Metastasis: crosstalk between tissue mechanics and tumour cell plasticity

Coban, Bircan; Bergonzini, Cecilia; Zweemer, Annelien J.M.; Danen, Erik H.J.

doi:10.1038/s41416-020-01150-7

Cited by 32 publications

(20 citation statements)

References 153 publications

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“…Epithelial-mesenchymal transition (EMT) is the process through which epithelial cells alter their phenotype, enabling them to lose their main epithelial cell traits and convert into cells expressing mesenchymal cell markers (1,2). Following the EMT, cells switch from polygonal to spindle-like fusiform shape, lose cell polarity, and gain increased resistance to apoptosis and the ability to migrate and invade (3)(4)(5)(6)(7)(8). The EMT occurs in various physiological and pathological conditions, including embryonic processes essential for normal development, tissue morphogenesis and repair, tissue reconstruction, fibrogenesis, and tumorigenesis (9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Communication Between Epithelial–Mesenchymal Plasticity and Cancer Stem Cells: New Insights Into Cancer Progression

Zheng

Dai²,

Feng

et al. 2021

Front. Oncol.

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The epithelial–mesenchymal transition (EMT) is closely associated with the acquisition of aggressive traits by carcinoma cells and is considered responsible for metastasis, relapse, and chemoresistance. Molecular links between the EMT and cancer stem cells (CSCs) have indicated that EMT processes play important roles in the expression of CSC-like properties. It is generally thought that EMT-related transcription factors (EMT-TFs) need to be downregulated to confer an epithelial phenotype to mesenchymal cells and increase cell proliferation, thereby promoting metastasis formation. However, the genetic and epigenetic mechanisms that regulate EMT and CSC activation are contradictory. Emerging evidence suggests that EMT need not be a binary model and instead a hybrid epithelial/mesenchymal state. This dynamic process correlates with epithelial–mesenchymal plasticity, which indicates a contradictory role of EMT during cancer progression. Recent studies have linked the epithelial–mesenchymal plasticity and stem cell-like traits, providing new insights into the conflicting relationship between EMT and CSCs. In this review, we examine the current knowledge about the interplay between epithelial–mesenchymal plasticity and CSCs in cancer biology and evaluate the controversies and future perspectives. Understanding the biology of epithelial–mesenchymal plasticity and CSCs and their implications in therapeutic treatment may provide new opportunities for targeted intervention.

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Section: Introductionmentioning

confidence: 99%

Communication Between Epithelial–Mesenchymal Plasticity and Cancer Stem Cells: New Insights Into Cancer Progression

Zheng

Dai²,

Feng

et al. 2021

Front. Oncol.

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“…Recent studies have added a range of novel emerging cancer-related processes that require the participation of integrins, including the establishment of a pre-metastatic niche, epithelial-to-mesenchymal transition (EMT), metabolic rewiring, cancer cell stemness and dormancy ( Barkan et al, 2010 ; Goel et al, 2014 ; Seguin et al, 2015 ; Ata and Antonescu, 2017 ; Ji et al, 2020 ; Park and Nam, 2020 ; Winkler et al, 2020 ; Coban et al, 2021 ). The involvement of integrin αvβ6 in activation of TGFβ was recently connected to SOX4 mediated cancer immune evasion: αvβ6 blocking antibodies could inhibit SOX4 expression and sensitize mouse models for triple negative breast cancer to T cell mediated killing in response to immune checkpoint inhibitors ( Bagati et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Targeting Integrins for Cancer Therapy - Disappointments and Opportunities

Bergonzini

Kroese

Zweemer

et al. 2022

Front. Cell Dev. Biol.

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Integrins mediate adhesive interactions between cells and their environment, including neighboring cells and extracellular matrix (ECM). These heterodimeric transmembrane receptors bind extracellular ligands with their globular head domains and connect to the cytoskeleton through multi-protein interactions at their cytoplasmic tails. Integrin containing cell–matrix adhesions are dynamic force-responsive protein complexes that allow bidirectional mechanical coupling of cells with their environment. This allows cells to sense and modulate tissue mechanics and regulates intracellular signaling impacting on cell faith, survival, proliferation, and differentiation programs. Dysregulation of these functions has been extensively reported in cancer and associated with tumor growth, invasion, angiogenesis, metastasis, and therapy resistance. This central role in multiple hallmarks of cancer and their localization on the cell surface makes integrins attractive targets for cancer therapy. However, despite a wealth of highly encouraging preclinical data, targeting integrin adhesion complexes in clinical trials has thus far failed to meet expectations. Contributing factors to therapeutic failure are 1) variable integrin expression, 2) redundancy in integrin function, 3) distinct roles of integrins at various disease stages, and 4) sequestering of therapeutics by integrin-containing tumor-derived extracellular vesicles. Despite disappointing clinical results, new promising approaches are being investigated that highlight the potential of integrins as targets or prognostic biomarkers. Improvement of therapeutic delivery at the tumor site via integrin binding ligands is emerging as another successful approach that may enhance both efficacy and safety of conventional therapeutics. In this review we provide an overview of recent encouraging preclinical findings, we discuss the apparent disagreement between preclinical and clinical results, and we consider new opportunities to exploit the potential of integrin adhesion complexes as targets for cancer therapy.

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“…Various cell adhesion molecules, with integrins being the largest family, fundamentally coregulate resistance to therapy. [9][10][11][12] Rich in collagens and other ECM proteins, PDAC cells express high levels of the cognate integrin receptors. 13,14 Among these, the ubiquitously expressed b1 subunit is central to 12 out of the 24 integrin receptor combinations.…”

Section: Introductionmentioning

confidence: 99%