https://www.um.es/biomybiotec/web/Seminarios/2010/papers/Cano_2.pdf

Epithelial-Mesenchymal Transitions in Development and Disease

The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.

Molecular mechanisms of epithelial–mesenchymal transition

Commensurate with their roles in regulating cytokine-dependent inflammation and immunity, signal transducer and activator of transcription (STAT) proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer. Persistently activated STAT3 and, to some extent, STAT5 increase tumour cell proliferation, survival and invasion while suppressing anti-tumour immunity. The persistent activation of STAT3 also mediates tumour-promoting inflammation. STAT3 has this dual role in tumour inflammation and immunity by promoting pro-oncogenic inflammatory pathways, including nuclear factor-kappaB (NF-kappaB) and interleukin-6 (IL-6)-GP130-Janus kinase (JAK) pathways, and by opposing STAT1- and NF-kappaB-mediated T helper 1 anti-tumour immune responses. Consequently, STAT3 is a promising target to redirect inflammation for cancer therapy.

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STATs in cancer inflammation and immunity: a leading role for STAT3

Head and neck squamous cell carcinomas (HNSCCs) are caused by tobacco and alcohol consumption and by infection with high-risk types of human papillomavirus (HPV). Tumours often develop within preneoplastic fields of genetically altered cells. The persistence of these fields after treatment presents a major challenge, because it might lead to local recurrences and second primary tumours that are responsible for a large proportion of deaths. Aberrant signalling pathways have been identified in HNSCCs and inhibition of epidermal growth factor receptor (EGFR) has proved a successful therapeutic strategy. In this Review, we discuss the recent literature on tumour heterogeneity, field cancerization, molecular pathogenesis and the underlying causative cancer genes that can be exploited for novel and personalized treatments of patients with HNSCC.

The molecular biology of head and neck cancer

Epithelial–mesenchymal transition (EMT) is a cellular programme that is known to be crucial for embryogenesis, wound healing and malignant progression. During EMT, cell–cell and cell–extracellular matrix interactions are remodelled, which leads to the detachment of epithelial cells from each other and the underlying basement membrane, and a new transcriptional programme is activated to promote the mesenchymal fate. In the context of neoplasias, EMT confers on cancer cells increased tumour-initiating and metastatic potential and a greater resistance to elimination by several therapeutic regimens. In this Review, we discuss recent findings on the mechanisms and roles of EMT in normal and neoplastic tissues, and the cell-intrinsic signals that sustain expression of this programme. We also highlight how EMT gives rise to a variety of intermediate cell states between the epithelial and the mesenchymal state, which could function as cancer stem cells. In addition, we describe the contributions of the tumour microenvironment in inducing EMT and the effects of EMT on the immunobiology of carcinomas. Epithelial–mesenchymal transition (EMT) is crucial for embryogenesis, wound healing and cancer development, and confers greater resistance to cancer therapies. This Review discusses the mechanisms of EMT and its roles in normal and neoplastic tissues, the contribution of cell-intrinsic signals and the microenvironment to inducing EMT, and its effects on the immunobiology of carcinomas.

New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer

Aberrant epidermal growth factor receptor (EGFR) signaling is a major cause of tumor progression and metastasis; the underlying mechanisms, however, are not well understood. In particular, it remains elusive whether deregulated EGFR pathway is involved in epithelial-mesenchymal transition (EMT), an early event that occurs during metastasis of cancers of an epithelial origin. Here, we show that EGF induces EGFR-expressing cancer cells to undergo a transition from the epithelial to the spindle-like mesenchymal morphology. EGF reduced E-cadherin expression and increased that of mesenchymal proteins. In search of a downstream mediator that may account for EGF-induced EMT, we focused on transcription repressors of E-cadherin, TWIST, SLUG, and Snail and found that cancer cells express high levels of TWIST and that EGF enhances its expression. EGF significantly increases TWIST transcripts and protein in EGFR-expressing lines. Forced expression of EGFR reactivates TWIST expression in EGFR-null cells. TWIST expression is suppressed by EGFR and Janus-activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) inhibitors, but not significantly by those targeting phosphoinositide-3 kinase and MEK/ERK. Furthermore, constitutively active STAT3 significantly activates the TWIST promoter, whereas the JAK/STAT3 inhibitor and dominant-negative STAT3 suppressed TWIST promoter. Deletion/mutation studies further show that a 26-bp promoter region contains putative STAT3 elements required for the EGF-responsiveness of the TWIST promoter. Chromatin immunoprecipitation assays further show that EGF induces binding of nuclear STAT3 to the TWIST promoter. Immunohistochemical analysis of 130 primary breast carcinomas indicates positive correlations between non-nuclear EGFR and TWIST and between phosphorylated STAT3 and TWIST. Together, we report here that EGF/EGFR signaling pathways induce cancer cell EMT via STAT3-mediated TWIST gene expression.

