Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The epithelial-mesenchymal transition (EMT) is a basic developmental process that converts epithelial cells to mesenchymal cells. Although EMT might promote cancer metastasis, the molecular mechanisms for it remain to be fully clarified. To address this issue, we constructed an EMT-metastasis gene regulatory network model and quantified the potential landscape of cancer metastasis-promoting system computationally. We identified four steady-state attractors on the landscape, which separately characterize anti-metastatic (A), metastatic (M), and two other intermediate (I1 and I2) cell states. The tetrastable landscape and the existence of intermediate states are consistent with recent single-cell measurements. We identified one of the two intermediate states I1 as the EMT state. From a MAP approach, we found that for metastatic progression cells need to first undergo EMT (enter the I1 state), and then become metastatic (switch from the I1 state to the M state). Specifically, for metastatic progression, EMT genes (such as ZEB) should be activated before metastasis genes (such as BACH1). This suggests that temporal order is important for the activation of cellular programs in biological systems, and provides a possible mechanism of EMT-promoting cancer metastasis. To identify possible therapeutic targets from this landscape view, we performed sensitivity analysis for individual molecular factors, and identified optimal interventions for landscape control. We found that minimizing transition actions more effectively identifies optimal combinations of targets that induce transitions between attractors than single-factor sensitivity analysis. Overall, the landscape view not only suggests that intermediate states increase plasticity during cell fate decisions, providing a possible source for tumor heterogeneity that is critically important in metastatic progress, but also provides a way to identify therapeutic targets for preventing cancer progression.
 ...
PMID:A landscape view on the interplay between EMT and cancer metastasis. 3015 71

Mitogen-activated protein kinase (MAPK) signaling pathways organize a great constitution network that regulates several physiological processes, like cell growth, differentiation, and apoptotic cell death. Due to the crucial importance of this signaling pathway, dysregulation of the MAPK signaling cascades is involved in the pathogenesis of various human cancer types. Oxidative stress and DNA damage are two important factors which in common lead to carcinogenesis through dysregulation of this signaling pathway. Reactive oxygen species (ROS) are a common subproduct of oxidative energy metabolism and are considered to be a significant physiological modulator of several intracellular signaling pathways including the MAPK pathway. Studies demonstrated that the MAP kinases extracellular signal-regulated kinase (ERK) 1/2 and p38 were activated in response to oxidative stress. In addition, DNA damage is a partly common circumstance in cell life and may result in mutation, cancer, and even cell death. Recently, accumulating evidence illustrated that the MEK/ERK pathway is associated with the suitable performance of cellular DNA damage response (DDR), the main pathway of tumor suppression. During DDR, the MEK/ERK pathway is regularly activated, which contributes to the appropriate activation of DDR checkpoints to inhibit cell division. Therefore, the aim of this review is to comprehensively discuss the critical function of MAPK signaling in oxidative stress, DNA damage, and cancer progression.
 ...
PMID:RAS/MAPK signaling functions in oxidative stress, DNA damage response and cancer progression. 3081 Oct 39


<< Previous 1 2 3 4