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Ferroptosis, Necroptosis, and Pyroptosis in Gastrointestinal Cancers: The Chief Culprits of Tumor Progression and Drug Resistance.

ABSTRACT: In recent years, the incidence of gastrointestinal cancers is increasing, particularly in the younger population. Effective treatment is crucial for improving patients' survival outcomes. Programmed cell death, regulated by various genes, plays a fundamental role in the growth and development of organisms. It is also critical for maintaining tissue and organ homeostasis and takes part in multiple pathological processes. In addition to apoptosis, there are other types of programmed cell death, such as ferroptosis, necroptosis, and pyroptosis, which can induce severe inflammatory responses. Notably, besides apoptosis, ferroptosis, necroptosis, and pyroptosis also contribute to the occurrence and development of gastrointestinal cancers. This review aims to provide a comprehensive summary on the biological roles and molecular mechanisms of ferroptosis, necroptosis, and pyroptosis, as well as their regulators in gastrointestinal cancers and hope to open up new paths for tumor targeted therapy in the near future.

SUBMITTER: Zhu X

PROVIDER: S-EPMC10502844 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Ferroptosis, Necroptosis, and Pyroptosis in Gastrointestinal Cancers: The Chief Culprits of Tumor Progression and Drug Resistance.

Zhu Xudong X Li Shenglong S

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230712 26

In recent years, the incidence of gastrointestinal cancers is increasing, particularly in the younger population. Effective treatment is crucial for improving patients' survival outcomes. Programmed cell death, regulated by various genes, plays a fundamental role in the growth and development of organisms. It is also critical for maintaining tissue and organ homeostasis and takes part in multiple pathological processes. In addition to apoptosis, there are other types of programmed cell death, su ...[more]

PMID: 37436087

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Project description:This study aims to visualize research hotspots and trends of "ferroptosis in cancer", "necroptosis in cancer", "pyroptosis in cancer", and "cuproptosis in cancer" through a bibliometric analysis to facilitate understanding of future developments in basic and clinical research and to provide a new perspective on cancer treatment. From January 1, 2012 to October 31, 2022, in the field of "ferroptosis in cancer", a total of 2467 organizations from 79 different countries published 3302 articles. 2274 organizations from 72 different countries published 2233 articles in the field of " necroptosis in cancer". 1366 institutions from 58 different countries contributed 1445 publications in the field of "pyroptosis in cancer". In the field of " cuproptosis in cancer", the number of articles published in the last 10 years is relatively low, with a total of 109 articles published by 116 institutions from four different countries. In the field of "ferroptosis in cancer", Tang Daolin had published 66 documents, ranked the first, while Dixon SJ is the most cited author, cited 3148 times; In the fields of "necroptosis in cancer", Vandenabeele peter had published 35 papers and Degterev had been cited 995 times, ranked the first, respectively; Kanneganti thirumala-devi had published 24 papers, is the highest number of publications in the fields of "pyroptosis in cancer", while Shi JJ was the most cited author with being cited 508 times. Both Huang Yan and Wang Tao published three papers and tied for first place and Tsvetkov p ranks first with being cited 107 times in "cuproptosis in cancer". "Cell", "Cell", "Nature", and "Science" was the most frequently co-cited journal on "ferroptosis in cancer", "necroptosis in cancer", "pyroptosis in cancer", and "cuproptosis in cancer", respectively. Further exploration of inhibitors of different Programmed cell death (PCD) and their targeted therapies are potential treatment options for cancer, but more direct clinical evidence as well as higher level clinical trials remain to be explored. Further clarification of the mechanisms of crosstalk between these PCDs may provide effective cancer treatments. And the role of different types of PCDs, especially the novel ones discovered, in cancer can be expected to remain a hot topic of research in the cancer field for quite some time to come.

Project description:Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various biological activities, including the clearance of aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target for the development of cancer medications in recent years. However, because tumor cells show avoidance to apoptosis, which causes treatment resistance and recurrence, numerous studies have been devoted to alternative cancer cell mortality processes, namely necroptosis, pyroptosis, ferroptosis, and cuproptosis; these RCD modalities have been extensively studied and shown to be crucial to cancer therapy effectiveness. Furthermore, evidence suggests that tumor cells undergoing regulated death may alter the immunogenicity of the tumor microenvironment (TME) to some extent, rendering it more suitable for inhibiting cancer progression and metastasis. In addition, other types of cells and components in the TME undergo the abovementioned forms of death and induce immune attacks on tumor cells, resulting in enhanced antitumor responses. Hence, this review discusses the molecular processes and features of necroptosis, pyroptosis, ferroptosis, and cuproptosis and the effects of these novel RCD modalities on tumor cell proliferation and cancer metastasis. Importantly, it introduces the complex effects of novel forms of tumor cell death on the TME and the regulated death of other cells in the TME that affect tumor biology. It also summarizes the potential agents and nanoparticles that induce or inhibit novel RCD pathways and their therapeutic effects on cancer based on evidence from in vivo and in vitro studies and reports clinical trials in which RCD inducers have been evaluated as treatments for cancer patients. Lastly, we also summarized the impact of modulating the RCD processes on cancer drug resistance and the advantages of adding RCD modulators to cancer treatment over conventional treatments.

