The systemic evolutionary theory of the origin of cancer (SETOC): an update
Abstract The Systemic Evolutionary Theory of the Origin of Cancer (SETOC) is a recently proposed theory founded on two primary principles: the cooperative and endosymbiotic process of cell evolution as described by Lynn Margulis, and the integration of complex systems operating in eukaryotic cells,...
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2025-01-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-025-01069-w |
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| author | Antonio Mazzocca Giovanni Ferraro Giovanni Misciagna |
| author_facet | Antonio Mazzocca Giovanni Ferraro Giovanni Misciagna |
| author_sort | Antonio Mazzocca |
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| description | Abstract The Systemic Evolutionary Theory of the Origin of Cancer (SETOC) is a recently proposed theory founded on two primary principles: the cooperative and endosymbiotic process of cell evolution as described by Lynn Margulis, and the integration of complex systems operating in eukaryotic cells, which is a core concept in systems biology. The SETOC proposes that malignant transformation occurs when cells undergo a continuous adaptation process in response to long-term injuries, leading to tissue remodeling, chronic inflammation, fibrosis, and ultimately cancer. This process involves a maladaptive response, wherein the 'endosymbiotic contract’ between the nuclear-cytoplasmic system (derived from the primordial archaeal cell) and the mitochondrial system (derived from the primordial α-proteobacterium) gradually breaks down. This ultimately leads to uncoordinated behaviors and functions in transformed cells. The decoupling of the two cellular subsystems causes transformed cells to acquire phenotypic characteristics analogous to those of unicellular organisms, as well as certain biological features of embryonic development that are normally suppressed. These adaptive changes enable cancer cells to survive in the harsh tumor microenvironment characterized by low oxygen concentrations, inadequate nutrients, increased catabolic waste, and increased acidity. De-endosymbiosis reprograms the sequential metabolic functions of glycolysis, the TCA cycle, and oxidative phosphorylation (OxPhos). This leads to increased lactate fermentation (Warburg effect), respiratory chain dysfunction, and TCA cycle reversal. Here, we present an updated version of the SETOC that incorporates the fundamental principles outlined by this theory and integrates the epistemological approach used to develop it. |
| format | Article |
| id | doaj-art-dc19f7f961d3481baf99159df1caf217 |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| spelling | doaj-art-dc19f7f961d3481baf99159df1caf2172025-01-19T12:27:23ZengBMCMolecular Medicine1528-36582025-01-0131111110.1186/s10020-025-01069-wThe systemic evolutionary theory of the origin of cancer (SETOC): an updateAntonio Mazzocca0Giovanni Ferraro1Giovanni Misciagna2Interdisciplinary Department of Medicine, University of Bari School of MedicineAssociation for Systems ScienceAssociation for Systems ScienceAbstract The Systemic Evolutionary Theory of the Origin of Cancer (SETOC) is a recently proposed theory founded on two primary principles: the cooperative and endosymbiotic process of cell evolution as described by Lynn Margulis, and the integration of complex systems operating in eukaryotic cells, which is a core concept in systems biology. The SETOC proposes that malignant transformation occurs when cells undergo a continuous adaptation process in response to long-term injuries, leading to tissue remodeling, chronic inflammation, fibrosis, and ultimately cancer. This process involves a maladaptive response, wherein the 'endosymbiotic contract’ between the nuclear-cytoplasmic system (derived from the primordial archaeal cell) and the mitochondrial system (derived from the primordial α-proteobacterium) gradually breaks down. This ultimately leads to uncoordinated behaviors and functions in transformed cells. The decoupling of the two cellular subsystems causes transformed cells to acquire phenotypic characteristics analogous to those of unicellular organisms, as well as certain biological features of embryonic development that are normally suppressed. These adaptive changes enable cancer cells to survive in the harsh tumor microenvironment characterized by low oxygen concentrations, inadequate nutrients, increased catabolic waste, and increased acidity. De-endosymbiosis reprograms the sequential metabolic functions of glycolysis, the TCA cycle, and oxidative phosphorylation (OxPhos). This leads to increased lactate fermentation (Warburg effect), respiratory chain dysfunction, and TCA cycle reversal. Here, we present an updated version of the SETOC that incorporates the fundamental principles outlined by this theory and integrates the epistemological approach used to develop it.https://doi.org/10.1186/s10020-025-01069-wCancer theoriesEndosymbiosisArchaeaEvolutionSystems biologyMitochondria |
| spellingShingle | Antonio Mazzocca Giovanni Ferraro Giovanni Misciagna The systemic evolutionary theory of the origin of cancer (SETOC): an update Molecular Medicine Cancer theories Endosymbiosis Archaea Evolution Systems biology Mitochondria |
| title | The systemic evolutionary theory of the origin of cancer (SETOC): an update |
| title_full | The systemic evolutionary theory of the origin of cancer (SETOC): an update |
| title_fullStr | The systemic evolutionary theory of the origin of cancer (SETOC): an update |
| title_full_unstemmed | The systemic evolutionary theory of the origin of cancer (SETOC): an update |
| title_short | The systemic evolutionary theory of the origin of cancer (SETOC): an update |
| title_sort | systemic evolutionary theory of the origin of cancer setoc an update |
| topic | Cancer theories Endosymbiosis Archaea Evolution Systems biology Mitochondria |
| url | https://doi.org/10.1186/s10020-025-01069-w |
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