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Cell Apr 2023Most cancer-associated deaths occur due to metastasis, yet our understanding of metastasis as an evolving, heterogeneous, systemic disease and of how to effectively... (Review)
Review
Most cancer-associated deaths occur due to metastasis, yet our understanding of metastasis as an evolving, heterogeneous, systemic disease and of how to effectively treat it is still emerging. Metastasis requires the acquisition of a succession of traits to disseminate, variably enter and exit dormancy, and colonize distant organs. The success of these events is driven by clonal selection, the potential of metastatic cells to dynamically transition into distinct states, and their ability to co-opt the immune environment. Here, we review the main principles of metastasis and highlight emerging opportunities to develop more effective therapies for metastatic cancer.
Topics: Humans; Neoplasm Metastasis; Neoplasms
PubMed: 37059065
DOI: 10.1016/j.cell.2023.03.003 -
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 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 -
Medical Oncology (Northwood, London,... Jan 2021Metastasis is the most complex and deadly event. Tumor-stromal interface is a place where invasion of tumor cells in the form of single-cell or collective migration... (Review)
Review
Metastasis is the most complex and deadly event. Tumor-stromal interface is a place where invasion of tumor cells in the form of single-cell or collective migration occurs, with the latter being less common but more efficient. Initiation of metastasis relies on the tumor cell cross-talking with stromal cells and taking an epithelial-mesenchymal transition (EMT) in single cells, and a hybrid EMT in collective migratory cells. Stromal cross-talking along with an abnormal leaky vasculature facilitate intravasation of tumor cells, here the cells are called circulating tumor cells (CTCs). Tumor cells isolated from the primary tumor exploit several mechanisms to maintain their survival including rewiring metabolic demands to use sources available within the new environments, avoiding anoikis cell death when cells are detached from extracellular matrix (ECM), adopting flow mechanic by acquiring platelet shielding and immunosuppression by negating the activity of suppressor immune cells, such as natural killer (NK) cells. CTCs will adhere to the interstituim of the secondary organ/s, within which the newly arrived disseminative tumor cells (DTCs) undergo either dormancy or proliferation. Metastatic outgrowth is under the influence of several factors, such as the activity of macrophages, impaired autophagy and secondary site inflammatory events. Metastasis can be targeted by multiple ways, such as repressing the promoters of pre-metastatic niche (PMN) formation, suppressing environmental contributors, such as hypoxia, oxidative and metabolic stressors, and targeting signaling and cell types that take major contribution to the whole process. These strategies can be used in adjuvant with other therapeutics, such as immunotherapy.
Topics: Autophagy; Cell Movement; Cell Survival; Energy Metabolism; Epithelial-Mesenchymal Transition; Humans; Inflammation; Macrophages; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplastic Cells, Circulating; Signal Transduction; Tropism; Tumor Escape; Tumor Microenvironment
PubMed: 33394200
DOI: 10.1007/s12032-020-01447-w -
Nature Medicine Aug 2006
Review
Topics: Animals; Capillary Permeability; Gene Expression Regulation, Neoplastic; Humans; Models, Biological; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Neovascularization, Pathologic
PubMed: 16892035
DOI: 10.1038/nm1469 -
The New England Journal of Medicine Feb 2023
Topics: Humans; Carcinogenesis; Cell Transformation, Neoplastic; Mitochondrial Proteins; Neoplasm Metastasis
PubMed: 36791168
DOI: 10.1056/NEJMcibr2213497 -
Current Pharmaceutical Biotechnology Nov 2011
Topics: Humans; Neoplasm Metastasis
PubMed: 21470137
DOI: 10.2174/138920111798376897 -
Bosnian Journal of Basic Medical... Aug 2017Decades of cancer research have unraveled genetic, epigenetic and molecular pathways leading to plausible therapeutic targets; many of which hold great promise in... (Review)
Review
Decades of cancer research have unraveled genetic, epigenetic and molecular pathways leading to plausible therapeutic targets; many of which hold great promise in improving clinical outcomes. Metastatic tumors become evident early on and are one of the major causes of cancer-related fatalities worldwide. This review depicts the sequential events of cancer metastasis. Genetic and epigenetic heterogeneity influences local tumor cell invasion, intravasation, survival in circulation, extravasation and colonization to distant sites. Each sequential event is associated with heterogeneous tumor microenvironment, gain of competence, unique population of cancer stem cells (CSCs), circulatory pathway, compatible niche and immune system support. A tight regulation of metastasis-promoting mechanisms and, in parallel, evading inhibitory mechanisms contribute to the severity and site of metastasis. A comprehensive understanding of tumor cell fate as an individual entity, as well as in combination with different promoting factors and associated molecular mechanisms, is anticipated in the coming years. This will enable scientists to depict design strategies for targeted cancer therapies.
