Understanding the Complex Milieu of Epithelial-Mesenchymal Transition in Cancer Metastasis: New Insight Into the Roles of Transcription Factors

Abstract

Epithelial-mesenchymal transition (EMT) is a physiological program during which polarised, immobile epithelial cells lose connection with their neighbours and are converted to migratory mesenchymal phenotype. Mechanistically, EMT occurs via a series of genetic and cellular events leading to the repression of epithelial-associated markers and upregulation of mesenchymal-associated markers. EMT is very crucial for many biological processes such as embryogenesis and ontogenesis during human development, and again it plays a significant role in wound healing during a programmed replacement of the damaged tissues. However, this process is often hijacked in pathological conditions such as tumour metastasis, which constitutes the most significant drawback in the fight against cancer, accounting for about 90% of cancer-associated mortality globally. Worse still, metastatic tumours are not only challenging to treat with the available conventional radiotherapy and surgical interventions but also resistant to several cytotoxic agents during treatment, owing to their anatomically diffuse localisation in the body system. As the quest to find an effective method of addressing metastasis in cancer intervention heightens, understanding the molecular interplay involving the signalling pathways, downstream effectors, and their interactions with the EMT would be an important requisite while the challenges of metastasis continue to punctuate. Unfortunately, the molecular underpinnings that govern this process remain to be completely illuminated. However, it is becoming increasingly clear that EMT, which initiates every episode of metastasis, significantly requires some master regulators called EMT transcription factors (EMT-TFs). Thus, this review critically examines the roles of TFs as drivers of molecular rewiring that lead to tumour initiation, progression, EMT, metastasis, and colonisation. In addition, it discusses the interaction of various signalling molecules and effector proteins with these factors. It also provides insight into promising therapeutic targets that may inhibit the metastatic process to overcome the limitation of “undruggable” cancer targets in therapeutic design and upturn the current spate of drug resistance. More so, it extends the discussion from the basic understanding of the EMT binary switch model, and ultimately unveiling the E/M cellular plasticity along a phenotypic spectrum via multiple trans-differentiations. It wraps up on how this knowledge update shapes the diagnostic and clinical approaches that may demand a potential shift in investigative paradigm using novel technologies such as single-cell analyses to improve overall patient survival.

Multifunctional Drug-Loaded Phase-Change Nanoparticles Inhibit the Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma by Affecting the Activity of Activated Hepatic Stellate Cells

“…A dialysis bag containing 1 ml of a solution of PPL NPs was placed in a beaker containing 149 ml of PBS solution, keeping its volume at 150 ml throughout the experiment, and then, the beaker was placed in a rotary evaporator at 37 °C. Collect 1 ml of each sample solution from the dialysis bag at different times (1,2,3,4,5,6,7,8,9,10,11,12,24, and 36 h) and make up an equal volume of PBS immediately back to the dialysis bag. Repeat 3 times per set.…”

“…TGF- β is not only the most potent profibrotic cytokine but also a key component of extracellular matrix-induced EMT of tumor cells [ 7 , 8 ]. Scientists have demonstrated that the extratumoral microenvironment provides the necessary transduction signals for EMT and determines the fate of disseminated cells at peripheral metastatic sites [ 9 ], that is, whether proliferating and reverting to a more epithelial phenotype or remaining dormant for extended periods of time [ 5 ]. Understanding the molecular mechanisms in EMT protocols which initiate tumor invasion and metastasis is key to improving therapeutic interventions.…”

Knocking-Down CD147/EMMPRIN Expression in CT26 Colon Carcinoma Forces the Cells into Cellular and Angiogenic Dormancy That Can Be Reversed by Interactions with Macrophages

“…To overcome the quiescence-mediating signals in the remote organ [ 10 ], and to generate a metastatic lesion, the cell must re-acquire its epithelial properties through the activation of the mesenchymal-to-epithelial transition (MET) program, which enables proliferation, generation of macro-metastases, and cancer recurrence [ 11 ]. Thus, metastatic cells exhibit plasticity (epithelial–mesenchymal plasticity—EMP), and cells that co-express both epithelial and mesenchymal properties in varying degrees (known as E/M hybrids) are considered to have the greatest metastatic and aggressive potential [ 12 , 13 , 14 ]. EMT markers, such as reduced E-cadherin expression and increased vimentin expression, as well as increased EMT transcription factors (EMT-TFs), such as Snail/SNAI1, Slug/SNAI2, Zeb1, or Twist1, were shown to drive the EMT program, repress the epithelial markers, and induce a more mesenchymal phenotype associated with dormancy [ 15 ].…”

Emerging role of caldesmon in cancer: A potential biomarker for colorectal cancer and other cancers

“…Cancer cells activate EMT to move and migrate from the primary tumor to other parts of the body. EMT is an essential process of cellular plasticity for normal tissue and organ development, yet it is also involved in an array of oncogenic processes, including proliferation and invasion, angiogenesis, stemness, and resistance to chemoradiotherapy[ 73 , 74 ]. The process involves major changes in the phenotype of cancer cells within the primary tumor marked by loss of an epithelial phenotype and gain of a mesenchymal phenotype.…”

“…Once the primary cancer is formed, different triggers stimulate the movement of tumor cells for nourishment, exchange of nutrients and/or immune escape. These factors, such as hypoxia, oxidative stress, nutrient deprivation, and inflammation, activate a set of transcription factors, including transforming growth factor-beta (TGF-β), Wnt, SNAIL, TWIST and MAPK/ERK-ZEB1, among others[ 73 - 77 ]. All of these signaling pathways participate in crosstalk with each other and share interconnected regulatory components, which together with their targets form a complex network[ 78 ].…”