Omar Bennett
The ErbB family of proteins, also known as the epidermal growth factor receptor (EGFR) family, plays a crucial role in various biological processes such as proliferation, differentiation, migration, and apoptosis. Abnormal activation of ErbB signaling pathways has been implicated in the development of neurodegenerative diseases and cancer. Understanding the difference between constitutive and transient ErbB signaling is essential for developing effective therapeutic strategies. Constitutive signaling refers to the continuous activation of a signaling pathway, which is commonly observed in cancer cells due to factors such as receptor overexpression, ligand overproduction, or receptor mutations. On the other hand, transient signaling involves temporary activation in response to specific stimuli. In the context of ErbB signaling, transient activation of the extracellular signal-related kinase (Erk) pathway by nerve growth factor stimulates neuronal differentiation, while transient activation by EGF induces cell proliferation. Therapeutic approaches targeting these distinct signaling modalities need to be differentiated to effectively modulate disease states.
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What You'll Learn
The role of transient inflammatory signals in tumorigenesis
Transient inflammatory signals play a crucial role in the early stages of tumorigenesis, particularly in initiating the transformation of cells. While transient inflammatory signalling is insufficient to transform normal cells, it can trigger changes in cells that have already accumulated genetic or epigenetic alterations, setting the stage for oncogenic transformation. This process is influenced by immune cells, which can activate transient inflammatory signalling pathways, leading to the activation of specific circuits that drive transformation and tumour development.
In the context of breast cancer, for example, monocyte-induced transformation of immortal mammary epithelial cells involves the activation of a feed-forward inflammatory signalling circuit that involves the suppression of miR-200c and the activation of IL6. This circuit, comprised of IL6, miR-200c, PTPRZ1, JNK2, and various transcription factors, is also implicated in ErbB2 (Neu)-driven breast cancer in mouse models. Deleting IL6 from this circuit impairs mammary tumour development, highlighting the critical role of transient inflammatory signals in tumour initiation.
Chronic inflammation, caused by infections, autoimmune diseases, or stress, is a significant contributor to tumour progression and metastasis. It promotes cell survival, proliferation, invasion, and angiogenesis, creating a pro-tumourigenic microenvironment. For instance, chronic inflammation associated with obesity, depression, anxiety, or social isolation can trigger changes in immune function and inflammatory response, increasing the risk of tumour formation. Additionally, chronic inflammatory stimuli can lead to treatment resistance, as observed in cancers like colorectal cancer (CRC) and inflammatory bowel disease (IBD).
While transient inflammatory signals initiate the transformation process, maintaining the malignant state of cells relies on the formation of a constitutively activated inflammatory signalling circuit during this transformation. This circuit, once established, becomes self-perpetuating, with intrinsic and extrinsic signals regulating downstream genes related to tumour development. Thus, the interplay between transient and constitutive inflammatory signalling pathways is complex and requires distinct therapeutic strategies.
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Constitutive inflammatory signaling in cancer cells
The ErbB network is one of the most widely studied areas in signal transduction, with a particular focus on cancer research. ErbB receptors are involved in the control of diverse biological processes such as proliferation, differentiation, migration, and apoptosis. Their deregulated expression has been implicated in many types of human cancers and is associated with poor clinical prognosis.
In cancer cells, the maintenance of the malignant state is dependent on this constitutive inflammatory signaling. For instance, in ErbB2 (Neu)-driven breast cancer models, the deletion of IL6 impairs mammary tumorigenesis, highlighting the critical role of this cytokine in the process. Furthermore, the EGFR overexpression observed in cancer cells leads to constitutive activation of the receptor, playing an essential role in cancer development and malignancy.
The downstream signals generated by constitutively activated EGFR are not yet fully understood. However, studies have shown that constitutive EGFR signaling activates the transcription factor IRF3, leading to the expression of specific genes. This constitutive signaling is distinct from ligand-activated signals, which switch off IRF3-dependent transcription and activate canonical downstream pathways such as ERK and Akt. The distinct nature of constitutive and transient signaling pathways has important implications for therapeutic strategies, suggesting that they should be approached differently.
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The impact of constitutive neuregulin-1/ErbB signaling
Neuregulins (NRGs) are a family of growth factors that stimulate ErbB receptor tyrosine kinases. ErbB receptors are cell membrane receptor tyrosine kinases that are activated following ligand binding and receptor dimerization. In the context of cancer, constitutive neuregulin-1/ErbB signaling has been implicated in the proliferation of certain types of cancer cells, such as clear cell sarcoma of soft tissue (CCSST) and human vestibular schwannoma. For example, in CCSST, the phosphorylation status of ErbB3 revealed that the receptor pairs ErbB2/ErbB3 or ErbB3/ErbB4 were either constitutively activated in CCSST cells with high neuregulin-1 (NRG1) expression or activatable by exogenous NRG1 in cells with low NRG1 expression. This suggests that the NRG1/ErbB signaling pathway plays an important role in the growth and behavior of CCSST.
