Endogenous Molecular-Cellular Network Cancer Theory: A Systems Biology Approach

Abstract

In light of ever apparent limitation of the current dominant cancer mutation theory, a quantitative hypothesis for cancer genesis and progression, endogenous molecular-cellular network hypothesis has been proposed from the systems biology perspective, now for more than 10 years. It was intended to include both the genetic and epigenetic causes to understand cancer. Its development enters the stage of meaningful interaction with experimental and clinical data and the limitation of the traditional cancer mutation theory becomes more evident. Under this endogenous network hypothesis, we established a core working network of hepatocellular carcinoma (HCC) according to the hypothesis and quantified the working network by a nonlinear dynamical system. We showed that the two stable states of the working network reproduce the main known features of normal liver and HCC at both the modular and molecular levels. Using endogenous network hypothesis and validated working network, we explored genetic mutation pattern in cancer and potential strategies to cure or relieve HCC from a totally new perspective. Patterns of genetic mutations have been traditionally analyzed by posteriori statistical association approaches in light of traditional cancer mutation theory. One may wonder the possibility of a priori determination of any mutation regularity. Here, we found that based on the endogenous network theory the features of genetic mutations in cancers may be predicted without any prior knowledge of mutation propensities. Normal hepatocyte and cancerous hepatocyte stable states, specified by distinct patterns of expressions or activities of proteins in the network, provide means to directly identify a set of most probable genetic mutations and their effects in HCC. As the key proteins and main interactions in the network are conserved through cell types in an organism, similar mutational features may also be found in other cancers. This analysis yielded straightforward and testable predictions on an accumulated and preferred mutation spectrum in normal tissue. The validation of predicted cancer state mutation patterns demonstrates the usefulness and potential of a causal dynamical framework to understand and predict genetic mutations in cancer. We also obtained the following implication related to HCC therapy, (1) specific positive feedback loops are responsible for the maintenance of normal liver and HCC; (2) inhibiting proliferation and inflammation-related positive feedback loops, and simultaneously inducing liver-specific positive feedback loop is predicated as the potential strategy to cure or relieve HCC; (3) the genesis and regression of HCC is asymmetric. In light of the characteristic property of the nonlinear dynamical system, we demonstrate that positive feedback loops must be existed as a simple and general molecular basis for the maintenance of phenotypes such as normal liver and HCC, and regulating the positive feedback loops directly or indirectly provides potential strategies to cure or relieve HCC.

Towards the First Principles in Biology and Cancer: New Vistas in Computational Systems Biology of Cancer

“…This hypothesis was applied to study prostate, liver, and gastric cancers, and surprisingly, all cases fitted well with the same core composition [65]. The network resulted in a landscape consisting of many locally (robust) stable normal states and several unhealthy states with no obvious function [52].…”

“…At present, "the modeling of all interactions remains beyond our capabilities" [51]. The ENH concept was further developed in a subsequent paper by Ping Ao's group (e.g., [52]). Huang et al [53] expanded on the term of attractor state previously proposed by Kaufman as "a set of numerical values toward which a system tends to evolve, for a wide variety of starting conditions of the system."…”

“…Mutation as the only cause of cancer has been rejected based on this complex interplay of energy, information, and the matter, presented only in a qualitative way. Another addition worth mentioning is that the Ping Ao's endogenous core protein/gene is constant over the cancer development [52], Li and Wang's [68] endogenous gene set changes during this stage, which is more realistic. In addition, their method uses a set of mRNAs as well as relevant genes.…”

Evolution of the Telencephalon Anterior-Posterior Patterning by Core Endogenous Network Bifurcation

“…For the evolution of the telencephalon anterior-posterior patterning, we found that such a 5-node network alone is sufficient to draw an answer, but it is not enough for the evolution of the whole central nervous system, let alone the entire vertebrate body plan. The network described in this work can be taken as a subnetwork (Wang et al, 2018), which has the potential to expand into the global decision-making network for the evolution and development of the central nervous system or even the entire vertebrate body plan shaped by evolution.…”

Why Is Importance the Reprogramming and Remodeling In Malignant Hematopoietic Microenvironment and Its Hematopoietic Stem Cells Too

“…The role of hematopoietic research about single cell studies are important in last decade but we have some complex in the regenerative system. So, it is better to determine the exact role of involved molecules in clonal expansion and implication of invasion for deconstructing the molecular network including the normal situation to abnormal and malignant stem cells as well [5][6][7][8][25][26][27]. In fact, acute leukemia is a heterogeneous clonal disorder of hematopoietic progenitor cells characterized by proliferation of stem cell as such progenitor cell in bone marrow patients, and so identified a subpopulation of leukemic cells called leukemic stem cells(LSCs).…”