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Trends in Cancer Jan 2020Metastasis contributes to the vast majority of cancer-related mortality. Regulatory mechanisms of the multistep invasion-metastasis cascade are being unraveled. TP53 is... (Review)
Review
Metastasis contributes to the vast majority of cancer-related mortality. Regulatory mechanisms of the multistep invasion-metastasis cascade are being unraveled. TP53 is the most frequently mutated gene across human cancers. Accumulating evidence has shown that mutations of TP53 not only lead to loss of function or dominant negative effects, but also promotes a gain of function. Specifically, gain of function mutant p53 promotes cancer cell motility, invasion, and metastasis. Here, we summarize the mechanisms and functions of mutant p53 that foster metastasis in different types of cancers. We also discuss the prognostic value of mutant p53 and current status of therapeutic strategies targeting mutant p53. Future studies will shed light on discovering novel mechanisms of mutant p53-driven cancer metastasis and developing innovative therapeutics to improve clinical outcomes in patients harboring p53 mutations.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Exosomes; Extracellular Matrix; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Mice; Mitochondria; Mutation; Neoplasm Metastasis; RNA, Untranslated; Receptor Protein-Tyrosine Kinases; Signal Transduction; Transcription Factors; Tumor Suppressor Protein p53
PubMed: 31952783
DOI: 10.1016/j.trecan.2019.11.004 -
Nature Reviews. Cancer Apr 2016Tumour metastasis, the movement of tumour cells from a primary site to progressively colonize distant organs, is a major contributor to the deaths of cancer patients.... (Review)
Review
Tumour metastasis, the movement of tumour cells from a primary site to progressively colonize distant organs, is a major contributor to the deaths of cancer patients. Therapeutic goals are the prevention of an initial metastasis in high-risk patients, shrinkage of established lesions and prevention of additional metastases in patients with limited disease. Instead of being autonomous, tumour cells engage in bidirectional interactions with metastatic microenvironments to alter antitumour immunity, the extracellular milieu, genomic stability, survival signalling, chemotherapeutic resistance and proliferative cycles. Can targeting of these interactions significantly improve patient outcomes? In this Review preclinical research, combination therapies and clinical trial designs are re-examined.
Topics: Humans; Neoplasm Metastasis
PubMed: 27009393
DOI: 10.1038/nrc.2016.25 -
Cell Feb 2022Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we...
Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression.
Topics: Cohort Studies; Female; Genomics; High-Throughput Nucleotide Sequencing; Humans; Male; Neoplasm Metastasis; Organ Specificity; Prospective Studies
PubMed: 35120664
DOI: 10.1016/j.cell.2022.01.003 -
Cancer Cell Aug 2017The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is governed by cancer-cell-intrinsic... (Review)
Review
The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is governed by cancer-cell-intrinsic mechanisms that enable neoplastic cells to invade the local microenvironment, reach the circulation, and colonize distant sites, including the so-called epithelial-to-mesenchymal transition. Moreover, metastasis is regulated by microenvironmental and systemic processes, such as immunosurveillance. Here, we outline the cancer-cell-intrinsic and -extrinsic factors that regulate metastasis, discuss the key role of natural killer (NK) cells in the control of metastatic dissemination, and present potential therapeutic approaches to prevent or target metastatic disease by harnessing NK cells.
Topics: Animals; Humans; Immunologic Surveillance; Immunotherapy; Killer Cells, Natural; Neoplasm Metastasis; Neoplasms; Tumor Escape; Tumor Microenvironment
PubMed: 28810142
DOI: 10.1016/j.ccell.2017.06.009 -
Nature Jan 2016Metastasis is the main cause of death in people with cancer. To colonize distant organs, circulating tumour cells must overcome many obstacles through mechanisms that we... (Review)
Review
Metastasis is the main cause of death in people with cancer. To colonize distant organs, circulating tumour cells must overcome many obstacles through mechanisms that we are only now starting to understand. These include infiltrating distant tissue, evading immune defences, adapting to supportive niches, surviving as latent tumour-initiating seeds and eventually breaking out to replace the host tissue. They make metastasis a highly inefficient process. However, once metastases have been established, current treatments frequently fail to provide durable responses. An improved understanding of the mechanistic determinants of such colonization is needed to better prevent and treat metastatic cancer.
Topics: Animals; Cell Proliferation; Cell Survival; Humans; Neoplasm Metastasis; Neoplastic Cells, Circulating; Organ Specificity; Stem Cell Niche; Tumor Microenvironment
PubMed: 26791720
DOI: 10.1038/nature17038 -
Cell Jan 2019The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biological features and vulnerabilities of CTC...
The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biological features and vulnerabilities of CTC clusters remain largely unknown. Here, we profile the DNA methylation landscape of single CTCs and CTC clusters from breast cancer patients and mouse models on a genome-wide scale. We find that binding sites for stemness- and proliferation-associated transcription factors are specifically hypomethylated in CTC clusters, including binding sites for OCT4, NANOG, SOX2, and SIN3A, paralleling embryonic stem cell biology. Among 2,486 FDA-approved compounds, we identify Na/K ATPase inhibitors that enable the dissociation of CTC clusters into single cells, leading to DNA methylation remodeling at critical sites and metastasis suppression. Thus, our results link CTC clustering to specific changes in DNA methylation that promote stemness and metastasis and point to cluster-targeting compounds to suppress the spread of cancer.
