scholarly journals Cancer-Associated Glycosphingolipids as Tumor Markers and Targets for Cancer Immunotherapy

2021 ◽  
Vol 22 (11) ◽  
pp. 6145
Author(s):  
Sophie Groux-Degroote ◽  
Philippe Delannoy
Keyword(s):  
Cancer Cells ◽  
Intracellular Signaling ◽  
Cellular Therapy ◽  
Current Knowledge ◽  
Small Cell Lung Carcinoma ◽  
Active Immunotherapy ◽  
Special Focus ◽  
Adoptive Cellular Therapy ◽  
Aberrant Expression ◽  
Cell Lung Carcinoma

Aberrant expression of glycosphingolipids is a hallmark of cancer cells and is associated with their malignant properties. Disialylated gangliosides GD2 and GD3 are considered as markers of neuroectoderm origin in tumors, whereas fucosyl-GM1 is expressed in very few normal tissues but overexpressed in a variety of cancers, especially in small cell lung carcinoma. These gangliosides are absent in most normal adult tissues, making them targets of interest in immuno-oncology. Passive and active immunotherapy strategies have been developed, and have shown promising results in clinical trials. In this review, we summarized the current knowledge on GD2, GD3, and fucosyl-GM1 expression in health and cancer, their biosynthesis pathways in the Golgi apparatus, and their biological roles. We described how their overexpression can affect intracellular signaling pathways, increasing the malignant phenotypes of cancer cells, including their metastatic potential and invasiveness. Finally, the different strategies used to target these tumor-associated gangliosides for immunotherapy were discussed, including the use and development of monoclonal antibodies, vaccines, immune system modulators, and immune effector-cell therapy, with a special focus on adoptive cellular therapy with T cells engineered to express chimeric antigen receptors.

scholarly journals Hampering Stromal Cells in the Tumor Microenvironment as a Therapeutic Strategy to Destem Cancer Stem Cells

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3191
Author(s):  
Katherine Po Sin Chung ◽  
Rainbow Wing Hei Leung ◽  
Terence Kin Wah Lee
Keyword(s):  
Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Stromal Cells ◽  
Current Knowledge ◽  
Special Focus ◽  
Intrinsic Regulation ◽  
Mechanistic Basis ◽  
Novel Therapeutic Strategies

Cancer stem cells (CSCs) within the tumor bulk play crucial roles in tumor initiation, recurrence and therapeutic resistance. In addition to intrinsic regulation, a growing body of evidence suggests that the phenotypes of CSCs are also regulated extrinsically by stromal cells in the tumor microenvironment (TME). Here, we discuss the current knowledge of the interplay between stromal cells and cancer cells with a special focus on how stromal cells drive the stemness of cancer cells and immune evasive mechanisms of CSCs. Knowledge gained from the interaction between CSCs and stromal cells will provide a mechanistic basis for the development of novel therapeutic strategies for the treatment of cancers.

scholarly journals Chemotherapeutic drugs stimulate the release and recycling of extracellular vesicles to assist cancer cells in developing an urgent chemoresistance

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Xiaokun Wang ◽  
Dongjuan Qiao ◽  
Likun Chen ◽  
Meng Xu ◽  
Shupeng Chen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Small Cell Lung Carcinoma ◽  
Underlying Mechanism ◽  
Chemotherapeutic Agents ◽  
Chemotherapeutic Drugs ◽  
Xenograft Tumor ◽  
Tumor Models ◽  
Cell Lung Carcinoma

Abstract Background Chemotherapy is a widely used treatment for cancer. However, the development of acquired multidrug resistance (MDR) is a serious issue. Emerging evidence has shown that the extracellular vesicles (EVs) mediate MDR, but the underlying mechanism remains unclear, especially the effects of chemotherapeutic agents on this process. Methods Extracellular vesicles isolation was performed by differential centrifugation. The recipient cells that acquired ATP-binding cassette sub-family B member 1 (ABCB1) proteins were sorted out from co-cultures according to a stringent multi-parameter gating strategy by fluorescence-activated cell sorting (FACS). The transfer rate of ABCB1 was measured by flow cytometry. The xenograft tumor models in mice were established to evaluate the transfer of ABCB1 in vivo. Gene expression was detected by real-time PCR and Western blotting. Results Herein, we show that a transient exposure to chemotherapeutic agents can strikingly increase Rab8B-mediated release of extracellular vesicles (EVs) containing ABCB1 from drug-resistant cells, and accelerate these EVs to circulate back onto plasma membrane of sensitive tumor cells via the down-regulation of Rab5. Therefore, intercellular ABCB1 transfer is significantly enhanced; sensitive recipient cells acquire a rapid but unsustainable resistance to evade the cytotoxicity of chemotherapeutic agents. More fascinatingly, in the xenograft tumor models, chemotherapeutical drugs also locally or distantly increase the transfer of ABCB1 molecules. Furthermore, some Non-small-cell lung carcinoma (NSCLC) patients who are undergoing primary chemotherapy have a rapid increase of ABCB1 protein in their monocytes, and this is obviously associated with poor chemotherapeutic efficacy. Conclusions Chemotherapeutic agents stimulate the secretion and recycling of ABCB1-enriched EVs through the dysregulation of Rab8B and Rab5, leading to a significant increase of ABCB1 intercellular transfer, thus assisting sensitive cancer cells to develop an urgent resistant phenotype. Our findings provide a new molecular mechanism of how chemotherapeutic drugs assist sensitive cancer cells in acquiring an urgent resistance.

