• Dr Bharat Patodiya

Visualizing the genesis of cancer through a different perspective

Updated: Oct 31

A different perspective on carcinogenesis is offered by a recently proposed cancer theory known as the Systemic-Evolutionary Theory of the Origin of Cancer (SETOC) which views the process of cancer generation through a deep evolutionary root. The theory, which includes features of Margulian evolution (endosymbiosis) and systems cell biology, postulates that one of the main driving forces of carcinogenesis is “de-endosymbiosis” of two evolutionarily embedded cellular systems that have co-evolved in eukaryotic cells. These are the nuclear-cytoplasmic system (derived from the archaeal ancestor), and the mitochondrial system (derived from the α-proteobacterial ancestor), which refer to information and energy, respectively. Thus, the effect of de-endosymbiosis is a mismatch between information and energy in cells, which ultimately leads to uncoordinated cellular behavior. According to the SETOC, cancer is the result of cells in a tissue constantly trying to adapt to long-term damage (dynamic adaptation). Long-term tissue damage can lead to tissue changes, chronic inflammation, and fibrosis, as well as constant attempts by cells to regenerate and repair. The entity of this process is directly dependent on the nature, extent, and persistence of the injury. The consequence is an inappropriate response or “maladaptation” that is matched by a progressive de-endosymbiosis that eventually allows the origin of transformed cells. De-endosymbiosis is meant as the decoupling of information (the nuclear-cytoplasmic system) and energy (the mitochondrial system). The stepwise decoupling of the integrated endosymbiotic systems generates alterations in cellular and tissue organization that are important triggering assets of neoplastic transformation. The breakdown of the ancestral "contract of endosymbiosis" is triggered by the adaptability of cells to changes in the external and internal cellular environment that tends to set up new cellular homeostasis in a way that cells become more resistant to these changes instead of dying. As a consequence, phenotypic features similar to unicellular organisms (phylogenetic inversion) and embryonic development (ontogenetic inversion) can emerge. Thus, the transition to an ancestral-like phenotype allows for the emergence of new cellular organizations, resulting in unique adaptations that depend on new microenvironmental conditions. These emerging features are the adaptation of eukaryotic cells to survive in a hostile tumor microenvironment characterized by low oxygen concentrations, inadequate nutrient supply, increased metabolic waste products, and increased acidity. This is consistent with the hallmarks of cancer. For example, the acquisition of an invasive phenotype is an adaptive response to an altered microenvironment, allowing cells to migrate to seek a more favorable environment at a distance.

Biological tissues are “self-organized” structures stemming from integrated systems of eukaryotic cells. Under physiological conditions, the two cellular endosymbiotic systems are fully integrated to maintain a state of cellular homeostasis and differentiation, which is ensured by constant energy intake. Conversely, when a chronic injury occurs, energy intake declines, leading to the failure of endosymbiosis, and the acquisition of the de-differentiated state defining dysplasia that ultimately transforms into cancer. In conclusion, from the perspective of the SETOC, the process of tumor transformation can be seen as “cellular de-endosymbiosis” underlying dynamic adaptation by a cellular niche to persistent injuries that change the microenvironment. Malignant transformation can also be seen as an extreme attempt to adapt to a changing microenvironment. This view contributes to the understanding of carcinogenesis as an adaptive cellular response to factors that cause long-term tissue damage and promote continuous repair and regeneration of tissue.

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