Constitutive neuregulin-1/ErbB signaling has also been studied in the context of nervous system development. For example, non-neuronal cells in the vestibular sensory epithelium regulate synapse formation through erbB-dependent BDNF expression. In addition, neuregulin-1/ErbB signaling controls sequential steps during the development of a particular organ system, such as early precursor proliferation, maturation, and myelination of Schwann cells.
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The activation of IRF3 by constitutive EGFR signaling
The Epidermal Growth Factor Receptor (EGFR) is a well-studied receptor tyrosine kinase, which is commonly overexpressed in cancer cells. This overexpression leads to constitutive activation of the receptor, which in turn activates downstream signalling pathways. One such pathway involves the transcription factor IRF3.
The activation of IRF3 by constitutive EGFR signalling occurs through the recruitment of IRF3 and its kinase TBK1 to the EGFR. This results in the phosphorylation and activation of IRF3, which then translocates to the nucleus to induce the transcription of target genes. These genes are involved in the antiviral and innate immune response and may offer protection from virus-induced cell death. The activation of IRF3 by constitutive EGFR signalling is therefore thought to play a role in the clonal evolution of tumours.
In the absence of a ligand, EGFR signals constitutively and activates IRF3. However, when a ligand is present, such as EGF, the activation of IRF3 is lost, and EGFR activates canonical downstream signalling pathways such as ERK and Akt. These ligand-dependent pathways are associated with oncogenic signalling. Thus, the availability of a ligand acts as a switch, turning off IRF3-dependent signalling and triggering oncogenic signalling pathways.
The activation of IRF3 by constitutive EGFR signalling has been observed in cancer cells, where EGFR overexpression leads to a constitutive tyrosine phosphorylation of multiple tyrosine residues in the receptor. This results in the oscillation between two distinct and mutually exclusive modes of signalling, depending on the presence or absence of a ligand. In the absence of a ligand, EGFR constitutively activates IRF3, leading to the transcription of target genes such as IFI27, IFIT1, and TRAIL.
The activation of IRF3 by constitutive EGFR signalling is distinct from transient ERBB signalling. Transient inflammatory signalling initiates the transformation process, but the maintenance of the transformed state of malignant cells is dependent on constitutive inflammatory signalling circuits. Constitutive inflammatory signalling is commonly observed in cancer cells and is thought to be driven by extrinsic signals from the tumour microenvironment or intrinsic cancer cell-specific factors. Therapeutic strategies targeting these constitutively activated pathways may therefore differ from those targeting transiently activated pathways.
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Transient inflammatory signaling in cell transformation
Transient inflammatory signals are not enough to transform normal cells. However, transient inflammatory signals from immune cells can trigger the transformation of cells that have already accumulated some genetic or epigenetic alterations that provide the basis for oncogenic transformation.
In a co-culture model, it was found that the constitutive activation of the inflammatory circuit was triggered by transient inflammatory signalling that activates IL6. In other pathological circumstances, this circuit can also be triggered by other extrinsic signals from the microenvironment or intrinsic signalling in pre-transformed cells.
A transient inflammatory signal can be defined as the acute inflammatory activation of macrophages by Toll-like and related receptors, which is characterised by the transient activation of MAPK-, NF-κB- and IRF-mediated signalling pathways and the expression of pro-inflammatory genes. This activation state is inherently unstable and often transitions into a state of "tolerance", characterised by diminished signalling, repressive chromatin modifications, and an alternative gene expression program.
The transformation of immortal mammary epithelial cells into breast cancer cells is an example of transient inflammatory signalling in cell transformation. In this process, the red components of the circuit are overexpressed or activated, and the green components are repressed or deactivated upon oncogenic transformation.
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Frequently asked questions
Constitutive signaling refers to the abnormal activation of inflammatory signaling pathways in cancer cells. It is estimated that about 25% of cancers are caused by chronic inflammation. Constitutive signaling is distinct from transient signaling in that it is maintained by a constitutively activated inflammatory signaling circuit, whereas transient signaling is insufficient to transform normal cells.
Transient signaling refers to the temporary activation of inflammatory pathways that can initiate the transformation process. Transient signaling can be caused by intrinsic or extrinsic inflammatory signals from the tumor microenvironment.
Constitutive signaling plays a role in tumor development and progression. It is involved in the activation of transcription factors and the expression of genes related to tumor development. The maintenance of the transformed state of malignant cells depends on constitutive signaling.
ErbB signaling, also known as EGFR signaling, can be either constitutive or transient. Overexpression of EGFR in cancer cells can lead to constitutive signaling, which activates transcription factors such as IRF3 and induces the expression of genes involved in the antiviral and innate immune response. Transient ErbB signaling, on the other hand, can be induced by the addition of ligands such as EGF, resulting in the loss of IRF3 activity and activation of canonical downstream signaling pathways like ERK and Akt.
