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Cited by 33Cancer Risks and FactorsCancer, Lipids, and MetabolismAdipokines, Inflammation, and Metabolic Diseases

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

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Pellegata, Natalia S., Berriel Diaz, Mauricio, Rohm, Maria, Herzig, Stephan·2022·Cancer and Metastasis Reviews
DOI 10.1007/s10555-022-10058-yPMC PMC9470659
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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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Fig. 1 Overview of fibrosis in cancer and obesity. (1) ECM remodeling and fibrosis in cancer: The development of a fibrotic tumor stroma (desmoplastic reaction) is a multistep process in part driven by activation of cancer-associated fibroblasts (CAFs) and TGFbeta signaling. CAFs and ECM components exert different pro-tumorigenic processes including epithelial-mesenchymal transition (EMT) in tumor cells, thereby inducing tumor progression (metastasis formation). A fibrotic tumor stroma prevents immune cell infiltration, thereby reducing immune surveillance and responsiveness to cancer immunotherapy. (2) Adipose tissue fibrosis in obesity: Obesity-driven pathologic expansion of adipose tissue is characterized by adipocyte hypertrophy and cell death, chronic inflammation (including macrophage infiltration), and enhanced fibrosis. Fibrosis limits the expansion of adipose and contributes to metabolic dysfunction, including systemic inflammation and insulin resistance. Elevated TGFβ levels under obesity conditions contribute to adipose tissue fibrosis and inflammation. PDGF signaling induces a myofibroblast-like phenotype in a subset of adipocyte progenitors contributing to ECM deposition. (3) ECM remodeling and fibrosis linking metabolism and cancer: Mammary adipose tissue fibrosis contributes to malignant transformation and breast cancer progression through various mechanisms including collagen-derived endotrophin, increased tissue stiffness activating mechano-sensitive pathways, and induced inflammation (e.g., inducing a tumor-promoting macrophage phenotype). The degree of liver fibrosis is a strong predictor of NAFLD progression towards HCC. Activation of stellate cells (myofibroblast phenotype) by TGFβ and other cytokines mainly contributes to hepatic fibrosis. Stellate cell-secreted cytokines (including TGFbeta, PDGF, and VEGF) induce angiogenesis, reduced immune surveillance, and HCC progression. Obesity-induced pancreatic inflammation and desmoplasis contribute to PDAC progression and chemotherapy resistance
Fig. 1 Overview of fibrosis in cancer and obesity. (1) ECM remodeling and fibrosis in cancer: The development of a fibrotic tumor stroma (desmoplastic reaction) is a multistep process in part driven by activation of cancer-associated fibroblasts (CAFs) and TGFbeta signaling. CAFs and ECM components exert different pro-tumorigenic processes including epithelial-mesenchymal transition (EMT) in tumor cells, thereby inducing tumor progression (metastasis formation). A fibrotic tumor stroma prevents immune cell infiltration, thereby reducing immune surveillance and responsiveness to cancer immunotherapy. (2) Adipose tissue fibrosis in obesity: Obesity-driven pathologic expansion of adipose tissue is characterized by adipocyte hypertrophy and cell death, chronic inflammation (including macrophage infiltration), and enhanced fibrosis. Fibrosis limits the expansion of adipose and contributes to metabolic dysfunction, including systemic inflammation and insulin resistance. Elevated TGFβ levels under obesity conditions contribute to adipose tissue fibrosis and inflammation. PDGF signaling induces a myofibroblast-like phenotype in a subset of adipocyte progenitors contributing to ECM deposition. (3) ECM remodeling and fibrosis linking metabolism and cancer: Mammary adipose tissue fibrosis contributes to malignant transformation and breast cancer progression through various mechanisms including collagen-derived endotrophin, increased tissue stiffness activating mechano-sensitive pathways, and induced inflammation (e.g., inducing a tumor-promoting macrophage phenotype). The degree of liver fibrosis is a strong predictor of NAFLD progression towards HCC. Activation of stellate cells (myofibroblast phenotype) by TGFβ and other cytokines mainly contributes to hepatic fibrosis. Stellate cell-secreted cytokines (including TGFbeta, PDGF, and VEGF) induce angiogenesis, reduced immune surveillance, and HCC progression. Obesity-induced pancreatic inflammation and desmoplasis contribute to PDAC progression and chemotherapy resistanceCC BY · PubMed Central
Fig. 2 Angiogenesis and angiogenic signaling linking cancer and obesity. In the tumor microenvironment (TME), hypoxia induces pro-angiogenic signals, and the “angiogenic switch”, which in turn supports tumor growth, vascular leakiness, and extracellular matrix (ECM) remodeling. VEGF signaling and ANGPTL4 are important players in these processes and are associated with more aggressive tumor behavior. In obesity, the expansion of the adipose tissue (AT) leads to hypoxia, dysfunctional angiogenesis, inflammation, and elevated expression of VEGF and ANGPTL4. The obese AT secretes angiogenic factors and cytokines that promote tumor progression, including VEGF and ANGPTL4, which also act on the AT itself. Therefore, these two factors are an example of molecules at the crossroad between cancer and obesity, and represent targets for therapeutic intervention in both pathological conditions: inhibition of VEGF signaling and ANGPTL4 can inhibit tumor progression, and improve metabolic conditions in obesity, albeit in the latter the different role of VEGF in early and late disease stages needs to be taken into account
Fig. 2 Angiogenesis and angiogenic signaling linking cancer and obesity. In the tumor microenvironment (TME), hypoxia induces pro-angiogenic signals, and the “angiogenic switch”, which in turn supports tumor growth, vascular leakiness, and extracellular matrix (ECM) remodeling. VEGF signaling and ANGPTL4 are important players in these processes and are associated with more aggressive tumor behavior. In obesity, the expansion of the adipose tissue (AT) leads to hypoxia, dysfunctional angiogenesis, inflammation, and elevated expression of VEGF and ANGPTL4. The obese AT secretes angiogenic factors and cytokines that promote tumor progression, including VEGF and ANGPTL4, which also act on the AT itself. Therefore, these two factors are an example of molecules at the crossroad between cancer and obesity, and represent targets for therapeutic intervention in both pathological conditions: inhibition of VEGF signaling and ANGPTL4 can inhibit tumor progression, and improve metabolic conditions in obesity, albeit in the latter the different role of VEGF in early and late disease stages needs to be taken into accountCC BY · PubMed Central
Fig. 3 Overview of adrenergic signaling in cancer and obesity. Adrenergic signaling activates lipolysis, thermogenesis, and energy expenditure in the adipose tissue. Within tumor and tumor microenvironment, adrenergic signaling activates different pro-tumorigenic processes including tumor cell proliferation, angiogenic switch, and epithelial-mesenchymal transition (EMT). Obesity is associated with elevated circulating catecholamines, which can be reduced upon weight loss, but adrenergic signaling is dampened locally within the adipose tissue, contributing to reduced energy expenditure and impaired adipose tissue function. This affects tumors through indirect catecholamine-mediated effects including bioreactive lipids and adipokines. Elevated circulating catecholamines are also present in stress. Many direct tumor-promoting processes, as well as tumor-associated complications (cardiovascular events, cachexia), can be counteracted by beta-blockers. The lack of associations between stress or beta-blockers and cancer outcomes in some studies may result from variabilities in adrenergic signaling due to obesity
Fig. 3 Overview of adrenergic signaling in cancer and obesity. Adrenergic signaling activates lipolysis, thermogenesis, and energy expenditure in the adipose tissue. Within tumor and tumor microenvironment, adrenergic signaling activates different pro-tumorigenic processes including tumor cell proliferation, angiogenic switch, and epithelial-mesenchymal transition (EMT). Obesity is associated with elevated circulating catecholamines, which can be reduced upon weight loss, but adrenergic signaling is dampened locally within the adipose tissue, contributing to reduced energy expenditure and impaired adipose tissue function. This affects tumors through indirect catecholamine-mediated effects including bioreactive lipids and adipokines. Elevated circulating catecholamines are also present in stress. Many direct tumor-promoting processes, as well as tumor-associated complications (cardiovascular events, cachexia), can be counteracted by beta-blockers. The lack of associations between stress or beta-blockers and cancer outcomes in some studies may result from variabilities in adrenergic signaling due to obesityCC BY · PubMed Central
Fig. 4 Schematic representation of fibrosis-, angiogenesis- and beta-adrenergic signaling-related processes and factors contributing to the risk connection between obesity and cancer
Fig. 4 Schematic representation of fibrosis-, angiogenesis- and beta-adrenergic signaling-related processes and factors contributing to the risk connection between obesity and cancerCC BY · PubMed Central

