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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 -
International Journal of Molecular... Jun 2022Breast cancer is the most common malignancy in women worldwide. Metastasis is the leading cause of high mortality in most cancers. Although predicting the early stage of... (Review)
Review
Breast cancer is the most common malignancy in women worldwide. Metastasis is the leading cause of high mortality in most cancers. Although predicting the early stage of breast cancer before metastasis can increase the survival rate, breast cancer is often discovered or diagnosed after metastasis has occurred. In general, breast cancer has a poor prognosis because it starts as a local disease and can spread to lymph nodes or distant organs, contributing to a significant impediment in breast cancer treatment. Metastatic breast cancer cells acquire aggressive characteristics from the tumor microenvironment (TME) through several mechanisms including epithelial-mesenchymal transition (EMT) and epigenetic regulation. Therefore, understanding the nature and mechanism of breast cancer metastasis can facilitate the development of targeted therapeutics focused on metastasis. This review discusses the mechanisms leading to metastasis and the current therapies to improve the early diagnosis and prognosis in patients with metastatic breast cancer.
Topics: Breast Neoplasms; Epigenesis, Genetic; Epithelial-Mesenchymal Transition; Female; Humans; Lymph Nodes; Neoplasm Metastasis; Neoplasms, Second Primary; Tumor Microenvironment
PubMed: 35743249
DOI: 10.3390/ijms23126806 -
Signal Transduction and Targeted Therapy Mar 2020Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of... (Review)
Review
Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of cancer biology research and the emergence of new paradigms in the study of metastasis have revealed some of the molecular underpinnings of this dissemination process. The invading tumor cell, on its way to the target site, interacts with other proteins and cells. Recognition of these interactions improved the understanding of some of the biological principles of the metastatic cell that govern its mobility and plasticity. Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These characteristics of cancer cells are driven by genetic and epigenetic modifications within the tumor cell itself and its microenvironment. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. In this review, the authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.
Topics: Epigenesis, Genetic; Humans; Neoplasm Metastasis; Neoplasms; Tumor Microenvironment
PubMed: 32296047
DOI: 10.1038/s41392-020-0134-x -
Cell Systems Aug 2019Cancer metastasis is no longer viewed as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as successfully metastasizing... (Review)
Review
Cancer metastasis is no longer viewed as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as successfully metastasizing cells assume new phenotypes while jettisoning older behaviors. The lack of a systemic understanding of this complex phenomenon has limited progress in developing treatments for metastatic disease. Because metastasis has traditionally been investigated in distinct physiological compartments, the integration of these complex and interlinked aspects remains a challenge for both systems-level experimental and computational modeling of metastasis. Here, we present some of the current perspectives on the complexity of cancer metastasis, the multiscale nature of its progression, and a systems-level view of the processes underlying the invasive spread of cancer cells. We also highlight the gaps in our current understanding of cancer metastasis as well as insights emerging from interdisciplinary systems biology approaches to understand this complex phenomenon.
Topics: Animals; Disease Progression; Humans; Neoplasm Metastasis; Neoplasms; Signal Transduction; Systems Biology
PubMed: 31465728
DOI: 10.1016/j.cels.2019.07.003 -
Nature Medicine Jan 2021Despite recent therapeutic advances in cancer treatment, metastasis remains the principal cause of cancer death. Recent work has uncovered the unique biology of... (Review)
Review
Despite recent therapeutic advances in cancer treatment, metastasis remains the principal cause of cancer death. Recent work has uncovered the unique biology of metastasis-initiating cells that results in tumor growth in distant organs, evasion of immune surveillance and co-option of metastatic microenvironments. Here we review recent progress that is enabling therapeutic advances in treating both micro- and macrometastases. Such insights were gained from cancer sequencing, mechanistic studies and clinical trials, including of immunotherapy. These studies reveal both the origins and nature of metastases and identify new opportunities for developing more effective strategies to target metastatic relapse and improve patient outcomes.
