptor ACE2 is a Protective Factor for Cancer Progression

10.21203/rs.3.rs-42534/v1 ◽

2020 ◽

Author(s):

Zhilan Zhang ◽

Lin Li ◽

Mengyuan Li ◽

Xiaosheng Wang

Keyword(s):

Tumor Progression ◽

Clinical Outcomes ◽

Cancer Progression ◽

Antitumor Immunity ◽

Protective Factor ◽

Cancer Genomics ◽

Mesenchymal Transition ◽

Expression Levels ◽

Oncogenic Pathways ◽

Pan Cancer

Abstract Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 13 million people and has caused more than 570,000 deaths worldwide as of July 13, 2020. The SARS-CoV-2 human cell receptor ACE2 has recently received extensive attention for its role in SARS-CoV-2 infection. Many studies have also explored the association between ACE2 and cancer. However, a systemic investigation into associations between ACE2 and oncogenic pathways, tumor progression, and clinical outcomes in pan-cancer remains lacking. Methods: Using cancer genomics datasets from the Cancer Genome Atlas (TCGA) program, we performed computational analyses of associations between ACE2 expression and antitumor immunity, immunotherapy response, oncogenic pathways, tumor progression phenotypes, and clinical outcomes in 12 cancer cohorts. We also identified co-expression networks of ACE2 in cancer.Results: ACE2 upregulation was associated with increased antitumor immune signatures and PD-L1 expression, and favorable anti-PD-1/PD-L1/CTLA-4 immunotherapy response. ACE2 expression levels inversely correlated with the activity of cell cycle, mismatch repair, TGF-β, Wnt, VEGF, and Notch signaling pathways. Moreover, ACE2 expression levels had significant inverse correlations with tumor proliferation, stemness, and epithelial-mesenchymal transition (EMT). ACE2 upregulation was associated with favorable survival in pan-cancer and in multiple individual cancer types. Conclusions: ACE2 upregulation was associated with increased antitumor immunity and immunotherapy response, reduced tumor malignancy, and favorable survival in cancer, suggesting that ACE2 is a protective factor for cancer progression. Our data may provide potential clinical implications for treating cancer patients infected with SARS-CoV-2.

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TMIC-15. HYPERACTIVATING THE HIPPO PATHWAY EFFECTOR TAZ DIFFERENTIALLY DISTORTS THE TUMOR MICROENVIRONMENT, PROMOTES TUMOR-ASSOCIATED NEUTROPHIL INFILTRATION, AND PHENOCOPIES MESENCHYMAL-GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.1049 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi250-vi250

Author(s):

Patricia Yee ◽

Yiju Wei ◽

Zhijun Liu ◽

Hui Guo ◽

Umeshkumar Manjibhai Vekariya ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

Myeloid Cells ◽

Treatment Resistance ◽

Neutrophil Infiltration ◽

Adult Brain ◽

Tumor Evolution ◽

Binding Motif ◽

Mesenchymal Transition ◽

The Impact

Abstract Glioblastoma (GBM), the deadliest and most common adult brain malignancy, is molecularly and clinically heterogeneous. The most common subtype (both primary and recurrent), mesenchymal (MES)-GBM, has the worst prognosis and highest treatment resistance. MES-GBM exhibits hyperactive transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo tumor suppressive pathway effector whose expression in GBMs predicts short survival. Yet, how Hippo-TAZ dysregulation might drive GBM MES transition remains elusive, precluding subtype-specific treatments. Tumor evolution requires signaling dysregulation and co-opting the tumor microenvironment (TME). Understanding GBM heterogeneity was recently complicated by the notion that subtypes vary in TME immune composition. The MES-GBM TME is differentially-distorted in silico, with more tumor-associated macrophages/microglia (TAMs) and neutrophils (TANs). Yet, how TAZ hyperactivity, MES transition, and GBM TME distortion interrelate and impact tumor progression remains unknown. We suspected that TME distortion facilitates immune evasion, MES transition, and tumor progression, worsening treatment responses. To test this, we devised an orthotopic xenograft mouse model phenotypically and histopathologically recapitulating human MES-GBM by expressing constitutively-active TAZ (TAZ4SA) in human GBM cells lacking MES signatures (GBM4SA). GBM4SA mice lived significantly shorter compared to mice with GBM expressing vector (GBMvector) or mutant TAZ unable to bind its effector, TEAD (GBM4SA-S51A). Moreover, more myeloid cells infiltrate the GBM4SA TME than the GBMvector or GBM4SA-S51A TMEs. While most myeloid cells infiltrating the GBMvector and GBM4SA-S51A TMEs were TAMs, most infiltrating the GBM4SA TME were TANs, suggesting TAZ hyperactivation differentially distorts the TME. Next, to delineate the roles of TANs in GBM4SA tumor progression, mice were depleted of neutrophils by administering Ly6G antibody. Serial blood smears and flow cytometry revealed effective depletion was achieved. We are currently investigating the impact of systemic neutrophil depletion on GBM mesenchymal transition and tumor progression in hopes of informing future GBM clinical management and novel TME-targeted immunotherapies.