scholarly journals GLUL Ablation Can Confer Drug Resistance to Cancer Cells via a Malate-Aspartate Shuttle-Mediated Mechanism

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1945
Author(s):  
Magesh Muthu ◽  
Ranjeet Kumar ◽  
Azharuddin Sajid Syed Khaja ◽  
Jonathan D. Gilthorpe ◽  
Jenny L. Persson ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Cell Lines ◽  
Small Cell Lung Carcinoma ◽  
A549 Cells ◽  
Cancer Drug ◽  
Aminooxyacetic Acid ◽  
Cell Lung Carcinoma ◽  
Metabolic Fitness ◽  
Malate Aspartate Shuttle

Glutamate-ammonia ligase (GLUL) is important for acid-base homeostasis, ammonia detoxification, cell signaling, and proliferation. Here, we reported that GLUL ablation conferred resistance to several anticancer drugs in specific cancer cell lines while leaving other cell lines non-resistant to the same drugs. To understand the biochemical mechanics supporting this drug resistance, we compared drug-resistant GLUL knockout (KO) A549 non-small-cell lung carcinoma (NSCLC) cells with non-resistant GLUL KO H1299 NSCLC cells and found that the resistant A549 cells, to a larger extent, depended on exogenous glucose for proliferation. As GLUL activity is linked to the tricarboxylic acid (TCA) cycle via reversed glutaminolysis, we probed carbon flux through both glycolysis and TCA pathways by means of 13C5 glutamine, 13C5 glutamate, and 13C6 glucose tracing. We observed increased labeling of malate and aspartate in A549 GLUL KO cells, whereas the non-resistant GLUL KO H1299 cells displayed decreased 13C-labeling. The malate and aspartate shuttle supported cellular NADH production and was associated with cellular metabolic fitness. Inhibition of the malate-aspartate shuttle with aminooxyacetic acid significantly impacted upon cell viability with an IC50 of 11.5 μM in resistant GLUL KO A549 cells compared to 28 μM in control A549 cells, linking resistance to the malate-aspartate shuttle. Additionally, rescuing GLUL expression in A549 KO cells increased drug sensitivity. We proposed a novel metabolic mechanism in cancer drug resistance where the increased capacity of the malate-aspartate shuttle increased metabolic fitness, thereby facilitating cancer cells to escape drug pressure.

scholarly journals ADRB3 expression in tumor cells is a poor prognostic factor and promotes proliferation in non-small cell lung carcinoma

2020 ◽  
Vol 69 (11) ◽  
pp. 2345-2355
Author(s):  
Meng Zheng ◽  
Zhiling Zhou ◽  
Xiangting Tian ◽  
Dingzhang Xiao ◽  
Xinghua Hou ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Poor Prognostic Factor

Abstract The cross-talk between cancer cells and monocyte-derived alveolar macrophages (Mo-AMs) promotes non-small cell lung carcinoma (NSCLC) progression. In this study, we report that both cancer cells and Mo-AMs robustly express beta 3-adrenergic receptor (ADRB3) in NSCLC. ADRB3 supports lung cancer cells proliferation and promotes chronic inflammation. Genetic and pharmacologic inhibition of ADRB3 reverses tumor growth and inflammation in mouse. Furthermore, we demonstrate that M5D1, a novel anti-ADRB3 monoclonal antibody, inhibits human lung cancer cells proliferation and inflammation via affecting the intracellular mTOR pathway and activating p53. In NSCLC patients, we confirmed that upregulation of ADRB3 expression correlates with tumor progression and poor prognosis. Altogether, these results shed light on the role of ADRB3 in NSCLC and suggest that M5D1 could become powerful antitumor weapons.

scholarly journals Functional redundancy of HSPA1, HSPA2 and other HSPA proteins in non-small cell lung carcinoma (NSCLC); an implication for NSCLC treatment

