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      Obesity and cancer—extracellular matrix, angiogenesis, and adrenergic signaling as unusual suspects linking the two diseases

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          Abstract

          Obesity is an established risk factor for several human cancers. Given the association between excess body weight and cancer, the increasing rates of obesity worldwide are worrisome. A variety of obesity-related factors has been implicated in cancer initiation, progression, and response to therapy. These factors include circulating nutritional factors, hormones, and cytokines, causing hyperinsulinemia, inflammation, and adipose tissue dysfunction. The impact of these conditions on cancer development and progression has been the focus of extensive literature. In this review, we concentrate on processes that can link obesity and cancer, and which provide a novel perspective: extracellular matrix remodeling, angiogenesis, and adrenergic signaling. We describe molecular mechanisms involved in these processes, which represent putative targets for intervention. Liver, pancreas, and breast cancers were chosen as exemplary disease models. In view of the expanding epidemic of obesity, a better understanding of the tumorigenic process in obese individuals might lead to more effective treatments and preventive measures.

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          Most cited references231

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          Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

          This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.
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            Microenvironmental regulation of tumor progression and metastasis.

            Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
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              The biology and function of fibroblasts in cancer.

              Among all cells, fibroblasts could be considered the cockroaches of the human body. They survive severe stress that is usually lethal to all other cells, and they are the only normal cell type that can be live-cultured from post-mortem and decaying tissue. Their resilient adaptation may reside in their intrinsic survival programmes and cellular plasticity. Cancer is associated with fibroblasts at all stages of disease progression, including metastasis, and they are a considerable component of the general host response to tissue damage caused by cancer cells. Cancer-associated fibroblasts (CAFs) become synthetic machines that produce many different tumour components. CAFs have a role in creating extracellular matrix (ECM) structure and metabolic and immune reprogramming of the tumour microenvironment with an impact on adaptive resistance to chemotherapy. The pleiotropic actions of CAFs on tumour cells are probably reflective of them being a heterogeneous and plastic population with context-dependent influence on cancer.
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                Author and article information

                Contributors
                stephan.herzig@helmholtz-muenchen.de
                Journal
                Cancer Metastasis Rev
                Cancer Metastasis Rev
                Cancer Metastasis Reviews
                Springer US (New York )
                0167-7659
                1573-7233
                8 September 2022
                8 September 2022
                2022
                : 41
                : 3
                : 517-547
                Affiliations
                [1 ]GRID grid.4567.0, ISNI 0000 0004 0483 2525, Institute for Diabetes and Cancer, Helmholtz Center Munich, ; 85764 Neuherberg, Germany
                [2 ]GRID grid.5253.1, ISNI 0000 0001 0328 4908, Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, ; Heidelberg, Germany
                [3 ]GRID grid.452622.5, German Center for Diabetes Research (DZD), ; 85764 Neuherberg, Germany
                [4 ]GRID grid.6936.a, ISNI 0000000123222966, Chair Molecular Metabolic Control, Technical University Munich, ; Munich, Germany
                Article
                10058
                10.1007/s10555-022-10058-y
                9470659
                36074318
                3867369d-bea2-45c3-a951-6a705e24a3cc
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 7 June 2022
                : 29 July 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100005972, Deutsche Krebshilfe;
                Award ID: 70115158
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100010663, H2020 European Research Council;
                Award ID: 949017
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100009318, Helmholtz Association;
                Award ID: Initiative
                Award ID: Networking Fund
                Award Recipient :
                Funded by: European Foundation for the Study of Diabetes
                Funded by: Helmholtz Future Topic Aging and Metabolic Programming
                Award ID: AMPro
                Award ID: ZT-0026
                Award Recipient :
                Funded by: Else-Kröner-Fresenius-Stiftung
                Award ID: 2020 EKSE.23
                Award Recipient :
                Funded by: Edith-Haberland-Wagner Stiftung
                Funded by: FundRef http://dx.doi.org/10.13039/501100005972, DFG;
                Award ID: CRC/Transregio 205/2 314061271
                Award Recipient :
                Funded by: Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) (4209)
                Categories
                Article
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2022

                Oncology & Radiotherapy
                cancer,obesity,angiogenesis,fibrosis,adrenergic signaling
                Oncology & Radiotherapy
                cancer, obesity, angiogenesis, fibrosis, adrenergic signaling

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