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.
Highlights
Intratumor phenotypic heterogeneity is a defining characteristic of human tumors
Two mechanisms that contribute to Gastric cancer (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
Clonal evolution theory emphasizes that tumor heterogeneity is the result of heritable genetic and epigenetic variation [8], whereas cancer stem cell (CSC) theory proposes that cancer cells stay in different differentiated states and exhibit tumor heterogeneity [9]
Summary
Intratumor phenotypic heterogeneity is a defining characteristic of human tumors. Cancer cell populations within tumors manifest various traits, including growth rates [1, 2], metastatic capacity [3], and therapy resistance [4, 5]. Two models have been proposed to explain how heterogeneity arises and contributes to cancer progression. Clonal evolution theory emphasizes that tumor heterogeneity is the result of heritable genetic and epigenetic variation [8], whereas cancer stem cell (CSC) theory proposes that cancer cells stay in different differentiated states and exhibit tumor heterogeneity [9]. Genetic mutation, epigenetic variations and tumor microenvironment, which contribute to tumor heterogeneity have been discussed and reviewed [10,11,12,13,14]. Studies suggest that the relationship between genotype and phenotype is more complex than a one-to-one relation, and a complicated regulatory network may control heterogeneous functional phenotypes [11, 21,22,23,24,25]. A systematic understanding of the specific driving forces behind heterogeneous subtypes of cancer via an integrated network is required
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