Changing mutational and adaptive landscapes and the genesis of cancer

Abstract

By the time the process of oncogenesis has produced an advanced cancer, tumor cells have undergone extensive evolution. The cellular phenotypes resulting from this evolution have been well studied, and include accelerated growth rates, apoptosis resistance, immortality, invasiveness, and immune evasion. Yet with all of our current knowledge of tumor biology, the details of early oncogenesis have been difficult to observe and understand. Where different oncogenic mutations may work together to enhance the survival of a tumor cell, in isolation they are often pro-apoptotic, pro-differentiative or pro-senescent, and therefore often, somewhat paradoxically, disadvantageous to a cell. It is also becoming clear that somatic mutations, including those in known oncogenic drivers, are common in tissues starting at a young age. These observations raise the question: how do we largely avoid cancer for most of our lives? Here we propose that evolutionary forces can help explain this paradox. As humans and other organisms age or experience external insults such as radiation or smoking, the structure and function of tissues progressively degrade, resulting in altered stem cell niche microenvironments. As tissue integrity declines, it becomes less capable of supporting and maintaining resident stem cells. These stem cells then find themselves in a microenvironment to which they are poorly adapted, providing a competitive advantage to those cells that can restore their functionality and fitness through mutations or epigenetic changes. The resulting oncogenic clonal expansions then increase the odds of further cancer progression. Understanding how the causes of cancer, such as aging or smoking, affect tissue microenvironments to control the impact of mutations on somatic cell fitness can help reconcile the discrepancy between marked mutation accumulation starting early in life and the somatic evolution that leads to cancer at advanced ages or following carcinogenic insults.

Clinical characterization of patients with non-small cell lung cancer according to the intensity of smoking and stage in which non-small cell lung cancer is diagnosed

“…It could be suggested that environmentally induced carcinogenesis in general, and smoking in particular, is not limited to the sequential accumulation in time of mutations "essential" for tumor progression; but it is essential the tissue context in which the progression takes place, and the effect of exposure to environmental mutagen. 16,17,34,35 There is no doubt that all the patients included in this study developed lung cancer; However, a relationship between time without direct exposure to the cigarette and the lower stage at the moment of detecting the tumor is evident, so it would be plausible to assume that although the processes of tumor initiation and progression took place in all individuals, the evolution further neoplasia was "hampered" in patients who quit, perhaps, and according to the theory of adaptive oncogenesis, by persistence, or regeneration of less permissible neoplastic progression 16,17 cellular microenvironments. Observations parallel to these have been reported by other authors: Mong et al 36 carried out an impeccable cohort study in this regard; in which 77% of the patients had a history of previous smoking.…”

“…The theory of adaptive oncogenesis in turn suggests that the transforming nature of oncogenic mutations depends tissue context in which they occur, and not the simple accumulation in time and space. 16,17 The practical implications of both paradigms are still evident, to the point that there are authors who, based on the theory of somatic mutation, have advocated that two thirds of all human tumours are caused by the accumulation of mutations during normal divisions of the stem cells contained in the tissues. 18 Lung cancer is not excluded from the debate, since from the previous assertions, it has been suggested that the effect of smoking on the risk of developing this neoplasm is when more "additive".…”

Prelude and premise to the special issue: disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer”

“…Mutations are found in cancerous tissues and in normal tissues and "many (perhaps most) mutations observed in cancer cells occurred prior to somatic evolution and may not contribute to the cell's malignant phenotype" [35]. There is increasing evidence that the occurrence of "oncogenic" mutations is insufficient to explain cancer incidence [36]. It is evident that the process of cancer development, i.e., carcinogenesis, is not just derived from "simply clonally evolved epithelial cells that have accumulated a critical number of mutations but rather act as dysfunctional tissues where the mesenchymal component plays a critical role in tumour pathogenesis" [37 reviewed in 38].…”

Relevance of Non-Targeted Effects for Radiotherapy and Diagnostic Radiology

“…to the abolition of pre-cancerous cells [110]. Induction of NTE signalling probably has multiple roles depending on other factors such as genetic or epigenetic makeup [111], environmental or lifestyle factors [112] or age [113], all of which can modulate the processes of NTE and the outcomes which may ultimately emerge. Key…”