Abstract
The TGFβ and Ras-MAPK pathways play critical roles in cell development and cell cycle regulation, as well as in tumor formation and metastasis. In the absence of cellular transformation, these pathways operate in opposition to one another, where TGFβ maintains an undifferentiated cell state and suppresses proliferation, while Ras-MAPK pathways promote proliferation, survival and differentiation. However, in colorectal and pancreatic cancers, the opposing pathways' mechanisms are simultaneously activated in order to promote cancer progression and metastasis. Here, we highlight the roles of the TGFβ and Ras-MAPK pathways in normal and malignant states, and provide an explanation for how the concomitant activation of these pathways drives tumor biology. Finally, we survey potential therapeutic targets in these pathways.
Highlights
A cell must acquire several key characteristics in order to become cancerous: proliferation without limit in the absence of extracellular signals, resistance to apoptosis, evasion of anti-growth signals and immune destruction, as well as increased cellular motility [1,2]
As more is learned about these pathways in normal and cancerous cells, it becomes increasingly clear that crosstalk between the distinct pathway components are important for TGFb signal interpretation in a cell type and cell context dependent manner
Future studies are required to address the interdependency of these pathways, paying close attention to the connection between the cellular context in a study, the level of contribution of the Ras-MAPK pathway to the TGFb response, and the ultimate cellular response to TGFb ligand stimulation
Summary
A cell must acquire several key characteristics in order to become cancerous: proliferation without limit in the absence of extracellular signals, resistance to apoptosis, evasion of anti-growth signals and immune destruction, as well as increased cellular motility [1,2]. Src-activated Epidermal Growth Factor Receptor (EGFR) signals through Ras-MAPK to engender phosphorylation of the E-box binding transcription factor USF and facilitate its interaction with activated Smad2/3 to regulate PAI-1 gene expression [37]. The Ras-MAPK pathway features a cascade of sequential kinase phosphorylations/activations from RAF to ERK (Figure 1) This type of pathway architecture can lead to significant amplification of the original upstream receptor/ligand binding signal. The role of TGFb in cancer progression seems to be largely through lesions that stimulate the non-cannonical signaling, and are aided by inactivating lesions in the canonical pathway, which are associated with cell-cycle arrest and the apoptotic response.
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