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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 -
Journal of Hematology & Oncology Jul 2019Tumor metastasis is a major contributor to the death of cancer patients. It is driven not only by the intrinsic alterations in tumor cells, but also by the implicated... (Review)
Review
Tumor metastasis is a major contributor to the death of cancer patients. It is driven not only by the intrinsic alterations in tumor cells, but also by the implicated cross-talk between cancer cells and their altered microenvironment components. Tumor-associated macrophages (TAMs) are the key cells that create an immunosuppressive tumor microenvironment (TME) by producing cytokines, chemokines, growth factors, and triggering the inhibitory immune checkpoint proteins release in T cells. In doing so, TAMs exhibit important functions in facilitating a metastatic cascade of cancer cells and, meanwhile, provide multiple targets of certain checkpoint blockade immunotherapies for opposing tumor progression. In this article, we summarize the regulating networks of TAM polarization and the mechanisms underlying TAM-facilitated metastasis. Based on the overview of current experimental evidence dissecting the critical roles of TAMs in tumor metastasis, we discuss and prospect the potential applications of TAM-focused therapeutic strategies in clinical cancer treatment at present and in the future.
Topics: Animals; Antineoplastic Agents; Cytokines; Humans; Macrophages; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Tumor Microenvironment
PubMed: 31300030
DOI: 10.1186/s13045-019-0760-3 -
Cell Nov 2006Metastasis occurs when genetically unstable cancer cells adapt to a tissue microenvironment that is distant from the primary tumor. This process involves both the... (Review)
Review
Metastasis occurs when genetically unstable cancer cells adapt to a tissue microenvironment that is distant from the primary tumor. This process involves both the selection of traits that are advantageous to cancer cells and the concomitant recruitment of traits in the tumor stroma that accommodate invasion by metastatic cells. Recent conceptual and technological advances promote our understanding of the origins and nature of cancer metastasis.
Topics: Animals; Basement Membrane; Evolution, Molecular; Humans; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Phenotype
PubMed: 17110329
DOI: 10.1016/j.cell.2006.11.001 -
British Journal of Cancer Oct 2021Metastasis is the spread of cancer cells to new areas of the body by way of the lymph system or bloodstream. Mechanism-based therapeutics have transformed its treatment....
Metastasis is the spread of cancer cells to new areas of the body by way of the lymph system or bloodstream. Mechanism-based therapeutics have transformed its treatment. This issue of British Journal of Cancer will highlight recent advances in our understanding of metastasis, and how to block its spread.
Topics: Gene Regulatory Networks; Humans; Mitochondria; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasms; Precision Medicine
PubMed: 34226682
DOI: 10.1038/s41416-021-01401-1 -
Cell Feb 2017Malignant cells utilize diverse strategies that enable them to thrive under adverse conditions while simultaneously inhibiting the development of anti-tumor immune... (Review)
Review
Malignant cells utilize diverse strategies that enable them to thrive under adverse conditions while simultaneously inhibiting the development of anti-tumor immune responses. Hostile microenvironmental conditions within tumor masses, such as nutrient deprivation, oxygen limitation, high metabolic demand, and oxidative stress, disturb the protein-folding capacity of the endoplasmic reticulum (ER), thereby provoking a cellular state of "ER stress." Sustained activation of ER stress sensors endows malignant cells with greater tumorigenic, metastatic, and drug-resistant capacity. Additionally, recent studies have uncovered that ER stress responses further impede the development of protective anti-cancer immunity by manipulating the function of myeloid cells in the tumor microenvironment. Here, we discuss the tumorigenic and immunoregulatory effects of ER stress in cancer, and we explore the concept of targeting ER stress responses to enhance the efficacy of standard chemotherapies and evolving cancer immunotherapies in the clinic.
Topics: Animals; Endoplasmic Reticulum Stress; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Tumor Escape; Tumor Microenvironment; Unfolded Protein Response
PubMed: 28187289
DOI: 10.1016/j.cell.2016.12.004 -
Journal of Hematology & Oncology Aug 2021Pancreatic cancer's poor prognosis is caused by distal metastasis, which is associated with epigenetic changes. However, the role of the 3D epigenome in pancreatic...
BACKGROUND
Pancreatic cancer's poor prognosis is caused by distal metastasis, which is associated with epigenetic changes. However, the role of the 3D epigenome in pancreatic cancer biology, especially its metastasis, remains unclear.