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The Immune Endocannabinoid System of the Tumor Microenvironment

International Journal of Molecular Sciences ◽

10.3390/ijms21238929 ◽

2020 ◽

Vol 21 (23) ◽

pp. 8929

Author(s):

Melanie Kienzl ◽

Julia Kargl ◽

Rudolf Schicho

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

Immune Cells ◽

Cannabinoid Receptors ◽

Immune Cell ◽

Tumor Development ◽

Endocannabinoid System ◽

Cell Functions ◽

In Vitro Effects

Leukocytes are part of the tumor microenvironment (TME) and are critical determinants of tumor progression. Because of the immunoregulatory properties of cannabinoids, the endocannabinoid system (ECS) may have an important role in shaping the TME. Members of the ECS, an entity that consists of cannabinoid receptors, endocannabinoids and their synthesizing/degrading enzymes, have been associated with both tumor growth and rejection. Immune cells express cannabinoid receptors and produce endocannabinoids, thereby forming an “immune endocannabinoid system”. Although in vitro effects of exogenous cannabinoids on immune cells are well described, the role of the ECS in the TME, and hence in tumor development and immunotherapy, is still elusive. This review/opinion discusses the possibility that the “immune endocannabinoid system” can fundamentally influence tumor progression. The widespread influence of cannabinoids on immune cell functions makes the members of the ECS an interesting target that could support immunotherapy.

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NKG2D signaling regulates IL-17A-producing γδT cells to promote cancer progression

10.1101/2021.08.26.457761 ◽

2021 ◽

Author(s):

Sophie Curio ◽

Sarah C Edwards ◽

Toshiyasu Suzuki ◽

Jenny McGovern ◽

Chiara Triulzi ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Cancer Progression ◽

Cell Activation ◽

Tumor Development ◽

Cell Receptor ◽

Dependent Manner ◽

Γδt Cells ◽

Γδt Cell

γδT cells are unconventional T cells particularly abundant in mucosal tissues that play an important role in tissue surveillance and homeostasis. γδT cell activation is mediated by the T cell receptor composed of γ and δ chains, as well as activating receptors for stress-induced ligands, such as NKG2D. Contrary to the well-established anti-tumor function of γδT cells, recent studies have shown that γδT cells can promote tumor development in certain contexts. However, the mechanisms leading to this disease-promoting role remain poorly understood. Here, we show that mice lacking γδT cells survive longer in a mouse model of intestinal cancer, further supporting their pro-tumoral role. In a surprising conceptual twist, we found that these pro-tumor γδT cells are regulated by NKG2D signaling, a receptor normally associated with cancer cell killing. Germline deletion of Klrk1, the gene encoding NKG2D, reduced the frequency of γδT cells in the tumor microenvironment and delayed tumor progression. We further show that blocking NKG2D reduces the capability of γδT cells to produce IL-17A in the pre-metastatic lung and that co-culture of lung T cells with NKG2D ligand-expressing tumor cells specifically increases the frequency of γδT cells. Together, these data support the hypothesis that in a tumor microenvironment where NKG2D ligands are constitutively expressed, γδT cells accumulate in an NKG2D-dependent manner and drive tumor progression by secreting pro-inflammatory cytokines, such as IL-17A.

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

Molecules ◽

10.3390/molecules27010137 ◽

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.

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Toward understanding cancer stem cell heterogeneity in the tumor microenvironment

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1815345116 ◽

2018 ◽

Vol 116 (1) ◽

pp. 148-157 ◽

Cited By ~ 73

Author(s):

Federico Bocci ◽

Larisa Gearhart-Serna ◽

Marcelo Boareto ◽

Mariana Ribeiro ◽

Eshel Ben-Jacob ◽

...

Keyword(s):

Stem Cell ◽

Tumor Microenvironment ◽

Cancer Stem Cell ◽

Tumor Progression ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Spatiotemporal Dynamics ◽

Spatial Proximity ◽

Mesenchymal Transition

The epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) formation are two paramount processes driving tumor progression, therapy resistance, and cancer metastasis. Recent experiments show that cells with varying EMT and CSC phenotypes are spatially segregated in the primary tumor. The underlying mechanisms generating such spatiotemporal dynamics in the tumor microenvironment, however, remain largely unexplored. Here, we show through a mechanism-based dynamical model that the diffusion of EMT-inducing signals such as TGF-β, together with noncell autonomous control of EMT and CSC decision making via the Notch signaling pathway, can explain experimentally observed disparate localization of subsets of CSCs with varying EMT phenotypes in the tumor. Our simulations show that the more mesenchymal CSCs lie at the invasive edge, while the hybrid epithelial/mesenchymal (E/M) CSCs reside in the tumor interior. Further, motivated by the role of Notch-Jagged signaling in mediating EMT and stemness, we investigated the microenvironmental factors that promote Notch-Jagged signaling. We show that many inflammatory cytokines such as IL-6 that can promote Notch-Jagged signaling can (i) stabilize a hybrid E/M phenotype, (ii) increase the likelihood of spatial proximity of hybrid E/M cells, and (iii) expand the fraction of CSCs. To validate the predicted connection between Notch-Jagged signaling and stemness, we knocked down JAG1 in hybrid E/M SUM149 human breast cancer cells in vitro. JAG1 knockdown significantly restricted tumor organoid formation, confirming the key role that Notch-Jagged signaling can play in tumor progression. Together, our integrated computational–experimental framework reveals the underlying principles of spatiotemporal dynamics of EMT and CSCs.

