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      Tumor metastasis: Mechanistic insights and therapeutic interventions

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          Abstract

          Cancer metastasis is responsible for the vast majority of cancer‐related deaths worldwide. In contrast to numerous discoveries that reveal the detailed mechanisms leading to the formation of the primary tumor, the biological underpinnings of the metastatic disease remain poorly understood. Cancer metastasis is a complex process in which cancer cells escape from the primary tumor, settle, and grow at other parts of the body. Epithelial‐mesenchymal transition and anoikis resistance of tumor cells are the main forces to promote metastasis, and multiple components in the tumor microenvironment and their complicated crosstalk with cancer cells are closely involved in distant metastasis. In addition to the three cornerstones of tumor treatment, surgery, chemotherapy, and radiotherapy, novel treatment approaches including targeted therapy and immunotherapy have been established in patients with metastatic cancer. Although the cancer survival rate has been greatly improved over the years, it is still far from satisfactory. In this review, we provided an overview of the metastasis process, summarized the cellular and molecular mechanisms involved in the dissemination and distant metastasis of cancer cells, and reviewed the important advances in interventions for cancer metastasis.

          Abstract

          Cancer metastasis is a complex process in which cancer cells escape from the primary tumor, settle and grow at other parts of the body. A variety of stromal cells, immune cells and other molecular components surrounding the tumor provide signals that enhance the metastatic potential of cancer cells. With the deepening understanding of mechanisms of tumorigenesis and metastasis in recent years, a plethora of treatment approaches have been established in patients with metastatic cancer.

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          Most cited references406

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          Hallmarks of Cancer: The Next Generation

          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Cancer statistics, 2020

            Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.
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              Epithelial-mesenchymal transitions in development and disease.

              The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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                Author and article information

                Contributors
                zhangxing@sysucc.org.cn
                Journal
                MedComm (2020)
                MedComm (2020)
                10.1002/(ISSN)2688-2663
                MCO2
                MedComm
                John Wiley and Sons Inc. (Hoboken )
                2688-2663
                02 December 2021
                December 2021
                : 2
                : 4 ( doiID: 10.1002/mco2.v2.4 )
                : 587-617
                Affiliations
                [ 1 ] Melanoma and Sarcoma Medical Oncology Unit State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou China
                [ 2 ] State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou China
                Author notes
                [*] [* ] Correspondence

                Xing Zhang, Sun Yat‐sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China.

                Email: zhangxing@ 123456sysucc.org.cn

                Article
                MCO2100
                10.1002/mco2.100
                8706758
                34977870
                002c18f3-59f3-4266-86ed-7eb87d8a4bbb
                © 2021 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 01 November 2021
                : 12 October 2021
                : 03 November 2021
                Page count
                Figures: 4, Tables: 2, Pages: 31, Words: 21306
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 81772863
                Award ID: 82072958
                Funded by: China Postdoctoral Science Foundation , doi 10.13039/501100002858;
                Award ID: 2020M683119
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                December 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.7.0 mode:remove_FC converted:24.12.2021

                cancer,epithelial‐mesenchymal transition,immunotherapy,metastasis,targeted therapy,tumor microenvironment

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