Tumor Reversion
What is Tumor Reversion
Tumor phenotype can be successfully ‘reversed’
The irreversibility of cancer transformation is a concept taken for granted that proved to be groundless. Indeed, this belief can hardly accommodate with results provided by early studies in which cancer cells were co-cultured within morphogenetic fields, showing that the tumor may successfully ‘revert’ into a normal phenotype. Indeed, it is now widely accepted that essentially all cell types can be reprogrammed, at least in vitro.
An impressive body of data suggest that cancer cells may arise from unsuccessfully differentiated cells and reinforce the hypothesis for which cancer should be regarded as a ‘development gone awry’. Therefore, it can be hypothesized that the ‘abnormal’, cancerous phenotype could be ‘reversed’ by properly modifying the network of biophysical/molecular cues acting at the cell-microenvironment.
Since the sixties, it was ascertained that by placing tumor cells in modified cell culture or embryonic-like morphogenetic fields, cancer might be reoriented towards a normal phenotype by overriding carcinogenic events, irrespective of the presence of mutated gene inside their genome. Those effects were confirmed by changes in morphological, biochemical, behavioral as well as metabolomics features. These effects have been observed in vitro and also established in few clinical trials. Embryo and stem cell-dependent microenvironment may likely act by modifying some biophysical cues, as well as through soluble morphogens, involving several key pathways, including apoptosis and differentiation. Namely, by culturing cancer cells in embryonic-conditioned environments or by treating tumor cells with embryonic extracts, tumor specimens can be committed towards apoptosis or cell differentiation, ultimately leading to cancer reversion (Fig.1 and 2).
Additionally, several experimental and clinical studies demonstrated that those compounds exert a significant clinical activity, both as chemo-preventive agents as well as anti-cancer drugs
Cell reprogramming and Tumor Reversion
Cell reprogramming represents a major advancement in cell biology and has wide applications in regenerative medicine and cancer management. Indeed, pluripotent stem cells (iPSCs) can be obtained from somatic cells by the forced expression of a few transcription factors. Consequently, differentiation cannot be longer considered an ‘irreversible’ commitment. Plasticity of cells and tissues is indeed even wider than imagined and those results force us now to revise our conceptions on the fundamentals of biology.
If a somatic cell can be reprogrammed towards its totipotent state, why a cancer cell should not be ‘reversed’ becoming so far a ‘normal’ cell?
Perspectives
These data bear huge implications, from both a clinical and a theoretical perspective.
- For cancer is successfully ‘reverted’ by manipulating cell stroma interactions implies we have to change radically our methodological and theoretical approach.
- The reversion model allows providing promising therapeutic benefit by adopting a very new investigational method. Indeed, others, and we have proposed an unsupervised approach, based on an ‘inverse theoretical model’. Studies on anti-cancer drug discovery are usually aimed at identifying genetic/molecular differences among ‘normal’ vs ‘transformed’ cells. Instead, we propose to identify the critical steps of cancer transformation by analyzing the inverse problem, i.e. the occurrence of phenotype reprogramming investigated by means of an integrated systemic methodology. This framework will allow us in identifying the pivotal hubs governing the phenotypic transition.
- As cancer can be successfully ‘reprogrammed’ by modifying the dynamical cross talk with its microenvironment – namely by modulating EMT and MET – thus the cell-stroma interactions must be recognized as targets for pharmacological intervention [192]. This imply a reassessment of our pharmacological ‘luggage’ in order to identify those agents able in modifying the pivotal hubs governing the interaction among cells and their stroma. Identification of such pathways are likely to provide new targets for pharmacological intervention.
Perspectives
These data bear huge implications, from both a clinical and a theoretical perspective.
- For cancer is successfully ‘reverted’ by manipulating cell stroma interactions implies we have to change radically our methodological and theoretical approach.
- The reversion model allows providing promising therapeutic benefit by adopting a very new investigational method. Indeed, others, and we have proposed an unsupervised approach, based on an ‘inverse theoretical model’. Studies on anti-cancer drug discovery are usually aimed at identifying genetic/molecular differences among ‘normal’ vs ‘transformed’ cells. Instead, we propose to identify the critical steps of cancer transformation by analyzing the inverse problem, i.e. the occurrence of phenotype reprogramming investigated by means of an integrated systemic methodology. This framework will allow us in identifying the pivotal hubs governing the phenotypic transition.
- As cancer can be successfully ‘reprogrammed’ by modifying the dynamical cross talk with its microenvironment – namely by modulating EMT and MET – thus the cell-stroma interactions must be recognized as targets for pharmacological intervention [192]. This imply a reassessment of our pharmacological ‘luggage’ in order to identify those agents able in modifying the pivotal hubs governing the interaction among cells and their stroma. Identification of such pathways are likely to provide new targets for pharmacological intervention.
Cell reprogramming and Tumor Reversion
Cell reprogramming represents a major advancement in cell biology and has wide applications in regenerative medicine and cancer management. Indeed, pluripotent stem cells (iPSCs) can be obtained from somatic cells by the forced expression of a few transcription factors. Consequently, differentiation cannot be longer considered an ‘irreversible’ commitment. Plasticity of cells and tissues is indeed even wider than imagined and those results force us now to revise our conceptions on the fundamentals of biology.
If a somatic cell can be reprogrammed towards its totipotent state, why a cancer cell should not be ‘reversed’ becoming so far a ‘normal’ cell?
Overall, these considerations disclose new standpoints in cancer research and should receive even increased interest, given that understanding the mechanisms modulating the tumor microenvironment and the mesenchymal-epithelial transition [195, 196], may facilitate the design of a novel anticancer strategy focused on mimicking or activating the tumor reversion pathway