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Pharmacology & Therapeutics Oct 2023Metastatic progression combined with non-responsiveness towards systemic therapy often shapes the course of disease for cancer patients and commonly determines its... (Review)
Review
Metastatic progression combined with non-responsiveness towards systemic therapy often shapes the course of disease for cancer patients and commonly determines its lethal outcome. The complex molecular events that promote metastasis are a combination of both, the acquired pro-metastatic properties of cancer cells and a metastasis-permissive or -supportive tumor micro-environment (TME). Yet, dissemination is a challenging process for cancer cells that requires a series of events to enable cancer cell survival and growth. Metastatic cancer cells have to initially detach themselves from primary tumors, overcome the challenges of their intravasal journey and colonize distant sites that are suited for their metastases. The implicated obstacles including anoikis and immune surveillance, can be overcome by intricate intra- and extracellular signaling pathways, which we will summarize and discuss in this review. Further, emerging modulators of metastasis, like the immune-microenvironment, microbiome, sublethal cell death engagement, or the nervous system will be integrated into the existing working model of metastasis.
Topics: Humans; Neoplasms; Signal Transduction; Anoikis; Neoplasm Metastasis; Epithelial-Mesenchymal Transition; Tumor Microenvironment
PubMed: 37661054
DOI: 10.1016/j.pharmthera.2023.108522 -
Oncogene Nov 2018Anoikis is a critical obstacle to cancer metastasis. Colorectal cancer (CRC) exhibits a high rate of metastasis, leading to death, and the mechanisms involved in anoikis...
Anoikis is a critical obstacle to cancer metastasis. Colorectal cancer (CRC) exhibits a high rate of metastasis, leading to death, and the mechanisms involved in anoikis resistance are still unclear. We identified that the fatty acid oxidation (FAO) pathway was activated in detached CRC cells. Multiple genes in the FAO pathway, specifically the rate-limiting enzyme CPT1A, were upregulated in CRC cells grown in suspension. Reactive oxygen species elimination mediated by CPT1A in CRC cells was vital to anoikis resistance. In vivo experiments showed that CPT1A-suppressed CRC cells colonized the lung at a much lower rate than normal CRC cells, suggesting that CPT1A-mediated FAO activation increased metastatic capacity. In clinical tissue specimens from CRC patients, elevated expression of CPT1A was observed in metastatic sites compared with primary sites. Our results demonstrate that CPT1A-mediated FAO activation induces CRC cells to resist anoikis, suggesting that CPT1A is an attractive target for treating metastatic CRC.
Topics: Animals; Anoikis; Caco-2 Cells; Carnitine O-Palmitoyltransferase; Cell Line, Tumor; Colorectal Neoplasms; Fatty Acids; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Humans; Lipid Metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Oxidation-Reduction; Reactive Oxygen Species
PubMed: 29995871
DOI: 10.1038/s41388-018-0384-z -
Journal of Cellular Biochemistry Mar 2018Anoikis is known as a special type of programmed cell death which occurs in response to loss of correct cell-extracellular matrix (ECM) connections. This process could... (Review)
Review
Anoikis is known as a special type of programmed cell death which occurs in response to loss of correct cell-extracellular matrix (ECM) connections. This process could be as pivotal event in normal development and tissue homeostasis and found as important mechanism in cancer invasiveness and metastasis. The persistent infection with oncoviruses including EBV (Epstein Bar virus), HPV (Human Papillomaviruses), HBV (Hepatitis B virus), KSHV (Human herpesvirus 8), HTLV-1 (Human T-lymphotropic virus-1), and HCV (Hepatitis C virus) accounted as one of main risk factor for cancer progression. Some of them play critical roles in metastasis, especially in anoikis resistance which could contribute to metastasis of tumor cells. The better understanding of effects of oncoviruses on anoikis could contribute to finding of effective therapeutic platforms for treatment of virus-associated cancers. This paper highlighted effects of these oncoviruses on anoikis protection in cancer.
Topics: Animals; Anoikis; Humans; Neoplasms; Retroviridae
PubMed: 28836703
DOI: 10.1002/jcb.26363 -
Cell Communication and Signaling : CCS Sep 2023Metastatic cancer cells can develop anoikis resistance in the absence of substrate attachment and survive to fight tumors. Anoikis is mediated by endogenous... (Review)
Review
Metastatic cancer cells can develop anoikis resistance in the absence of substrate attachment and survive to fight tumors. Anoikis is mediated by endogenous mitochondria-dependent and exogenous death receptor pathways, and studies have shown that caspase-8-dependent external pathways appear to be more important than the activity of the intrinsic pathways. This paper reviews the regulation of anoikis by external pathways mediated by death receptors. Different death receptors bind to different ligands to activate downstream caspases. The possible mechanisms of Fas-associated death domain (FADD) recruitment by Fas and TNF receptor 1 associated-death domain (TRADD) recruitment by tumor necrosis factor receptor 1 (TNFR1), and DR4- and DR5-associated FADD to induce downstream caspase activation and regulate anoikis were reviewed. This review highlights the possible mechanism of the death receptor pathway mediation of anoikis and provides new insights and research directions for studying tumor metastasis mechanisms. Video Abstract.