Topics: Humans; Mutation; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Neoplastic Stem Cells; Survival Analysis; Treatment Outcome; Tumor Microenvironment
PubMed: 33442008
DOI: 10.1038/s41591-020-01195-4 -
Nature Apr 2023Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fluctuate...
Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fluctuate between an immune-evasive quiescent state and a proliferative state liable to immune-mediated elimination. Little is known about the clearing of reawakened metastatic cells and how this process could be therapeutically activated to eliminate residual disease in patients. Here we use models of indolent lung adenocarcinoma metastasis to identify cancer cell-intrinsic determinants of immune reactivity during exit from dormancy. Genetic screens of tumour-intrinsic immune regulators identified the stimulator of interferon genes (STING) pathway as a suppressor of metastatic outbreak. STING activity increases in metastatic progenitors that re-enter the cell cycle and is dampened by hypermethylation of the STING promoter and enhancer in breakthrough metastases or by chromatin repression in cells re-entering dormancy in response to TGFβ. STING expression in cancer cells derived from spontaneous metastases suppresses their outgrowth. Systemic treatment of mice with STING agonists eliminates dormant metastasis and prevents spontaneous outbreaks in a T cell- and natural killer cell-dependent manner-these effects require cancer cell STING function. Thus, STING provides a checkpoint against the progression of dormant metastasis and a therapeutically actionable strategy for the prevention of disease relapse.
Topics: Animals; Mice; Adenocarcinoma of Lung; Cell Cycle; Lung Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; T-Lymphocytes; Transforming Growth Factor beta; Killer Cells, Natural
PubMed: 36991128
DOI: 10.1038/s41586-023-05880-5 -
Journal of Hematology & Oncology Oct 2021In recent years, neutrophils have attracted increasing attention because of their cancer-promoting effects. An elevated neutrophil-to-lymphocyte ratio is considered a... (Review)
Review
In recent years, neutrophils have attracted increasing attention because of their cancer-promoting effects. An elevated neutrophil-to-lymphocyte ratio is considered a prognostic indicator for patients with cancer. Neutrophils are no longer regarded as innate immune cells with a single function, let alone bystanders in the pathological process of cancer. Their diversity and plasticity are being increasingly recognized. This review summarizes previous studies assessing the roles and mechanisms of neutrophils in cancer initiation, progression, metastasis and relapse. Although the findings are controversial, the fact that neutrophils play a dual role in promoting and suppressing cancer is undeniable. The plasticity of neutrophils allows them to adapt to different cancer microenvironments and exert different effects on cancer. Given the findings from our own research, we propose a reasonable hypothesis that neutrophils may be reprogrammed into a cancer-promoting state in the cancer microenvironment. This new perspective indicates that neutrophil reprogramming in the course of cancer treatment is a problem worthy of attention. Preventing or reversing the reprogramming of neutrophils may be a potential strategy for adjuvant cancer therapy.
Topics: Animals; Carcinogenesis; Cellular Reprogramming; Disease Progression; Humans; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Neutrophils; Tumor Microenvironment
PubMed: 34674757
DOI: 10.1186/s13045-021-01187-y -
Cancer Cell Aug 2022Metastasis, the major cause of cancer death, represents one of the major challenges in oncology. Scientists are still trying to understand the biological basis...
Metastasis, the major cause of cancer death, represents one of the major challenges in oncology. Scientists are still trying to understand the biological basis underlying the dissemination and outgrowth of tumor cells, why these cells can remain dormant for years, how they become resistant to the immune system or cytotoxic effects of systemic therapy, and how they interact with their new microenvironment. We asked experts to discuss some of the unknowns, advances, and areas of opportunity related to cancer metastasis.
