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Cited by 284Redox biology and oxidative stressCancer and biochemical researchCancer Cells and Metastasis

The DOI matches its Crossref record; 106 of the 106 references it cites were found in a registry or an index.

Reactive oxygen species: a volatile driver of field cancerization and metastasis

Open access
Liao, Zehuan, Chua, Damien, Tan, Nguan Soon·2019·Molecular Cancer
DOI 10.1186/s12943-019-0961-yPMC PMC6441160
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Abstract

Field cancerization and metastasis are the leading causes for cancer recurrence and mortality in cancer patients. The formation of primary, secondary tumors or metastasis is greatly influenced by multifaceted tumor-stroma interactions, in which stromal components of the tumor microenvironment (TME) can affect the behavior of the cancer cells. Many studies have identified cytokines and growth factors as cell signaling molecules that aid cell to cell communication. However, the functional contribution of reactive oxygen species (ROS), a family of volatile chemicals, as communication molecules are less understood. Cancer cells and various tumor-associated stromal cells produce and secrete a copious amount of ROS into the TME. Intracellular ROS modulate cell signaling cascades that aid in the acquisition of several hallmarks of cancers. Extracellular ROS help to propagate, amplify, and effectively create a mutagenic and oncogenic field which facilitate the formation of multifoci tumors and act as a springboard for metastatic tumor cells. In this review, we summarize our current knowledge of ROS as atypical paracrine signaling molecules for field cancerization and metastasis. Field cancerization and metastasis are often discussed separately; we offer a model that placed these events with ROS as the focal instigating agent in a broader "seed-soil" hypothesis.

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Fig. 1 Fate of ROS: NOX proteins are integral membrane proteins of cells and release superoxides (O2•−) as products directly into the extracellular space. Functional NOX proteins can also be internalized into forming redoxosomes, producing superoxides (O2•−) within the redoxosomes. Furthermore, from cells such as macrophages, exosomal NOX complexes can be released and being incorporated into surrounding cells via endocytosis. Besides NOX, xanthine oxidase and nitric oxide synthase proteins (both not shown) can also generate extracellular and intracellular superoxides (O2•−) respectively. Superoxides (O2•−) are relatively impermeable through the cell membrane. However, intracellular and extracellular SOD proteins catalyze the dismutation of superoxides (O2•−) into H2O2 and O2. H2O2 molecules are relatively permeable through the aquaporins of the cell membrane and hence, can travel easily from cell to cell, providing regional oxidative stress
Fig. 1 Fate of ROS: NOX proteins are integral membrane proteins of cells and release superoxides (O2•−) as products directly into the extracellular space. Functional NOX proteins can also be internalized into forming redoxosomes, producing superoxides (O2•−) within the redoxosomes. Furthermore, from cells such as macrophages, exosomal NOX complexes can be released and being incorporated into surrounding cells via endocytosis. Besides NOX, xanthine oxidase and nitric oxide synthase proteins (both not shown) can also generate extracellular and intracellular superoxides (O2•−) respectively. Superoxides (O2•−) are relatively impermeable through the cell membrane. However, intracellular and extracellular SOD proteins catalyze the dismutation of superoxides (O2•−) into H2O2 and O2. H2O2 molecules are relatively permeable through the aquaporins of the cell membrane and hence, can travel easily from cell to cell, providing regional oxidative stressCC BY · PubMed Central
Fig. 2 ROS in the TME: ROS can directly or indirectly modulate the functions of many cell types in the TME. ROS are able to transform normal epithelial cells and normal fibroblasts into malignant cells and CAFs respectively. ROS produced by cancer cells, TAMs and MDSCs can have an immunosuppressive effect on T-cells and B-cells. ROS can accumulate in the extracellular matrix, causing neighboring normal cells to acquire malignant phenotypes. Migration of the ROS-producing cells (cancer cells, CAFs, TAMs, MDSCs) to distant tissue or organ can start a new cancer field, transforming neighboring normal cells into cancer supporting cells or new malignant cells. This expanding field provides the appropriate “soil” for the survival and growth of newly-disseminated cancer cells or newly-transformed cells (the “seed”)
Fig. 2 ROS in the TME: ROS can directly or indirectly modulate the functions of many cell types in the TME. ROS are able to transform normal epithelial cells and normal fibroblasts into malignant cells and CAFs respectively. ROS produced by cancer cells, TAMs and MDSCs can have an immunosuppressive effect on T-cells and B-cells. ROS can accumulate in the extracellular matrix, causing neighboring normal cells to acquire malignant phenotypes. Migration of the ROS-producing cells (cancer cells, CAFs, TAMs, MDSCs) to distant tissue or organ can start a new cancer field, transforming neighboring normal cells into cancer supporting cells or new malignant cells. This expanding field provides the appropriate “soil” for the survival and growth of newly-disseminated cancer cells or newly-transformed cells (the “seed”)CC BY · PubMed Central

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Metadata

Authors
Liao, Z., Chua, D., & Tan, N. S.
Affiliations
Nanyang Technological University (SG)
Corresponding author
Tan, Nguan Soon
ORCID
Venue
Molecular Cancer
Publisher
Springer Science and Business Media LLC
Published
2019-03-30
Volume
18
Issue
1
Pages
65-65
ISSN
1476-4598 (ISSN-L)
DOI
10.1186/s12943-019-0961-y
PMC
PMC6441160
OpenAlex
W2943576188
Cited by
284
References
106
Citations by year
2026: 18 · 2025: 34 · 2024: 38 · 2023: 42 · 2022: 60 · 2021: 51 · 2020: 32 · 2019: 8
FWCI
3.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DR-NTU (Nanyang Technological University) (submittedVersion, cc-by)
Funders
Ministry of Education, Singapore (2014-T2-1-012, 2017-T1-002-103)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
reactive oxygen species, field cancerization, metastasis, tumor microenvironment, tumor-stroma interactions, paracrine signaling, multifocal tumors, cancer hallmarks, cytokines and growth factors
MeSH terms
Animals, Cell Communication, Humans, Neoplasm Metastasis, Neoplasms, Signal Transduction, Reactive Oxygen Species, Oxidative Stress

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