Project description:Introduction: Periodontitis is a chronic inflammatory oral disease that destroys soft and hard periodontal support tissues. Multiple cell death modes including apoptosis, necroptosis, pyroptosis, and ferroptosis play a crucial role in the pathogenicity of inflammatory diseases. This study aimed to identify genes associated with ferroptosis, necroptosis, and pyroptosis in different cells present in the periodontium of periodontitis patients. Methods: Gingival tissues' mRNA sequencing dataset GSE173078 of 12 healthy control and 12 periodontitis patients' and the microarray dataset GSE10334 of 63 healthy controls and 64 periodontitis patients' were obtained from Gene Expression Omnibus (GEO) database. A total of 910 differentially expressed genes (DEGs) obtained in GSE173078 were intersected with necroptosis, pyroptosis, and ferroptosis-related genes to obtain the differential genes associated with cell death (DCDEGs), and the expression levels of 21 differential genes associated with cell death were verified with dataset GSE10334. Results: Bioinformatic analysis revealed 21 differential genes associated with cell death attributed to ferroptosis, pyroptosis, and necroptosis in periodontitis patients compared with healthy controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed that 21 differential genes associated with cell death were related to various cellular and immunological pathways including inflammatory responses, necroptosis, and osteoclast differentiation. Additionally, the single-cell RNA (scRNA) sequencing data GSE171213 of 4 healthy controls and 5 periodontitis patients' periodontal tissue was analyzed to obtain cell clustering and cell types attributed to differential genes associated with cell death. We found that among 21 DCDEGs, SLC2A3, FPR2, TREM1, and IL1B were mainly upregulated in neutrophils present in the periodontium of periodontitis patients. Gene overlapping analysis revealed that IL-1B is related to necroptosis and pyroptosis, TREM1 and FPR2 are related to pyroptosis, and SLC2A3 is related to ferroptosis. Finally, we utilized the CIBERSORT algorithm to assess the association between DCDEGs and immune infiltration phenotypes, based on the gene expression profile of GSE10334. The results revealed that the upregulated SLC2A3, FPR2, TREM1, and IL1B were positively correlated with neutrophil infiltration in the periodontium. Discussion: The findings provide upregulated SLC2A3, FPR2, TREM1, and IL1B in neutrophils as a future research direction on the mode and mechanism of cell death in periodontitis and their role in disease pathogenicity.

Project description:Background Fibroblast activation protein (FAP) is a cell-surface serine protease that has both dipeptidyl peptidase as well as endopeptidase activities and could cleave substrates at post-proline bond. Previous findings showed that FAP was hard to be detected in normal tissues but significantly up-regulated in remodeling sites like fibrosis, atherosclerosis, arthritis and embryonic tissues. Though increasing evidence has demonstrated the importance of FAP in cancer progression, no multifactorial analysis has been developed to investigate its function in gastrointestinal cancers until now. Methods By comprehensive use of datasets from The Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), scTIME Portal and Human Protein Atlas (HPA), we evaluated the carcinogenesis potential of FAP in gastrointestinal cancers, analyzing the correlation between FAP and poor outcomes, immunology in liver, colon, pancreas as well as stomach cancers. Then liver cancer was selected as example to experimentally validate the pro-tumor and immune regulative role of FAP in gastrointestinal cancers. Results FAP was abundantly expressed in gastrointestinal cancers, such as LIHC, COAD, PAAD and STAD. Functional analysis indicated that the highly-expressed FAP in these cancers could affect extracellular matrix organization process and interacted with genes like COL1A1, COL1A2, COL3A1 and POSTN. In addition, it was also observed that FAP was positively correlated to M2 macrophages infiltration across these cancers. To verify these findings in vitro, we used LIHC as example and over-expressed FAP in human hepatic stellate LX2 cells, a main cell type that produce FAP in tumor tissues, and then investigate its role on LIHC cells as well as macrophages. Results showed that the medium from FAP-over-expressed LX2 cells could significantly promote the motility of MHCC97H and SK-Hep1 LIHC cells, increase the invasion of THP-1 macrophages and induce them into pro-tumor M2 phenotype. Conclusion In summary, we employed bioinformatic tools and experiments to perform a comprehensive analysis about FAP. Up-regulation of FAP in gastrointestinal cancers was primarily expressed in fibroblasts and contributes to tumor cells motility, macrophages infiltration and M2 polarization, revealing the multifactorial role of FAP in gastrointestinal cancers progression.

Dataset Information

Ferroptosis, Necroptosis, and Pyroptosis in Gastrointestinal Cancers: The Chief Culprits of Tumor Progression and Drug Resistance.

Publications

Ferroptosis, Necroptosis, and Pyroptosis in Gastrointestinal Cancers: The Chief Culprits of Tumor Progression and Drug Resistance.

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