Abstract
BackgroundCancer reversion, converting the phenotypes of a cancer cell into those of a normal cell, has been sporadically observed throughout history. However, no systematic analysis has been attempted so far.ResultsTo investigate this from a systems biological perspective, we have constructed a logical network model of colorectal tumorigenesis by integrating key regulatory molecules and their interactions from previous experimental data. We identified molecular targets that can reverse cancerous cellular states to a normal state by systematically perturbing each molecular activity in the network and evaluating the resulting changes of the attractor landscape with respect to uncontrolled proliferation, EMT, and stemness. Intriguingly, many of the identified targets were well in accord with previous studies. We further revealed that the identified targets constitute stable network motifs that contribute to enhancing the robustness of attractors in cancerous cellular states against diverse regulatory signals.ConclusionsThe proposed framework for systems analysis is applicable to the study of tumorigenesis and reversion of other types of cancer.
Highlights
Cancer reversion, converting the phenotypes of a cancer cell into those of a normal cell, has been sporadically observed throughout history
Proposed network model recapitulating the various cancer reversion phenomena With our logical network model of colorectal cancer, we have tested whether it can successfully recapitulate both the dynamics of colon cancer cell and various cancer reversion phenomena reported in previous studies [18]
We have projected the 12 mutation profiles sets randomly selected from four consensus molecular subtypes (CMS) of colorectal cancer into our network model to obtain 48 CMS network models [29]
Summary
Cancer reversion, converting the phenotypes of a cancer cell into those of a normal cell, has been sporadically observed throughout history. The most common features of cancer are uncontrolled proliferation, epithelial-mesenchymal transition (EMT), and stemness [2]. These features and their underlying mechanisms were extensively studied, cancer still remains as a complex disease with no single cure probably due to a lack of systematic approach. Cancer is evolved from normal cells which are transformed by a number of genetic mutations accumulated in various signaling pathways during tumorigenesis [3]. Such alterations often make cancer cells more robust than normal cells to an external apoptotic stimulus such as targeted drugs in therapeutic approach.
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