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Cell Communication and Signaling : CCS Aug 2023Breast cancer exhibits the highest global incidence among all tumor types. Regardless of the type of breast cancer, metastasis is a crucial cause of poor prognosis.... (Review)
Review
Breast cancer exhibits the highest global incidence among all tumor types. Regardless of the type of breast cancer, metastasis is a crucial cause of poor prognosis. Anoikis, a form of apoptosis initiated by cell detachment from the native environment, is an outside-in process commencing with the disruption of cytosolic connectors such as integrin-ECM and cadherin-cell. This disruption subsequently leads to intracellular cytoskeletal and signaling pathway alterations, ultimately activating caspases and initiating programmed cell death. Development of an anoikis-resistant phenotype is a critical initial step in tumor metastasis. Breast cancer employs a series of stromal alterations to suppress anoikis in cancer cells. Comprehensive investigation of anoikis resistance mechanisms can inform strategies for preventing and regressing metastatic breast cancer. The present review first outlines the physiological mechanisms of anoikis, elucidating the alterations in signaling pathways, cytoskeleton, and protein targets that transpire from the outside in upon adhesion loss in normal breast cells. The specific anoikis resistance mechanisms induced by pathological changes in various spatial structures during breast cancer development are also discussed. Additionally, the genetic loci of targets altered in the development of anoikis resistance in breast cancer, are summarized. Finally, the micro-RNAs and targeted drugs reported in the literature concerning anoikis are compiled, with keratocin being the most functionally comprehensive. Video Abstract.
Topics: Humans; Anoikis; Signal Transduction; Neoplasms; Integrins; Cytoskeleton; Cell Line, Tumor
PubMed: 37537585
DOI: 10.1186/s12964-023-01183-4 -
Genes & Development Apr 2016Primary tumors are known to constantly shed a large number of cancer cells into systemic dissemination, yet only a tiny fraction of these cells is capable of forming... (Review)
Review
Primary tumors are known to constantly shed a large number of cancer cells into systemic dissemination, yet only a tiny fraction of these cells is capable of forming overt metastases. The tremendous rate of attrition during the process of metastasis implicates the existence of a rare and unique population of metastasis-initiating cells (MICs). MICs possess advantageous traits that may originate in the primary tumor but continue to evolve during dissemination and colonization, including cellular plasticity, metabolic reprogramming, the ability to enter and exit dormancy, resistance to apoptosis, immune evasion, and co-option of other tumor and stromal cells. Better understanding of the molecular and cellular hallmarks of MICs will facilitate the development and deployment of novel therapeutic strategies.
Topics: Animals; Anoikis; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Humans; Neoplasm Metastasis; Neoplasms; Neoplastic Stem Cells
PubMed: 27083997
DOI: 10.1101/gad.277681.116 -
Journal of Experimental & Clinical... Oct 2023Epstein-Barr virus (EBV) is the first discovered human tumor virus that is associated with a variety of malignancies of both lymphoid and epithelial origin including...
Anoikis resistance and immune escape mediated by Epstein-Barr virus-encoded latent membrane protein 1-induced stabilization of PGC-1α promotes invasion and metastasis of nasopharyngeal carcinoma.
BACKGROUND
Epstein-Barr virus (EBV) is the first discovered human tumor virus that is associated with a variety of malignancies of both lymphoid and epithelial origin including nasopharyngeal carcinoma (NPC). The EBV-encoded latent membrane protein 1 (LMP1) has been well-defined as a potent oncogenic protein, which is intimately correlated with NPC pathogenesis. Anoikis is considered to be a physiological barrier to metastasis, and avoiding anoikis is a major hallmark of metastasis. However, the role of LMP1 in anoikis-resistance and metastasis of NPC has not been fully identified.
METHODS
Trypan blue staining, colony formation assay, flow cytometry, and TUNEL staining, as well as the detection of apoptosis and anoikis resistance-related markers was applied to evaluate the anoikis-resistant capability of NPC cells cultured in ultra-low adhesion condition. Co-immunoprecipitation (Co-IP) experiment was performed to determine the interaction among LMP1, PRMT1 and PGC-1α. Ex vivo ubiquitination assay was used to detect the ubiquitination level of PGC-1α. Anoikis- resistant LMP1-positive NPC cell lines were established and applied for the xenograft and metastatic animal experiments.