Topics: Anoikis; Proteolysis; Caspases; Mitochondria; Protein Processing, Post-Translational
PubMed: 37667281
DOI: 10.1186/s12964-023-01247-5 -
Thoracic Cancer Jan 2023Lung adenocarcinoma (LUAD) is the most prevalent histotype of non-small cell lung cancer. Anoikis, an alternative form of programmed cell death, plays a pivotal role in...
BACKGROUND
Lung adenocarcinoma (LUAD) is the most prevalent histotype of non-small cell lung cancer. Anoikis, an alternative form of programmed cell death, plays a pivotal role in cancer invasion and metastasis, preventing the detached cancer cells from readhering to other substrates for abnormal proliferation. The aim of this study was to conduct a comprehensive analyses of the prognostic implications of anoikis-related genes (ARGs) in LUAD.
METHODS
ARGs were selected from The Cancer Genome Atlas (TCGA) database and Genecards dataset using differential expression analysis. The signature incorporating ARGs was identified using univariate Cox regression analysis and LASSO regression analysis. Furthermore, a nomogram containing the signature and clinical information was developed through univariate and multivariate Cox regression analysis. Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curves were applied to evaluate the predictive validity of these risk models. Finally, functional analysis of the selected ARGs in signature and analysis of immune landscape were also conducted.
RESULTS
A 16-gene signature was integrated to stratify LUAD patients into different survival risk groups. The prognostic risk score generated from the signature and TNM stage were identified as independent prognostic factors and utilized to develop a nomogram. Both the signature and the nomogram showed satisfactory prediction performance in predicting overall survival (OS) of LUAD patients. The ARGs were enriched in several biological functions and signaling pathways. Finally, differences of immune landscape were investigated among the high- and low-risk groups stratified by the signature.
CONCLUSIONS
This study revealed potential relationships between ARGs and prognosis of LUAD. The prognostic predictors identified in present study could be utilized as potential biomarkers for clinical applications.
Topics: Humans; Anoikis; Carcinoma, Non-Small-Cell Lung; Tumor Microenvironment; Lung Neoplasms; Prognosis; Adenocarcinoma of Lung
PubMed: 36507553
DOI: 10.1111/1759-7714.14766 -
Science Signaling Mar 2023Membrane blebs form signaling hubs that enable tumor cells to resist death by anoikis.
Membrane blebs form signaling hubs that enable tumor cells to resist death by anoikis.
Topics: Anoikis; Signal Transduction
PubMed: 36976865
DOI: 10.1126/scisignal.adh9176 -
Cell Death & Disease Sep 2021Tumor cells require high levels of cholesterol for membrane biogenesis for rapid proliferation during development. Beyond the acquired cholesterol from low-density...
Tumor cells require high levels of cholesterol for membrane biogenesis for rapid proliferation during development. Beyond the acquired cholesterol from low-density lipoprotein (LDL) taken up from circulation, tumor cells can also biosynthesize cholesterol. The molecular mechanism underlying cholesterol anabolism in esophageal squamous cell carcinoma (ESCC) and its effect on patient prognosis are unclear. Dysregulation of lipid metabolism is common in cancer. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been implicated in various cancer types; however, its role in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we identified that LPCAT1 is highly expressed in ESCC and that LPCAT1 reprograms cholesterol metabolism in ESCC. LPCAT1 expression was negatively correlated with patient prognosis. Cholesterol synthesis in ESCC cells was significantly inhibited following LPCAT1 knockdown; cell proliferation, invasion, and migration were significantly reduced, along with the growth of xenograft subcutaneous tumors. LPCAT1 could regulate the expression of the cholesterol synthesis enzyme, SQLE, by promoting the activation of PI3K, thereby regulating the entry of SP1/SREBPF2 into the nucleus. LPCAT1 also activates EGFR leading to the downregulation of INSIG-1 expression, facilitating the entry of SREBP-1 into the nucleus to promote cholesterol synthesis. Taken together, LPCAT1 reprograms tumor cell cholesterol metabolism in ESCC and can be used as a potential treatment target against ESCC.