Topics: Animals; Antineoplastic Agents; Humans; Neoplasm Metastasis; Neoplastic Stem Cells
PubMed: 28278128
DOI: 10.17305/bjbms.2017.1908 -
Seminars in Oncology Nursing Feb 1992Understanding of the process by which tumor cells develop heterogeneity, invade local tissues, and spread to distant tissues is a major goal of cancer research, as it... (Review)
Review
Understanding of the process by which tumor cells develop heterogeneity, invade local tissues, and spread to distant tissues is a major goal of cancer research, as it will determine whether clinicians will be able to design more effective therapies for different cancers. Although much has been learned, much remains to be learned. The following summarizes our current knowledge about metastasis: 1. Cancer is the result of transformation of single cells. 2. Transformed cells are less stable and have an increased rate of spontaneous mutation than non-metastatic cells of similar origin. 3. Cells within a tumor are heterogeneous in biological characteristics. 4. The metastatic process is selective for highly malignant cells from within the heterogeneous tumor. 5. The metastatic process is a complex sequence of events with an outcome dependent on both tumor cell and host properties. 6. By the time of diagnosis, many primary solid tumors are biologically heterogeneous and have disseminated to regional or distant sites. 7. By the time of initial diagnosis, metastases in some state of development are thought to exist in approximately 50% of patients. 8. Cancer metastasis is the major cause of treatment failure and mortality in individuals with malignant tumors. The complexity and diversity of human cancer, in conjunction with the complexity and diversity of human beings diagnosed with cancer presents a major challenge to oncology clinicians and researchers.
Topics: Humans; Lymphatic Metastasis; Neoplasm Invasiveness; Neoplasm Metastasis
PubMed: 1546218
DOI: 10.1016/0749-2081(92)90007-p -
Nature Reviews. Disease Primers Oct 2020Bone is the most frequent site for metastasis for many cancers, notably for tumours originating in the breast and the prostate. Tumour cells can escape from the primary... (Review)
Review
Bone is the most frequent site for metastasis for many cancers, notably for tumours originating in the breast and the prostate. Tumour cells can escape from the primary tumour site and colonize the bone microenvironment. Within the bone, these disseminated tumour cells, as well as those arising in the context of multiple myeloma, may assume a state of dormancy, remaining quiescent for years before resuming proliferation and causing overt metastasis, which causes bone destruction via activation of osteoclast-mediated osteolysis. This structural damage can lead to considerable morbidity, including pain, fractures and impaired quality of life. Although treatment of bone metastases and myeloma bone disease is rarely curative, disease control is often possible for many years through the use of systemic anticancer treatments on a background of multidisciplinary supportive care. This care should include bone-targeted agents to inhibit tumour-associated osteolysis and prevent skeletal morbidity as well as use of appropriate local treatments such as radiation therapy, orthopaedic surgery and specialist palliative care to minimize the impact of metastatic bone disease on physical functioning. In this Primer, we provide an overview of the clinical features, the pathophysiology and the specific treatment approaches to prevent and treat bone metastases from solid tumours as well as myeloma bone disease.
Topics: Bone Neoplasms; Humans; Neoplasm Metastasis; Neoplasms
PubMed: 33060614
DOI: 10.1038/s41572-020-00216-3