RESULTS
Our current findings reveal the role of LMP1-stabilized peroxisome proliferator activated receptor coactivator-1a (PGC-1α) in anoikis resistance and immune escape to support the invasion and metastasis of NPC. Mechanistically, LMP1 enhances PGC-1α protein stability by promoting the interaction between arginine methyltransferase 1 (PRMT1) and PGC-1α to elevate the methylation modification of PGC-1α, thus endowing NPC cells with anoikis-resistance. Meanwhile, PGC-1α mediates the immune escape induced by LMP1 by coactivating with STAT3 to transcriptionally up-regulate PD-L1 expression.
CONCLUSION
Our work provides insights into how virus-encoded proteins recruit and interact with host regulatory elements to facilitate the malignant progression of NPC. Therefore, targeting PGC-1α or PRMT1-PGC-1α interaction might be exploited for therapeutic gain for EBV-associated malignancies.
Topics: Animals; Humans; Nasopharyngeal Carcinoma; Herpesvirus 4, Human; Anoikis; Nasopharyngeal Neoplasms; Carcinoma; Epstein-Barr Virus Infections; Membrane Proteins; Viral Matrix Proteins; Cell Line, Tumor; Protein-Arginine N-Methyltransferases; Repressor Proteins
PubMed: 37803433
DOI: 10.1186/s13046-023-02835-6 -
Frontiers in Immunology 2023Anoikis is a programmed cell death process that was proven to be associated with cancer. Uroepithelial carcinoma of the bladder (BLCA) is a malignant disease of the...
BACKGROUND
Anoikis is a programmed cell death process that was proven to be associated with cancer. Uroepithelial carcinoma of the bladder (BLCA) is a malignant disease of the urinary tract and has a strong metastatic potential. To determine whether anoikis-associated genes can predict the prognosis of BLCA accurately, we evaluated the prognostic value of anoikis-associated genes in BLCA and constructed the best model to predict prognosis.
METHOD
The BLCA transcriptome data were downloaded from TCGA and GEO databases, and genes with differential expression were selected and then clustered using non-negative matrix factorization (NMF). The genes with the most correlation with anoikis were screened and identified using univariate Cox regression, lasso regression, and multivariate Cox regression. The GEO dataset was used for external validation. Nomograms were created based on risk characteristics in combination with clinical variants and the performance of the model was validated with receiver operating characteristic (ROC) curves. The immunotherapeutic significance of this risk score was assessed using the immune phenomenon score (IPS). IC50 values of predictive chemotherapeutic agents were calculated. Finally, we used RT-qPCR to determine the mRNA expression of four genes, , , , and .
RESULT
We screened 406 tumor samples and 19 normal tissue samples from the TCGA database. Based on anoikis-associated genes, we classified patients into two subtypes (C1 and C2) using NMF method. Subsequently, nine core genes were screened by multiple methods after analysis, which were used to construct risk profiles. The design of nomograms based on risk profiles and clinical variables, ROC, and calibration curves confirmed that the model could well have the ability to predict the survival of BLCA patients at 1, 3, and 5 years. By predicting the IC50 values of chemotherapeutic drugs, it was learned that the high-risk group (HRG) was more susceptible to paclitaxel, gemcitabine, and cisplatin, and the low-risk group (LRG) was more susceptible to veriparib and afatinib.
CONCLUSION
In summary, the risk score of anoikis-associated genes can be applied as a predictor to predict the prognosis of BLCA in clinical practice.
Topics: Humans; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Urinary Bladder; Anoikis; Genes, cdc
PubMed: 37275895
DOI: 10.3389/fimmu.2023.1122570 -
Critical Reviews in Oncogenesis 2016Anoikis is a unique mode of apoptotic cell death that occurs consequentially to insufficient cell-matrix interactions. Resistance to anoikis is a critical contributor to... (Review)
Review
Anoikis is a unique mode of apoptotic cell death that occurs consequentially to insufficient cell-matrix interactions. Resistance to anoikis is a critical contributor to tumor invasion and metastasis. The phenomenon is regulated by integrins, which upon engagement with components of the extracellular matrix (ECM) form adhesion complexes and the actin cytoskeleton drives the formation of cell protrusions used to adhere to ECM, directing cell migration. The epithelial-mesenchymal transition (EMT) confers stem cell properties and leads to acquisition of a migratory and invasive phenotype by causing adherens junction breakdown and circumventing anoikis in the tumor microenvironment. The investigation of drug discovery platforms for apoptosis-driven therapeutics identified several novel agents with antitumor action via reversing resistance to anoikis, inhibiting survival pathways and impacting the EMT landscape in human cancer. In this review, we discuss current evidence on the contribution of the anoikis phenomenon functionally linked to EMT to cancer metastasis and the therapeutic value of antitumor drugs that selectively reverse anoikis resistance and/or EMT to impair tumor progression toward the development/optimization of apoptosis-driven therapeutic targeting of metastatic disease.
