The role of contextual signal TGF-β1 inducer of epithelial mesenchymal transition in metastatic lung adenocarcinoma patients with brain metastases: an update on its pathological significance and therapeutic potential

Abstract

Lung adenocarcinoma (LA) is the most common cause of cancer-related death worldwide. Despite the advances over last decade in new targeted therapies, cancer genetics, diagnostics, staging, and surgical techniques as well as new chemotherapy and radiotherapy protocols, the death rate from LA remains high. The tumour microenvironment is composed of several cytokines, one of which is transforming growth factor β1 (TGF-β1), which modulates and mediates the expression of epithelial-mesenchymal transition (EMT), correlated with invasive growth in LAs, and exhibits its pleiotropic effects through binding to transmembrane receptors TβR-1 (also termed activin receptor-like kinases - ALKs) and TβR-2. Accordingly, there is an urgent need to elucidate the molecular mechanisms associated with the tumoural spreading process and therapeutic resistance of this serious pathology. In this review, we briefly discuss the current role of contextual signal TGF-β1 inducer of epithelial mesenchymal transition in metastatic lung adenocarcinoma patients with brain metastases, and give an overview of our current mechanistic understanding of the TGF-β1-related pathways in brain metastases progression, TGF-β1 pathway inhibitors that could be used for clinical treatment, and examination of models used to study these processes. Finally, we summarise the current progress in the therapeutic approaches targeting TGF-β1.

Keywords: EMT; TGF-β1; brain metastasis; lung adenocarcinoma; pathology.

Fig. 1

Canonical (Smad-dependent) and non-canonical (Smad-independent) pathways. An oversimplified and modified (from [30]) scheme depicting the TGF-β pathway as well as a model of cerebral metastasis from lung adenocarcinoma. A) Disaggregation of cells from primary tumour mass to a particular metastatic niche is mediated mainly through integrins and proteases expressed at the surface of cancer cells, vasculature, and stromal cells [48]. In summary, cells [*] break through the vascular basement membrane via the expression of cellular matrix metalloproteinase activity – MMP2 and MMP9. Many angiogenic factors secreted by both tumour and stromal cells, such as VEGF and platelet-derived growth factor β (PDGF-β), which are transcriptionally directly driven by hypoxia-inducible factor 1 or 2 (HIF1–HIF2). B) Lung adenocarcinoma is commonly defined as a slow-growing cancer that arises mostly from distal airways, typically with glandular histology displaying biomarkers that are consistent with an origin in the distal lung, including thyroid transcription factor 1 (NKX2-1) and keratin (7) with complex early diagnosis because it usually involves the periphery of the lung and has scarce symptoms, promoting early metastasis. C) The TGF-β1 signalling is regarded as an initial, complex, and yet crucial cytokine to induce EMT during cancer progression and metastasis (20) in a Smad2/Smad3 complex-dependent C-terminal phosphorylated downstream manner via ALK-5 receptors, and also dependent on the protein-serine/threonine kinases that participate in the Ras-Raf-MEK5-ERK5 signal transduction cascade and nuclear translocation