Topics: Humans; Immune System; Neoplasm Metastasis; Neoplasms; Tumor Microenvironment
PubMed: 35944497
DOI: 10.1016/j.ccell.2022.07.010 -
International Journal of Molecular... Jun 2019Transforming growth factor β (TGF-β) is a secreted cytokine that regulates cell proliferation, migration, and the differentiation of a plethora of different cell... (Review)
Review
Transforming growth factor β (TGF-β) is a secreted cytokine that regulates cell proliferation, migration, and the differentiation of a plethora of different cell types. Consistent with these findings, TGF-β plays a key role in controlling embryogenic development, inflammation, and tissue repair, as well as in maintaining adult tissue homeostasis. TGF-β elicits a broad range of context-dependent cellular responses, and consequently, alterations in TGF-β signaling have been implicated in many diseases, including cancer. During the early stages of tumorigenesis, TGF-β acts as a tumor suppressor by inducing cytostasis and the apoptosis of normal and premalignant cells. However, at later stages, when cancer cells have acquired oncogenic mutations and/or have lost tumor suppressor gene function, cells are resistant to TGF-β-induced growth arrest, and TGF-β functions as a tumor promotor by stimulating tumor cells to undergo the so-called epithelial-mesenchymal transition (EMT). The latter leads to metastasis and chemotherapy resistance. TGF-β further supports cancer growth and progression by activating tumor angiogenesis and cancer-associated fibroblasts and enabling the tumor to evade inhibitory immune responses. In this review, we will consider the role of TGF-β signaling in cell cycle arrest, apoptosis, EMT and cancer cell metastasis. In particular, we will highlight recent insights into the multistep and dynamically controlled process of TGF-β-induced EMT and the functions of miRNAs and long noncoding RNAs in this process. Finally, we will discuss how these new mechanistic insights might be exploited to develop novel therapeutic interventions.
Topics: Animals; Carcinogenesis; Epithelial-Mesenchymal Transition; Humans; Immune Evasion; Neoplasm Metastasis; Signal Transduction; Transforming Growth Factor beta
PubMed: 31195692
DOI: 10.3390/ijms20112767 -
Clinical and Translational Medicine Feb 2022Deciphering intra- and inter-tumoural heterogeneity is essential for understanding the biology of gastric cancer (GC) and its metastasis and identifying effective...
BACKGROUND
Deciphering intra- and inter-tumoural heterogeneity is essential for understanding the biology of gastric cancer (GC) and its metastasis and identifying effective therapeutic targets. However, the characteristics of different organ-tropism metastases of GC are largely unknown.
METHODS
Ten fresh human tissue samples from six patients, including primary tumour and adjacent non-tumoural samples and six metastases from different organs or tissues (liver, peritoneum, ovary, lymph node) were evaluated using single-cell RNA sequencing. Validation experiments were performed using histological assays and bulk transcriptomic datasets.
RESULTS
Malignant epithelial subclusters associated with invasion features, intraperitoneal metastasis propensity, epithelial-mesenchymal transition-induced tumour stem cell phenotypes, or dormancy-like characteristics were discovered. High expression of the first three subcluster-associated genes displayed worse overall survival than those with low expression in a GC cohort containing 407 samples. Immune and stromal cells exhibited cellular heterogeneity and created a pro-tumoural and immunosuppressive microenvironment. Furthermore, a 20-gene signature of lymph node-derived exhausted CD8 T cells was acquired to forecast lymph node metastasis and validated in GC cohorts. Additionally, although anti-NKG2A (KLRC1) antibody have not been used to treat GC patients even in clinical trials, we uncovered not only malignant tumour cells but one endothelial subcluster, mucosal-associated invariant T cells, T cell-like B cells, plasmacytoid dendritic cells, macrophages, monocytes, and neutrophils may contribute to HLA-E-KLRC1/KLRC2 interaction with cytotoxic/exhausted CD8 T cells and/or natural killer (NK) cells, suggesting novel clinical therapeutic opportunities in GC. Additionally, our findings suggested that PD-1 expression in CD8 T cells might predict clinical responses to PD-1 blockade therapy in GC.
CONCLUSIONS
This study provided insights into heterogeneous microenvironment of GC primary tumours and organ-specific metastases and provide support for precise diagnosis and treatment.
Topics: Genetic Heterogeneity; Humans; Neoplasm Metastasis; Sequence Analysis, RNA; Single-Cell Analysis; Stomach Neoplasms; Tumor Microenvironment
PubMed: 35184420
DOI: 10.1002/ctm2.730