Topics: Animals; Anoikis; Antineoplastic Agents; Disease Progression; Epithelial-Mesenchymal Transition; Female; Humans; Male; Neoplasms
PubMed: 27915969
DOI: 10.1615/CritRevOncog.2016016955 -
Molecular Therapy. Nucleic Acids Jun 2021Viral infections lead to the death of more than a million people each year around the world, both directly and indirectly. Viruses interfere with many cell functions,... (Review)
Review
Viral infections lead to the death of more than a million people each year around the world, both directly and indirectly. Viruses interfere with many cell functions, particularly critical pathways for cell death, by affecting various intracellular mediators. MicroRNAs (miRNAs) are a major example of these mediators because they are involved in many (if not most) cellular mechanisms. Virus-regulated miRNAs have been implicated in three cell death pathways, namely, apoptosis, autophagy, and anoikis. Several molecules (e.g., BECN1 and B cell lymphoma 2 [BCL2] family members) are involved in both apoptosis and autophagy, while activation of anoikis leads to cell death similar to apoptosis. These mechanistic similarities suggest that common regulators, including some miRNAs (e.g., miR-21 and miR-192), are involved in different cell death pathways. Because the balance between cell proliferation and cell death is pivotal to the homeostasis of the human body, miRNAs that regulate cell death pathways have drawn much attention from researchers. miR-21 is regulated by several viruses and can affect both apoptosis and anoikis via modulating various targets, such as PDCD4, PTEN, interleukin (IL)-12, Maspin, and Fas-L. miR-34 can be downregulated by viral infection and has different effects on apoptosis, depending on the type of virus and/or host cell. The present review summarizes the existing knowledge on virus-regulated miRNAs involved in the modulation of cell death pathways. Understanding the mechanisms for virus-mediated regulation of cell death pathways could provide valuable information to improve the diagnosis and treatment of many viral diseases.
PubMed: 33898103
DOI: 10.1016/j.omtn.2021.03.011 -
Frontiers in Molecular Biosciences 2023To investigate the potential association between Anoikis-related genes, which are responsible for preventing abnormal cellular proliferation, and rheumatoid arthritis...
To investigate the potential association between Anoikis-related genes, which are responsible for preventing abnormal cellular proliferation, and rheumatoid arthritis (RA). Datasets GSE89408, GSE198520, and GSE97165 were obtained from the GEO with 282 RA patients and 28 healthy controls. We performed differential analysis of all genes and genes. We performed a protein-protein interaction network analysis and identified hub genes based on and cytoscape. Consistent clustering was performed with subgrouping of the disease. SsGSEA were used to calculate immune cell infiltration. Spearman's correlation analysis was employed to identify correlations. Enrichment scores of the GO and KEGG were calculated with the ssGSEA algorithm. The WGCNA and the database were used to mine hub genes' interactions with drugs. There were 26 differentially expressed Anoikis-related genes ( = 0.05, log2FC = 1) and HLA genes exhibited differential expression ( < 0.05) between the disease and control groups. Protein-protein interaction was observed among differentially expressed genes, and the correlation between and was found to be the highest; There were significant differences in the degree of immune cell infiltration between most of the immune cell types in the disease group and normal controls ( < 0.05). Anoikis-related genes were highly correlated with HLA genes. Based on the expression of Anoikis-related genes, RA patients were divided into two disease subtypes (cluster1 and cluster2). There were 59 differentially expressed Anoikis-related genes found, which exhibited significant differences in functional enrichment, immune cell infiltration degree, and gene expression ( < 0.05). Cluster2 had significantly higher levels in all aspects than cluster1 did. The co-expression network analysis showed that cluster1 had 51 hub differentially expressed genes and cluster2 had 72 hub differentially expressed genes. Among them, three hub genes of cluster1 were interconnected with 187 drugs, and five hub genes of cluster2 were interconnected with 57 drugs. Our study identified a link between Anoikis-related genes and RA, and two distinct subtypes of RA were determined based on Anoikis-related gene expression. Notably, cluster2 may represent a more severe state of RA.
