Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

Papanikolaou, Sofia; Vourda, Aikaterini; Syggelos, Spyros A.; Gyftopoulos, Kostis

doi:10.3390/cancers13112795

Cited by 42 publications

(28 citation statements)

References 269 publications

(303 reference statements)

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“…EMT plays a major role in tumour progression, therefore we analysed the expression levels of N-cadherin and of E-cadherin, two well-known markers of EMT [ 35 ], the expression levels of these proteins were analysed ( Figure 7 ). Interestingly, we found a significant downregulation of N-Cadherin with a concurrent upregulation of E-Cadherin in fibroblasts treated with metformin compared to untreated cells.…”

Section: Resultsmentioning

confidence: 99%

Metformin Treatment Induces Different Response in Pheochromocytoma/Paraganglioma Tumour Cells and in Primary Fibroblasts

Martinelli

Amore

Mello

et al. 2022

Cancers

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Pheochromocytoma/paragangliomas (PPGLs) are neuroendocrine tumours, often non-metastatic, but without available effective treatment for their metastatic form. Recent studies have shown that metformin exhibits antiproliferative activity in many human cancers, including PPGLs. Nevertheless, no data are available on the role of metformin on PPGL cells (two-dimension, 2D) and spheroids (three-dimension, 3D) migration/invasion. In this study, we observed that metformin exerts an antiproliferative effect on 2D and 3D cultures of pheochromocytoma mouse tumour tissue (MTT), either silenced or not for the SDHB subunit. However, metformin did not affect MTT migration. On the other hand, metformin did not have a short-term effect on the proliferation of mouse primary fibroblasts, but significantly decreased their ability to migrate. Although the metabolic changes induced by metformin were similar between MTT and fibroblasts (i.e., an overall decrease of ATP production and an increase in intracellular lactate concentration) the activated signalling pathways were different. Indeed, after metformin administration, MTT showed a reduced phosphorylation of Akt and Erk1/2, while fibroblasts exhibited a downregulation of N-Cadherin and an upregulation of E-Cadherin. Herein, we demonstrated that metformin has different effects on cell growth and spread depending on the cell type nature, underlining the importance of the tumour microenvironment in dictating the drug response.

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Section: Resultsmentioning

confidence: 99%

Metformin Treatment Induces Different Response in Pheochromocytoma/Paraganglioma Tumour Cells and in Primary Fibroblasts

Martinelli

Amore

Mello

et al. 2022

Cancers

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“…Wnt signaling deregulation has been implicated during several stages of the metastatic cascade in multiple human malignancies. For example, while the Wnt pathway is critical for EMT during embryonic development [ 220 ], aberrant Wnt signaling can induce an EMT phenotype in cancer cells, promoting migratory and invasiveness capabilities through multiple mechanisms, including the regulation of stem cell activity in prostate cancer [ 221 ]. In breast cancer cells, activation of canonical Wnt signaling stabilizes the EMT transcriptional factor snail family transcriptional repressor 2 (SNAI2) by inhibiting GSK3β activity and promoting transcription of EMT-related genes [ 222 ].…”

Section: Wnt Signaling and Prostate Cancer Metastasismentioning

confidence: 99%

Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer

et al. 2022

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Aberrant activation of the Wnt pathway is emerging as a frequent event during prostate cancer that can facilitate tumor formation, progression, and therapeutic resistance. Recent discoveries indicate that targeting the Wnt pathway to treat prostate cancer may be efficacious. However, the functional consequence of activating the Wnt pathway during the different stages of prostate cancer progression remains unclear. Preclinical work investigating the efficacy of targeting Wnt signaling for the treatment of prostate cancer, both in primary and metastatic lesions, and improving our molecular understanding of treatment responses is crucial to identifying effective treatment strategies and biomarkers that help guide treatment decisions and improve patient care. In this review, we outline the type of genetic alterations that lead to activated Wnt signaling in prostate cancer, highlight the range of laboratory models used to study the role of Wnt genetic drivers in prostate cancer, and discuss new mechanistic insights into how the Wnt cascade facilitates prostate cancer growth, metastasis, and drug resistance.

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“…They are activated in the early events of EMT, and they could hence be said to play cardinal roles in development, fibrosis, and tumour aggressiveness. Sometimes, they control the expression of each other and function synergistically at target genes ( 42 ).…”

Section: Emt and Metastasismentioning

confidence: 99%

“…The homeodomain consists of three-alpha helices. In this segment, the helix-loop-helix (or helix-turn-helix (HTH)) motif functions as the E-box-binding site and allows the protein to bind to the E-cadherin promoter region ( 42 ), and thus regulates the transcription of the adjacent DNA. Generally, the homeobox codes for a specific sequence that functions as part of evolutionarily conserved signalling pathways, which is particularly active in morphogenesis.…”

Section: Emt and Metastasismentioning

confidence: 99%

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

et al. 2021

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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.

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Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

Cited by 42 publications

References 269 publications

Metformin Treatment Induces Different Response in Pheochromocytoma/Paraganglioma Tumour Cells and in Primary Fibroblasts

Metformin Treatment Induces Different Response in Pheochromocytoma/Paraganglioma Tumour Cells and in Primary Fibroblasts

Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer

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

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