Topics: 1-Acylglycerophosphocholine O-Acyltransferase; Animals; Anoikis; Apoptosis; Base Sequence; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cholesterol; Disease Progression; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Inbred NOD; Mice, SCID; Middle Aged; Neoplasm Invasiveness; Neoplasm Proteins; Prognosis; Signal Transduction; Transcription Factors; Transcription, Genetic; Up-Regulation; Mice
PubMed: 34518524
DOI: 10.1038/s41419-021-04132-6 -
Drug Resistance Updates : Reviews and... Jul 2024Anoikis, known as matrix detachment-induced apoptosis or detachment-induced cell death, is crucial for tissue development and homeostasis. Cancer cells develop means to... (Review)
Review
Anoikis, known as matrix detachment-induced apoptosis or detachment-induced cell death, is crucial for tissue development and homeostasis. Cancer cells develop means to evade anoikis, e.g. anoikis resistance, thereby allowing for cells to survive under anchorage-independent conditions. Uncovering the mechanisms of anoikis resistance will provide details about cancer metastasis, and potential strategies against cancer cell dissemination and metastasis. Here, we summarize the principal elements and core molecular mechanisms of anoikis and anoikis resistance. We discuss the latest progress of how anoikis and anoikis resistance are regulated in cancers. Furthermore, we summarize emerging data on selective compounds and nanomedicines, explaining how inhibiting anoikis resistance can serve as a meaningful treatment modality against cancers. Finally, we discuss the key limitations of this therapeutic paradigm and possible strategies to overcome them. In this review, we suggest that pharmacological modulation of anoikis and anoikis resistance by bioactive compounds could surmount anoikis resistance, highlighting a promising therapeutic regimen that could be used to overcome anoikis resistance in cancers.
Topics: Anoikis; Humans; Neoplasms; Antineoplastic Agents; Animals; Drug Resistance, Neoplasm; Neoplasm Metastasis
PubMed: 38850692
DOI: 10.1016/j.drup.2024.101099 -
International Journal of Molecular... Feb 2021Fibrinolytic factors like plasminogen, tissue-type plasminogen activator (tPA), and urokinase plasminogen activator (uPA) dissolve clots. Though mere... (Review)
Review
Fibrinolytic factors like plasminogen, tissue-type plasminogen activator (tPA), and urokinase plasminogen activator (uPA) dissolve clots. Though mere extracellular-matrix-degrading enzymes, fibrinolytic factors interfere with many processes during primary cancer growth and metastasis. Their many receptors give them access to cellular functions that tumor cells have widely exploited to promote tumor cell survival, growth, and metastatic abilities. They give cancer cells tools to ensure their own survival by interfering with the signaling pathways involved in senescence, anoikis, and autophagy. They can also directly promote primary tumor growth and metastasis, and endow tumor cells with mechanisms to evade myelosuppression, thus acquiring drug resistance. In this review, recent studies on the role fibrinolytic factors play in metastasis and controlling cell-death-associated processes are presented, along with studies that describe how cancer cells have exploited plasminogen receptors to escape myelosuppression.
Topics: Anoikis; Autophagy; Cell Survival; Cellular Senescence; Drug Resistance, Neoplasm; Exosomes; Extracellular Matrix; Humans; Neoplasm Metastasis; Neoplasms; Plasminogen; Plasminogen Inactivators; Signal Transduction
PubMed: 33669052
DOI: 10.3390/ijms22052304 -
Oncogene Dec 2023The tripartite motif (TRIM) protein family has been investigated in multiple human cancers, including gastric cancer (GC). However, the role of TRIM69 in the anoikis...
The tripartite motif (TRIM) protein family has been investigated in multiple human cancers, including gastric cancer (GC). However, the role of TRIM69 in the anoikis resistance and metastasis of GC cells remains to be elucidated. We identified the differentially expressed genes in anoikis-resistant GC cells using RNA-sequencing analysis. The interaction between TRIM69 and PRKCD was analyzed by coimmunoprecipitation and mass spectrometry. Our results have shown that TRIM69 was significantly downregulated in anoikis-resistant GC cells. TRIM69 overexpression markedly suppressed the anoikis resistance and metastasis of GC cells in vitro and in vivo. TRIM69 knockdown had the opposite effects. Mechanistically, TRIM69 interacted with PRKCD through its B-box domain and catalyzed the K48-linked polyubiquitination of PRKCD. Moreover, TRIM69 inhibited BDNF production in a PRKCD-dependent manner. Importantly, overexpression of PRKCD or BDNF blocked the effects of TRIM69 on the anoikis resistance and metastasis of GC cells. Interestingly, a TRIM69PRKCDBDNF cell subset was positively associated with metastasis in GC patients. TRIM69-mediated suppression of the anoikis resistance and metastasis of GC cells via modulation of the PRKCD/BDNF axis, with potential implications for novel therapeutic approaches for metastatic GC.
Topics: Humans; Anoikis; Brain-Derived Neurotrophic Factor; Cell Line, Tumor; Neoplasm Metastasis; Proteasome Endopeptidase Complex; Protein Kinase C-delta; Stomach Neoplasms; Tripartite Motif Proteins; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 37864033
DOI: 10.1038/s41388-023-02873-6