Endogenous molecular network reveals two mechanisms of heterogeneity within gastric cancer

// Site Li 1 , Xiaomei Zhu 2 , Bingya Liu 1, 3 , Gaowei Wang 1 , Ping Ao 1, 4, 5 1 Shanghai Center for Systems Biomedicine, Ministry of Education Key Laboratory of Systems Biomedicine, Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China 2 GenMath, Seattle, WA 98105, USA 3 Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China 4 State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China 5 Department of Physics, Shanghai Jiao Tong University, Shanghai 200240, China Correspondence to: Ping Ao, e-mail: aoping@sjtu.edu.cn Keywords: gastric cancer, endogenous molecular network, intratumor heterogeneity, attractor, systems biology Received: October 9, 2014      Accepted: April 10, 2015      Published: April 24, 2015 ABSTRACT Intratumor heterogeneity is a common phenomenon and impedes cancer therapy and research. 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. A qualitative systematic framework, the endogenous molecular network hypothesis, has recently been proposed to understand cancer genesis and progression. Here, a minimal network corresponding to such framework was found for GC and was quantified via a stochastic nonlinear dynamical system. We then further extended the framework to address the important question of intratumor heterogeneity quantitatively. 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. 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.