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Damian Robert Sojka ◽  
Agnieszka Gogler-Pigłowska ◽  
Natalia Vydra ◽  
Alexander Jorge Cortez ◽  
Piotr Teodor Filipczak ◽  
...  
Keyword(s):  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Good Prognosis ◽  
Small Cell ◽  
Cell Phenotype ◽  
Small Cell Lung ◽  
Aberrant Expression ◽  
Cell Lung Carcinoma ◽  
Hsp70 Family ◽  
The Impact

Abstract Heat shock proteins (HSPs) are a large group of chaperones considered critical for maintaining cellular proteostasis. Their aberrant expression in tumors can modulate the course of processes defined as hallmarks of cancer. Previously, we showed that both stress-inducible HSPA1 and testis-enriched HSPA2, highly homologous members of the HSPA (HSP70) family, are often overexpressed in non-small cell lung carcinoma (NSCLC). HSPA1 is among the best characterized cancer-related chaperones, while the significance of HSPA2 for cancer remains poorly understood. Previously we found that in primary NSCLC, HSPA1 was associated with good prognosis while HSPA2 correlated with bad prognosis, suggesting possible different roles of these proteins in cancer. Therefore, in this work we investigated the impact of HSPA1 and HSPA2 on NSCLC cell phenotype. We found that neither paralog-selective nor simultaneous knockdown of HSPA1 and HSPA2 gene expression reduced growth and chemoresistance of NSCLC cells. Only blocking of HSPA proteins using pan-HSPA inhibitors, VER-155008 or JG-98, exerted potent anticancer effect on NSCLC cells, albeit the final outcome was cell type-dependent. Pan-HSPA inhibition sensitized NSCLC cells to bortezomib, but not to platinum derivates. Our result suggests the inhibitors of proteasome and HSPAs seem an effective drug combination for pre-clinical development in highly aggressive NSCLC.

scholarly journals Transcriptional activation of cyclin D1 via HER2/HER3 contributes to cell survival and EGFR tyrosine kinase inhibitor resistance in non-small cell lung carcinoma

2019 ◽  
Author(s):  
Bin Liu ◽  
Deng Chen ◽  
Shipeng Chen ◽  
Ali Saber ◽  
Hidde Haisma
Keyword(s):  
Lung Cancer ◽  
Cell Survival ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Wild Type ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma

AbstractSeveral different mechanisms are implicated in the resistance of lung cancer cells to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and only few have been functionally investigated. Here, using genetically knocked out EGFR and TKI-resistant lung cancer cells, we show that loss of wild-type EGFR attenuates cell proliferation, migration and 3D-spherid formation, whereas loss of mutant EGFR or resistance to TKIs reinforces those processes. Consistently, disruption of wild-type EGFR leads to suppression of HER2/HER3, while mutant EGFR ablation or resistance to TKIs increases HER2/HER3 expression, compensating for EGFR loss. Furthermore, HER2/HER3 nuclear translocation mediates overexpression of cyclin D1, leading to tumor cell survival and drug resistance. Cyclin D1/CDK4/6 inhibition resensitizes erlotinib-resistant (ER) cells to erlotinib. Analysis of cyclin D1 expression in patients with non-small cell lung carcinoma (NSCLC) showed that its expression is negatively associated with overall survival and disease-free survival. Our results provide biological and mechanistic insights into targeting EGFR and TKI resistance.

scholarly journals Staurosporine Induces the Generation of Polyploid Giant Cancer Cells in Non-Small-Cell Lung Carcinoma A549 Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Alexander Glassmann ◽  
Carmen Carrillo Garcia ◽  
Viktor Janzen ◽  
Dominik Kraus ◽  
Nadine Veit ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
A549 Cells ◽  
Small Cell ◽  
Dependent Manner ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Inhibition Of Proliferation ◽  
Polyploid Giant Cancer Cells

Cultivation of A549 non-small-cell lung carcinoma (NSCLC) cells in the presence of staurosporine (SSP) leads to a reduction or a lack of proliferation in a concentration-dependent manner. This inhibition of proliferation is accompanied by the generation of polyploid giant cancer cells (PGCCs) that are characterized by cell flattening, increased cell size, polyploidy, and polynucleation as determined by crystal violet staining, BrdU and DiI labelling, and flow cytometry as well as video time-lapse analysis. Continuous SSP treatment of A549 cells can preserve PGCCs for at least two months in a resting state. Upon removal of SSP, A549 PGCCs restart to divide and exhibit a proliferation pattern and cellular morphology indistinguishable from cells where PGCCs originally derived from. Thus, SSP-treated A549 cells represent a simple and reliable experimental model for the reversible generation of PGCCs and their subsequent experimental analysis.