PubMed: 38046810
DOI: 10.3389/fmolb.2023.1202371 -
Organogenesis 2018Diabetes can be treated with β cell replacement therapy, where a patient is transplanted with cadaveric human islets to restore glycemic control. Despite this being an... (Review)
Review
Diabetes can be treated with β cell replacement therapy, where a patient is transplanted with cadaveric human islets to restore glycemic control. Despite this being an effective treatment, the process of isolating islets from the pancreas requires collagenase digestion which disrupts the islet extracellular matrix (ECM) and activates anoikis-mediated apoptosis. To improve islet survival in culture and after transplantation, the islet microenvironment may be enhanced with the addition of ECM components which are lost during isolation. Furthermore, novel β cell replacement strategies, such as stem cell-derived beta cell (SCβC) treatments or alternative transplant sites and devices, could benefit from a better understanding of how β cells interact with ECM. In this mini-review, we discuss the current understanding of the pancreas and islet ECM composition and review decellularization approaches to generate a native pancreatic ECM scaffold for use in both islet and SCβC culture and transplantation.
Topics: Animals; Anoikis; Extracellular Matrix; Humans; Islets of Langerhans Transplantation; Tissue Engineering
PubMed: 30252586
DOI: 10.1080/15476278.2018.1517509 -
Frontiers in Endocrinology 2023Prostate cancer is one of the most common malignancies in males wherein 1 in 8 men are diagnosed with this disease in their lifetime. The urgency to find novel... (Review)
Review
Prostate cancer is one of the most common malignancies in males wherein 1 in 8 men are diagnosed with this disease in their lifetime. The urgency to find novel therapeutic interventions is associated with high treatment resistance and mortality rates associated with castration-resistant prostate cancer. Anoikis is an apoptotic phenomenon for normal epithelial or endothelial cells that have lost their attachment to the extracellular matrix (ECM). Tumor cells that lose their connection to the ECM can die via apoptosis or survive via anoikis resistance and thus escaping to distant organs for metastatic progression. This review discusses the recent advances made in our understanding of the signaling effectors of anoikis in prostate cancer and the approaches to translate these mechanistic insights into therapeutic benefits for reducing lethal disease outcomes (by overcoming anoikis resistance). The prostate tumor microenvironment is a highly dynamic landscape wherein the balance between androgen signaling, cell lineage changes, epithelial-mesenchymal transition (EMT), extracellular matrix interactions, actin cytoskeleton remodeling as well as metabolic changes, confer anoikis resistance and metastatic spread. Thus, these mechanisms also offer unique molecular treatment signatures, exploitation of which can prime prostate tumors to anoikis induction with a high translational significance.
Topics: Male; Humans; Anoikis; Prostate; Tumor Microenvironment; Endothelial Cells; Prostatic Neoplasms
PubMed: 37091854
DOI: 10.3389/fendo.2023.1160267 -
Cancer Cell Sep 2017Most metastasizing tumor cells reach distant sites by entering the circulatory system. Within the bloodstream, they are exposed to severe stress due to loss of adhesion... (Review)
Review
Most metastasizing tumor cells reach distant sites by entering the circulatory system. Within the bloodstream, they are exposed to severe stress due to loss of adhesion to extracellular matrix, hemodynamic shear forces, and attacks of the immune system, and only a few cells manage to extravasate and to form metastases. We review the current understanding of the cellular and molecular mechanisms that allow tumor cells to survive in the intravascular environment and that mediate and promote tumor cell extravasation. As these processes are critical for the metastatic spread of tumor cells, we discuss implications for potential therapeutic approaches and future research.
Topics: Animals; Anoikis; Cell Survival; Extravasation of Diagnostic and Therapeutic Materials; Humans; Immune System; Neoplastic Cells, Circulating; Stress, Mechanical
PubMed: 28898694
DOI: 10.1016/j.ccell.2017.07.001