Topics: Animals; Breast Neoplasms; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; DNA Methylation; Disease Models, Animal; Female; Humans; Mice; Mice, Inbred NOD; Nanog Homeobox Protein; Neoplasm Metastasis; Neoplastic Cells, Circulating; Octamer Transcription Factor-3; Repressor Proteins; SOXB1 Transcription Factors; Sin3 Histone Deacetylase and Corepressor Complex
PubMed: 30633912
DOI: 10.1016/j.cell.2018.11.046 -
Cancer Cell Apr 2015How neoplastic cells respond to therapy is not solely dependent on the complexity of the genomic aberrations they harbor but is also regulated by numerous dynamic... (Review)
Review
How neoplastic cells respond to therapy is not solely dependent on the complexity of the genomic aberrations they harbor but is also regulated by numerous dynamic properties of the tumor microenvironment. Identifying and targeting critical pathways that improve therapeutic efficacy by bolstering anti-tumor immune responses holds great potential for improving outcomes and impacting long-term patient survival. Macrophages are key regulators of homeostatic tissue and tumor microenvironments. Therefore, therapeutics impacting macrophage presence and/or bioactivity have shown promise in preclinical models and are now being evaluated in the clinic. This review discusses the molecular/cellular pathways identified so far whereby macrophages mediate therapeutic responses.
Topics: Animals; Drug Resistance, Neoplasm; Humans; Immunity, Cellular; Immunotherapy; Macrophages; Mice; Models, Immunological; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 25858805
DOI: 10.1016/j.ccell.2015.02.015 -
The Journal of Clinical Investigation Nov 2023The metastasis of cancer cells is the main cause of death in patients with gastric cancer (GC). Mounting evidence has demonstrated the vital importance of...
The metastasis of cancer cells is the main cause of death in patients with gastric cancer (GC). Mounting evidence has demonstrated the vital importance of tumor-associated macrophages in promoting tumor invasion and metastasis; however, the interaction between tumor cells and macrophages in GC is largely unknown. In this study, we demonstrated that cyclase-associated protein 2 (CAP2) was upregulated in GC, especially in cases with lymph node metastasis, and was correlated with a poorer prognosis. The transcription factor JUN directly bound to the promoter region of CAP2 and activated CAP2 transcription. The N-terminal domain of CAP2 bound to the WD5 to WD7 domains of receptor for activated C kinase 1 (RACK1) and induced M2 macrophage polarization by activating the SRC/focal adhesion kinase (FAK)/ERK signaling pathway, which resulted in IL-4 and IL-10 secretion. Polarized M2 macrophages induced premetastatic niche formation and promoted GC metastasis by secreting TGFB1, which created a TGFB1/JUN/CAP2 positive-feedback loop to activate CAP2 expression continuously. Furthermore, we identified salvianolic acid B as an inhibitor of CAP2, which effectively inhibited GC cell invasion capabilities by suppressing the SRC/FAK/ERK signaling pathway. Our data suggest that CAP2, a key molecule mediating the interaction between GC cells and tumor-associated macrophages, may be a promising therapeutic target for suppressing tumor metastasis in GC.
Topics: Humans; Tumor-Associated Macrophages; Stomach Neoplasms; Signal Transduction; Lymphatic Metastasis; MAP Kinase Signaling System; Cell Line, Tumor; Neoplasm Metastasis; Membrane Proteins; Adaptor Proteins, Signal Transducing
PubMed: 37707957
DOI: 10.1172/JCI166224 -
Cell Reports Aug 2022Circulating tumor cells (CTCs) are the seeds of distant metastasis, and the number of CTCs detected in the blood of cancer patients is associated with a worse prognosis.... (Review)
Review
Circulating tumor cells (CTCs) are the seeds of distant metastasis, and the number of CTCs detected in the blood of cancer patients is associated with a worse prognosis. CTCs face critical challenges for their survival in circulation, such as anoikis, shearing forces, and immune surveillance. Thus, understanding the mechanisms and interactions of CTCs within the blood microenvironment is crucial for better understanding of metastatic progression and the development of novel treatment strategies. CTCs interact with different hematopoietic cells, such as platelets, red blood cells, neutrophils, macrophages, natural killer (NK) cells, lymphocytes, endothelial cells, and cancer-associated fibroblasts, which can affect CTC survival in blood. This interaction may take place either via direct cell-cell contact or through secreted molecules. Here, we review interactions of CTCs with blood cells and discuss the potential clinical relevance of these interactions as biomarkers or as targets for anti-metastatic therapies.
Topics: Biology; Biomarkers, Tumor; Blood Cells; Cell Count; Endothelial Cells; Humans; Neoplasm Metastasis; Neoplastic Cells, Circulating; Tumor Microenvironment
PubMed: 36044866
DOI: 10.1016/j.celrep.2022.111298 -
Science (New York, N.Y.) Feb 2021Detailed phylogenies of tumor populations can recount the history and chronology of critical events during cancer progression, such as metastatic dissemination. We...
Detailed phylogenies of tumor populations can recount the history and chronology of critical events during cancer progression, such as metastatic dissemination. We applied a Cas9-based, single-cell lineage tracer to study the rates, routes, and drivers of metastasis in a lung cancer xenograft mouse model. We report deeply resolved phylogenies for tens of thousands of cancer cells traced over months of growth and dissemination. This revealed stark heterogeneity in metastatic capacity, arising from preexisting and heritable differences in gene expression. We demonstrate that these identified genes can drive invasiveness and uncovered an unanticipated suppressive role for We also show that metastases disseminated via multidirectional tissue routes and complex seeding topologies. Overall, we demonstrate the power of tracing cancer progression at subclonal resolution and vast scale.
Topics: Animals; CRISPR-Cas Systems; Cell Line, Tumor; Cell Lineage; Clone Cells; Gene Expression Regulation, Neoplastic; Humans; Keratin-17; Lung Neoplasms; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Seeding; Neoplasm Transplantation; Phenotype; RNA-Seq; Single-Cell Analysis; Transcriptome; Transplantation, Heterologous
PubMed: 33479121
DOI: 10.1126/science.abc1944