Exploring The Underlying Physical Mechanism And Relationships Among Tumor,EMT,and Cancer Stem Cells With Heterogeneity

Cancer is considered to be one of the most deadly diseases for human beings in recent years.Many studies have been demonstrated that recurrence and metastasis are the greatest obstacles in cancer curing.If a tumor is metastasis to other organs,it will become a fatal cancer.There are many factors can result to the cancer recurrence and metastasis.Cancer stem cells(CSCs)have been regarded as cancer seeds,that have very close relationship with the cancer recurrence.Epithelial-mesenchymal transition(EMT)has been studied to be a key step for cancer metastasis.As the EMT process can help tumor cells migrate from one tissue to the other.Furthermore,EMT process also contributes to make the non-stem cells turning to stemness cells.Heterogeneity is ubiquitous in organisms such as stem cells.Researchers have been reported that heterogeneity is also existed in cancer cells and CSCs.Heterogeneity of cancer cell or CSCs can result the tumor with multiple sub-populations which manifested diverse cancer specificity.These make the cancer curing more difficult.Furthermore,many meta-states of cancer are the beginning of micro-metastasis in the body,which will increase the possibility of metastasis to a large extent.In this thesis,we aim to quantify the mechanisms and relationship of the cancer,EMT and cancer stem cells in an integrated way.This can help us systematic understanding the physical mechanisms and interrelationships among cancer,metastasis and development.Moreover,we quantify the heterogeneity of SC,CSC and cancer at both genetic and epigenetic effects.Elucidating the origin of heterogeneity of SC,CSCS and cancer has clinical significance which will help to understand the cellular basis of treatment,therapeutic resistance,and cancer relapse.The main contents include:We constructed a gene regulatory network involving the specific genes and micro-RNAs of SC,cancer and CSCs.In this network,it contains one marker gene of stem cell(OCT4),two oncogenes of cancer(P53 and MDM2),one significance gene of metastasis(ZEB)and two micro-RNAs(miR-145 and miR-200)which are very vital in the regulations.These regulations we used are all from literature research(text mining).We use Gillespie algorithm to simulate our gene regulatory network.To explore the epigenetic aspects precisely,we set more time scale parameters of the regulatory process such as protein binding/unbinding and protein synthesis/degradation rate.We develop a landscape framework to quantify the adiabatic and non-adiabatic regime of SC,CSC and cancer.In the adiabatic condition(relatively fast regulatory and synthesis rates among genes),seven states(SC,CSC,Cancer,Premalignant,Normal,Lesion and Hyperplasia)emerge.In non-adiabatic regime(relatively slow regulatory and synthesis rates among genes),multiple meta-stable states emerged which can explain the origin of heterogeneity.We calculated the barrier heights and flux of the states.The barrier heights can demonstrate the stability of the states and the switching frequency between states.This will help us understanding the cancer mechanism in a quantitative way.In the landscape,there are three pathways which lead from normal to cancer.We calculated the flux of the three pathways.The flux can help us figure out which pathway is the dominant in the cancer formation.We use global sensitivity analysis to uncover which regulation is more sensitive.We found three regulations which are vital to cancer or stem cells:mir200-|ZEB;OCT4?OCT4 and P53?P53.The regulations may be useful for cancer curing as it may provide reference significance on drug design.This may give a guide on clinical experiments of cancer...