https://cancerres.aacrjournals.org/content/canres/67/19/9066.full.pdf

Epidermal Growth Factor Receptor Cooperates with Signal Transducer and Activator of Transcription 3 to Induce Epithelial-Mesenchymal Transition in Cancer Cells via Up-regulation of TWIST Gene Expression

Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway.

The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate. Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO) and glioma-associated oncogene homolog (GLI) family of zinc finger transcription factors. Both are regarded as important targets for cancer therapeutics. While most efforts have been devoted towards pharmacologically targeting SMO, developing GLI-targeted approach has its merit because of the fact that GLI proteins can be activated by both Shh ligand-dependent and -independent mechanisms. To date, two SMO inhibitors (LDE225/Sonidegib and GDC-0449/Vismodegib) have received FDA approval for treating basal cell carcinoma while many clinical trials are being conducted to evaluate the efficacy of this exciting class of targeted therapy in a variety of cancers. In this review, we provide an overview of the biology of the Shh pathway and then detail the current landscape of the Shh-SMO-GLI pathway inhibitors including those in preclinical studies and clinical trials.

/pdf/targeting-the-sonic-hedgehog-signaling-pathway-review-of-1knw2lkbar.pdf

Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors

Since its discovery, the STAT3 transcription factor has been extensively studied for its function as a transcriptional regulator and its role as a mediator of development, normal physiology, and pathology of many diseases, including cancers. These efforts have uncovered an array of genes that can be positively and negatively regulated by STAT3, alone and in cooperation with other transcription factors. Through regulating gene expression, STAT3 has been demonstrated to play a pivotal role in many cellular processes including oncogenesis, tumor growth and progression, and stemness. Interestingly, recent studies suggest that STAT3 may behave as a tumor suppressor by activating expression of genes known to inhibit tumorigenesis. Additional evidence suggested that STAT3 may elicit opposing effects depending on cellular context and tumor types. These mixed results signify the need for a deeper understanding of STAT3, including its upstream regulators, parallel transcription co-regulators, and downstream target genes. To help facilitate fulfilling this unmet need, this review will be primarily focused on STAT3 downstream target genes that have been validated to associate with tumorigenesis and/or malignant biology of human cancers.

/pdf/stat3-target-genes-relevant-to-human-cancers-4uidiw9tja.pdf

STAT3 Target Genes Relevant to Human Cancers

Emerging evidences suggest the existence of a new mode of epidermal growth factor receptor (EGFR) signalling pathway in which activated EGFR undergoes nuclear translocalization and subsequently regulates gene expression and potentially mediates other cellular processes. This signalling route is distinct from the better-characterized, traditional EGFR pathway that involves transduction of mitogenic signals through activation of multiple signalling cascades. Transcriptional activity of nuclear EGFR appears to depend on its C-terminal transactivation domain and its physical and functional interaction with other transcription factors that contain DNA-binding activity. Likely via its ability to upregulate gene expression, nuclear EGFR pathway is associated with major characteristics of more aggressive tumours: increased proliferative potential, nitric oxide synthesis, and accelerated G1/S cell cycle progression. A role of nuclear EGFR in prognostic prediction is further suggested in patients with breast carcinomas and oropharyngeal squamous cell carcinomas. It is noted that significant advances were made towards the knowledge of the nuclear EGFR pathway; however, many aspects of this new pathway remain unresolved and will be discussed in this review. As a number of other receptor tyrosine kinases (RTKs) and cytokine receptors also undergo similar nuclear translocalization, a better understanding of the physiological and malignant nature of the nuclear EGFR pathway will likely shed light into the biology of cancer with nuclear RTKs.

/pdf/nuclear-egfr-signalling-network-in-cancers-linking-egfr-3elk28ki95.pdf

Hui-Wen Lo

Papers

Epidermal Growth Factor Receptor Cooperates with Signal Transducer and Activator of Transcription 3 to Induce Epithelial-Mesenchymal Transition in Cancer Cells via Up-regulation of TWIST Gene Expression

Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway.

Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors

STAT3 Target Genes Relevant to Human Cancers

Nuclear EGFR signalling network in cancers: linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival