Endogenous Molecular Network Reveals Mechanisms Of Heterogeneity Within Gastric Cancer

Intratumor heterogeneity is a common phenomenon and impedes cancer therapy and research.Two models,the clonal evolution and cancer stem cell model,were proposed to explain cancer development,progression and tumor cell heterogeneity.According to the two models,morphological and physiological heterogeneity arise among tumor cells within the same tumour as a consequence of genetic change,epigenetic modification and environmental differences.In addition,some cancers contain a hierarchy in which tumorigenic cancer stem cells differentiate into non-tumorigenic progeny,in which was regarded as a unidirectional process.However,evolving evidences showed that genetic change,epigenetic modification and environmental differences are not enough to explain the morphological and physiological heterogeneity of tumor cells.Besides,considerable plasticity was found in tumor cells.Recently,the endogenous molecular network theory was proposed from a systematic and quantitative perspective to understand the cancer genesis,development and heterogeneity.We then further extended the framework to address the important question of intratumor heterogeneity quantitatively.Gastric cancer(GC)cells have generally been classified into two heterogeneous cellular phenotypes,the gastric and intestinal types,yet the mechanisms of maintaining two phenotypes and controlling phenotypic transition are largely unknown.Here,a minimal network corresponding to such framework was found for GC and was quantified via a stochastic nonlinear dynamical system.The working network characterized main known features of normal gastric epithelial and GC cell phenotypes.Our results demonstrated that four positive feedback loops in the network are critical for GC cell phenotypes.Moreover,two mechanisms that contribute to GC cell heterogeneity were identified: particular positive feedback loops are responsible for the maintenance of intestinal and gastric phenotypes;GC cell progression routes that were revealed by the dynamical behaviors of individual key components are heterogeneous.Moreover,we compared the similarity and differences among the endogenous molecular network and the clonal evolution and cancer stem cell theory and found that the endogenous molecular network is compatible with the other two models.Genetic change,epigenetic modification and environmental differences can regulate phenotype of tumor cells through influenceing the activity and stability of particular positive feedback loops in the network.In this work,we constructed an endogenous molecular network of GC that can be expanded in the future and would broaden the known mechanisms of intratumor heterogeneity.