Molecular Mechanism Of Transition From Inflammation To Cancer Investigated By Multiscale Network Modeling

Chronic inflammatory diseases and chronic inflammation-related cancer bring a global public health burden,and lack of efficient treatments makes this situation worse.Ample evidences suggest that these two disorders are closely related.Basic knowledge corresponding to these two diseases,respectively,have been achieved by previous studies.However,the cellular and molecular mechanism that control the evolution of inflammation from acute phase to a chronic inflammation,and further malignant transition to caner remains unclear.Although a large number of experiment data have been obtained by clinical and laboratory studies,few breakthroughs were obtained.The immune system of human body is comprised by immune molecules,cells,tissue and organ etc.which shows a multiscale nature in space.While the timescale corresponding to each interaction between species in immune system may vary from sub-second to mouths,or even years.The multilevel and highly non-linearity nature of immune system makes it difficult to address the aforementioned problem.Recently,system biology modeling has increasingly been proved to be a useful tool in addressing problems encountered in complex biological systems.In this work,we take advantage of network modeling methods,integrated processes include gene transcription regulation in nucleus,intracellular signaling transduction,molecule-to-cell and cell-to-cell interactions and also the interaction among molecules,cells and tissue,constructed a multi-nodes model which describing the kinetics of the inflammation system.Our modeling results provide valuable insights to the problem posed above.Specific works and innovations are as follows:First,we studied the tolerance phenomenon of TNF-agene transcription in LPS stimulated macrophages.This work provided a mechanistic explanation to the regulation mechanism of endotoxin tolerance,and revealed how the regulation at signal transduction level and the regulation at gene level differently affect the transcription profile of a specific gene.This is important in understanding the role of gene transcription regulation in diseases(such as septic shock).Second,we studied the regulation mechanism of how the immune system transition from an acute inflammation state to a chronic inflammation state,with the cigarette smoke induced chronic obstructive pulmonary disease(COPD)as a specific example.The most important finding in this work is the identification of a key component in the disease network that controls this transition,i.e.the coupled positive feedback loops.Further,we have fund the mathematical basis for this phenomenon,i.e.bifurcation theory.This work also provides a clear mechanistic explanation to problems such as how cessation of smoking affects the development of COPD,how exactly the susceptibility towards COPD among populations is defined,etc.Our model also revealed that a specific phenotype of this heterogeneous disease may corresponding to several different endotypes,which provides valuable guides to the development of personalized medicine for COPD.Finally,we address the problem how CS-induced COPD contributes to lung cancer.In this work,we created a simple model on the basis of previous works,and use this simple model as a guide for the construction of the mechanistic model.We have identified key network modules that regulates the generation of COPD,the initiation of tumor and malignant growth of tumor.Combined with previous COPD model,we provide a clear mechanistic explanation to problems that when tumor is eliminated,and when tumor may malignant progression.These findings are valuable guides for the development of immunotherapy and personalized medicine for cancer treatment.