scholarly journals Gene Expression Profile of the A549 Human Non-Small Cell Lung Carcinoma Cell Line following Treatment with the Seeds ofDescurainia sophia, a Potential Anticancer Drug

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Bu-Yeo Kim ◽  
Jun Lee ◽  
Sung Joon Park ◽  
Ok-Sun Bang ◽  
No Soo Kim
Keyword(s):  
Gene Expression ◽  
Cancer Cells ◽  
Human Cancer ◽  
Small Cell Lung Carcinoma ◽  
Ethanol Extract ◽  
Inhibitory Effect ◽  
Human Lung Cancer ◽  
Molecular Evidence ◽  
Cell Lung Carcinoma ◽  
Dose Dependent

Descurainia sophiahas been traditionally used in Korean medicine for treatment of diverse diseases and their symptoms, such as cough, asthma, and edema. Our previous results showed that ethanol extract of the seeds ofD. sophia(EEDS) has a potent cytotoxic effect on human cancer cells. In this study, we reveal the molecular events that are induced by EEDS treatment in A549 human lung cancer cells. The dose-dependent effect of EEDS on gene expression was measured via a microarray analysis. Gene ontology and pathway analyses were performed to identify functional involvement of genes regulated by EEDS. From gene expression analyses, two major dose-dependent patterns were observed after EEDS treatment. One pattern consisted of 1,680 downregulated genes primarily involved in metabolic processes (FDR < 0.01). The second pattern consisted of 1,673 upregulated genes primarily involved in signaling processes (FDR < 0.01). Pathway activity analyses revealed that the metabolism-related pathways and signaling-related pathways were regulated by the EEDS in dose-dependent and reciprocal manners. In conclusion, the identified biphasic regulatory mechanism involving activation of signaling pathways may provide molecular evidence to explain the inhibitory effect of EEDS on A549 cell growth.

scholarly journals Structural characterization of centipede oligopeptides and capability detection in human small cell lung carcinoma: inducing apoptosis

RSC Advances ◽  
2019 ◽  
Vol 9 (19) ◽  
pp. 10927-10936
Author(s):  
JingQuan Zhao ◽  
Jianmei Yang ◽  
Zerui Hao ◽  
Yulin An ◽  
Mingqiang Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Lung Carcinoma ◽  
Structural Characterization ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Lung Cancer Cells ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma

SSMO-5 mediated the lung cancer cells apoptosis by activating the caspases and regulating the interaction of p53/MDM2.

scholarly journals The G4 Resolvase DHX36 Possesses a Prognosis Significance and Exerts Tumour Suppressing Function Through Multiple Causal Regulations in Non-Small Cell Lung Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuxin Cui ◽  
Zhilei Li ◽  
Junxia Cao ◽  
Jane Lane ◽  
Emily Birkin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Small Cell Lung Carcinoma ◽  
Peptide Hormone ◽  
Rna Degradation ◽  
Small Cell ◽  
Lung Cancer Cells ◽  
Small Cell Lung ◽  
Protein Activity ◽  
Cell Lung Carcinoma

Lung cancer is one of the most prevalent cancers in both men and women worldwide. The nucleic acid G4 structures have been implicated in the transcriptional programmes of cancer-related genes in some cancers such as lung cancer. However, the role of the dominant G4 resolvase DHX36 in the progression of lung cancer remains unknown. In this study, by bioinformatic analysis of public datasets (TCGA and GEO), we find DHX36 is an independent prognosis indicator in non-small-cell lung carcinoma (NSCLC) with subtype dependence. The stable lentiviral knockdown of the DHX36 results in accelerated migration and aggregation of the S-phase subpopulation in lung cancer cells. The reduction of DHX36 level de-sensitises the proliferation response of lung cancer cells to chemotherapeutic drugs such as paclitaxel with cell dependence. The knockdown of this helicase leads to promoted tumour growth, demonstrated by a 3D fluorescence spheroid lung cancer model, and the stimulation of cell colony formation as shown by single-cell cultivation. High throughput proteomic array indicates that DHX36 functions in lung cancer cells through regulating multiple signalling pathways including activation of protein activity, protein autophosphorylation, Fc-receptor signalling pathway, response to peptide hormone and stress-activated protein kinase signalling cascade. A causal transcriptomic analysis suggests that DHX36 is significantly associated with mRNA surveillance, RNA degradation, DNA replication and Myc targets. Therefore, we unveil that DHX36 presents clinical significance and plays a role in tumour suppression in lung cancer, and propose a potentially new concept for an anti-cancer therapy based on helicase-specific targeting.

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