METHODS
Here, we developed high-resolution 3D epigenomic maps of cells derived from normal pancreatic epithelium, primary and metastatic pancreatic cancer by in situ Hi-C, ChIP-seq, ATAC-seq, and RNA-seq to identify key genes involved in pancreatic cancer metastasis RESULTS: We found that A/B compartments, contact domains, and chromatin loops changed significantly in metastatic pancreatic cancer cells, which are associated with epigenetic state alterations. Moreover, we found that upregulated genes, which were located in switched compartments, changed contact domains, and metastasis-specific enhancer-promoter loops, were related to cancer metastasis and poor prognosis of patients with pancreatic cancer. We also found that transcription factors in specific enhancer-promoter loop formation were also associated with metastasis. Finally we demonstrated that LIPC, looped to metastasis-specific enhancers, could promote pancreatic cancer metastasis.
CONCLUSIONS
These results highlight the multiscale 3D epigenome reprogramming during pancreatic cancer metastasis and expand our knowledge of mechanisms of gene regulation during pancreatic cancer metastasis.
Topics: Animals; Cell Line; Cell Line, Tumor; Epigenesis, Genetic; Epigenome; Epigenomics; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasm Metastasis; Pancreatic Neoplasms; Promoter Regions, Genetic; Tumor Cells, Cultured
PubMed: 34348759
DOI: 10.1186/s13045-021-01131-0 -
Cold Spring Harbor Perspectives in... Nov 2020Sterile inflammation within primary tumor tissues can spread to distant organs that are devoid of tumor cells. This happens in a manner dependent on tumor-led secretome,... (Review)
Review
Sterile inflammation within primary tumor tissues can spread to distant organs that are devoid of tumor cells. This happens in a manner dependent on tumor-led secretome, before the actual metastasis occurs. The premetastatic microenvironment is established in this way and is at least partly regulated by hijacking the host innate immune system. The biological manifestation of premetastasis include increased vascular permeability, cell mobilization via the blood stream, degradation of the extracellular matrix, immunosuppression, and host antineoplastic activities.
Topics: Animals; Humans; Neoplasm Metastasis; Neoplasms; Tumor Microenvironment
PubMed: 31615874
DOI: 10.1101/cshperspect.a036897 -
Cold Spring Harbor Perspectives in... Apr 2020The dynamic interplay between neoplastic cells and the immune microenvironment regulates every step of the metastatic process. Immune cells contribute to invasion by... (Review)
Review
The dynamic interplay between neoplastic cells and the immune microenvironment regulates every step of the metastatic process. Immune cells contribute to invasion by secreting a cornucopia of inflammatory factors that promote epithelial-to-mesenchymal transition and remodeling of the stroma. Cancer cells then intravasate to the circulatory system assisted by macrophages and use several pathways to avoid recognition by cytotoxtic lymphocytes and phagocytes. Circulating tumor cells that manage to adhere to the vasculature and encounter premetastic niches are able to use the associated myeloid cells to extravasate into ectopic organs and establish a dormant microscopic colony. If successful at avoiding repetitive immune attack, dormant cells can subsequently grow into overt, clinically detectable metastatic lesions, which ultimately account to most cancer-related deaths. Understanding how disseminated tumor cells evade and corrupt the immune system during the final stages of metastasis will be pivotal in developing new therapeutic modalities that combat metastasis.
Topics: Cell Adhesion; Epithelial-Mesenchymal Transition; Humans; Macrophages; Neoplasm Metastasis; Neoplastic Cells, Circulating; Tumor Microenvironment
PubMed: 31501262
DOI: 10.1101/cshperspect.a037424 -
Cancer Research Jun 2018The premetastatic niche formed by primary tumor-derived molecules contributes to fixation of cancer metastasis. The design of efficient therapies is limited by the... (Review)
Review
The premetastatic niche formed by primary tumor-derived molecules contributes to fixation of cancer metastasis. The design of efficient therapies is limited by the current lack of knowledge about the details of cellular and molecular mechanisms involved in the premetastatic niche formation. Recently, the role of pericytes in the premetastatic niche formation and lung metastatic tropism was explored by using state-of-the-art techniques, including lineage-tracing and mice with pericyte-specific KLF4 deletion. Strikingly, genetic inactivation of KLF4 in pericytes inhibits pulmonary pericyte expansion and decreases metastasis in the lung. Here, we summarize and evaluate recent advances in the understanding of pericyte contribution to premetastatic niche formation. .
Topics: Animals; Humans; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lung; Lung Neoplasms; Neoplasm Metastasis; Pericytes
PubMed: 29789421
DOI: 10.1158/0008-5472.CAN-17-3883