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Metadata

Authors
Pellegata, N. S., Berriel Diaz, M., Rohm, M., & Herzig, S.
Affiliations
University Hospital Heidelberg (DE)
Corresponding author
Herzig, Stephan
ORCID
Venue
Cancer and Metastasis Reviews
Publisher
Springer Science and Business Media LLC
Published
2022-09
Volume
41
Issue
3
Pages
517-547
ISSN
  • 0167-7659 (ISSN-L)
  • 1573-7233
DOI
10.1007/s10555-022-10058-y
PMC
PMC9470659
OpenAlex
W4294992477
Cited by
33
References
266
Citations by year
2026: 6 · 2025: 9 · 2024: 6 · 2023: 12
FWCI
0.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer and Metastasis Reviews (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
  • Site cant be reached (submittedVersion, cc-by)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
Funders
  • Deutsche Krebshilfe (70115158)
  • H2020 European Research Council (949017)
  • Helmholtz Association (Initiative, Networking Fund)
  • European Foundation for the Study of Diabetes
  • Helmholtz Future Topic Aging and Metabolic Programming (AMPro, ZT-0026)
  • Else-Kröner-Fresenius-Stiftung (2020 EKSE.23)
  • Edith-Haberland-Wagner Stiftung
  • DFG (CRC/Transregio 205/2 314061271)
  • Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Risks and Factors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Keywords
obesity, cancer, extracellular matrix remodeling, angiogenesis, adrenergic signaling, obesity-related cancer risk, liver cancer, pancreatic cancer, breast cancer, inflammation, hyperinsulinemia, adipose tissue dysfunction, tumor progression
MeSH terms
Adipose Tissue, Extracellular Matrix, Humans, Neoplasms, Obesity, Adrenergic Agents

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