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Leptin promotes expression of EMT-related transcription factors and invasion in a Src and FAK-dependent pathway in MCF10A mammary epithelial cells

10.1101/739169 ◽

2019 ◽

Author(s):

Monserrat Olea-Flores ◽

Miriam Zuñiga-Eulogio ◽

Arvey Tacuba-Saavedra ◽

Magdalena Bueno-Salgado ◽

Andrea Sánchez-Carvajal ◽

...

Keyword(s):

Transcription Factors ◽

Tumor Progression ◽

Signaling Pathways ◽

Matrix Metalloproteases ◽

Migration And Invasion ◽

Mcf10a Cell ◽

Dependent Manner ◽

Mesenchymal Transition ◽

Mcf10a Cells ◽

Invadopodia Formation

AbstractLeptin is one of the main adipokines secreted in breast tissue, and has been associated with epithelial-mesenchymal transition (EMT) and tumor progression in breast cancer. Leptin promotes EMT, cell migration and invasion in epithelial breast cells, leading to tumor progression. However, the molecular mechanism that underlies these events is not fully understood; however, the activation of different signaling pathways appears to be essential. In this sense, the effect of leptin on the activation of kinases like Src and FAK, which regulate signaling pathways that activate the EMT program, has not been completely described. Therefore, we investigated the involvement of these kinases using an in vitro model for leptin-induced EMT process in the non-tumorigenic MCF10A cell line. To this end, MCF10A cells were stimulated with leptin, and Src and FAK activation was assessed. Specific events occurring during EMT were also evaluated in the presence or absence of the kinases’s chemical inhibitors PP2 and PF-573228. For instance, we tested the expression and subcellular localization of the EMT-related transcription factors Twist and □-catenin, by western blot and immunofluorescence. We also evaluated the secretion and activation of matrix metalloproteases (MMP-2 and MMP-9) by gelatin zymography. Invasiveness properties of leptin-stimulated cells were determined by invadopodia formation assays, and by the transwell chamber method. Our results showed that leptin promotes EMT through Src and FAK activation, which leads to the secretion and activation of MMP-2 and MMP-9, invadopodia formation and cell invasion in MCF10A cells. In conclusion, our data suggest that leptin promotes an increase in the expression levels of Twist and □-catenin, the secretion of MMP-2, MMP-9, the invadopodia formation and invasion in MCF10A cells in a Src and FAK-dependent manner.

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MicroRNAs: Their Role in Metabolism, Tumor Microenvironment, and Therapeutic Implications in Head and Neck Squamous Cell Carcinoma

Cancers ◽

10.3390/cancers13225604 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5604

Author(s):

Shine-Gwo Shiah ◽

Sung-Tau Chou ◽

Jang-Yang Chang

Keyword(s):

Tumor Microenvironment ◽

Epithelial Mesenchymal Transition ◽

Tumor Development ◽

Cell Communication ◽

Cell Types ◽

Metabolic Reprogramming ◽

Mesenchymal Transition ◽

Therapeutic Implications ◽

Rna Molecules ◽

Non Coding Rna

MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that negatively regulate gene expression by binding to target mRNAs. Deregulated miRNAs can act as either oncogenic miRNAs or tumor suppressor miRNAs in controlling proliferation, differentiation, apoptosis, metastasis, epithelial–mesenchymal transition, and immune responses, which are all involved in the carcinogenesis process of HNSCC. Recent findings have shown that metabolic reprogramming is an important hallmark of cancer, which is necessary for malignant transformation and tumor development. Some reprogrammed metabolisms are believed to be required for HNSCC against an unfavorable tumor microenvironment (TME). The TME is composed of various cell types embedded in the altered extracellular matrix, among which exosomes, secreted by cancer cells, are one of the most important factors. Tumor-derived exosomes reshape the tumor microenvironment and play a crucial role in cell-to-cell communication during HNSCC development. Exosomes encapsulate many biomolecules, including miRNAs, circulate in body fluids, and can transmit intercellular regulatory messages to nearby and distant sites, which indicates that exosomal miRNAs have the potential to become non-invasive biomarkers. This review aims to clarify the functions of diverse miRNAs in HNSCC metabolic reprogramming and tumor-derived exosomes. In addition, it also emphasizes the potential role of miRNA as a biomarker in the diagnosis, prognosis, and treatment of HNSCC cancer.

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