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

Dongre, Anushka; Weinberg, Robert A.

doi:10.1038/s41580-018-0080-4

Cited by 2,641 publications

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“…This step is termed the mesenchymalepithelial transition (MET); the reverse of EMT. [10][11][12][13] Each step is crucial for metastasis to occur, however, due to the complexity of the process and the number of proteins and signaling molecules involved, targeting metastasis has proven challenging. The initial steps, EMT and invasion are ideal for drug therapeutic strategies as this will halt the metastatic cascade early on.…”

Section: Cellular Migrationmentioning

confidence: 99%

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Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

Chopra

Sangarappillai

Romero‐Canelón

et al. 2020

Advanced Therapeutics

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Lysyl oxidase‐like 2 (LOXL2) is an emerging drug target against metastatic disease owing to its role in the upregulation of key processes including epithelial‐mesenchymal transition (EMT) and invasion. Recent activity in the field of small molecule LOXL2 inhibitor development by pharmaceutical and academic laboratories has renewed interest in targeting LOXL2. Herein, 1) the viability of LOXL2 as a drug target for the treatment of metastatic disease through an investigation of its biological actions is determined; 2) the pitfalls of an antibody approach are considered; and 3) the small molecule approaches emerging in the scientific and patent literature are reviewed. This review identifies that LOXL2 is localized and active intracellularly and extracellularly in invasive cancer cells. LOXL2 has been implicated in a number of established signaling pathways involved in tumor progression, further highlighting its appeal as a target in metastatic disease. Previously, limited chemical inhibitors have been developed; however, their selectivity profile for the LOX family has proven controversial. Antibodies, such as simtuzumab, have been developed selectively against LOXL2. Simtuzumab, in particular, progresses into phase II trials but it was ultimately terminated. The small molecule inhibitors of LOXL2 are summarized, some of which are now in the early stages of clinical trials.

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Section: Cellular Migrationmentioning

confidence: 99%

“…In the final sequence the metastatic cells must colonize the secondary location via cell proliferation. This step is termed the mesenchymal‐epithelial transition (MET); the reverse of EMT …”

Section: Introductionmentioning

confidence: 99%

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

Chopra

Sangarappillai

Romero‐Canelón

et al. 2020

Advanced Therapeutics

View full text Add to dashboard Cite

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“…Circulating tumor cells (CTCs) are cell populations that act as cancer seeds by detaching from primary lesions, entering blood vessels and thus causing metastasis (Hamilton and Rath, ). Increasing evidence has demonstrated that the cellular process in which epithelial cells acquire a mesenchymal phenotype (epithelial–mesenchymal transition, EMT) leads to an increase in cellular invasion and spread (Diepenbruck and Christofori, ; Dongre and Weinberg, ). Such EMT–CTC subpopulations are considered the roots of metastases (Kölbl et al , ).…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of PD‐L1 expression on cell‐surface vimentin‐positive circulating tumor cells in gastric cancer patients

et al. 2020

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Although circulating tumor cells (CTCs) have shown promise as potential biomarkers for diagnostic and prognostic assessment in gastric cancer (GC), determining the predictive and prognostic value of programmed death‐ligand 1 (PD‐L1)‐positive CTCs in patients with GC is a challenge. Here, we identified that the expression of total vimentin (VIM) protein was positively correlated with PD‐L1 and inhibited CD8+ T‐cell activation in patients with GC according to bioinformatics analysis. Notably, coexpression of PD‐L1 and cell‐surface VIM (CSV) was detected by immunofluorescence and immunohistochemistry assay in locally advanced GC tumor specimens and metastatic lymph nodes. Likewise, CSV expression level was significantly decreased after transiently knocking down PD‐L1 in GC cell lines. Based on our established CTC detection platform, CTCs were isolated from peripheral blood samples collected from 70 patients (38 resectable and 32 unresectable) with GC using magnetic positive selection and a CSV‐specific monoclonal antibody, 84‐1. CSV+PD‐L1+CTCs were observed in 50 of 70 (71%) GC patient samples, ranging from 0 to 261 mL−1. A higher number of CSV+PD‐L1+CTCs were significantly associated with a short survival duration and poor therapeutic response. This study demonstrated that detection of PD‐L1+CTCs using a CSV‐enrichment method has promising value as a clinically relevant prognostic marker for GC.

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“…31,65 It is important to mention that TGF-β is one of the growth factors responsible for the epithelialmesenchymal transition, which induces the formation of activated fibrocytes suggested by Robert Weinberg to be responsible for fibrosis and disease progression in cancer. 66 Furthermore, the bone marrow of PMF patients contains high numbers of naked nuclei with heavily condensed chromatin, which are probably the reminiscence of megakaryocytes that died by an immune-mediated process defined para-apoptosis. 31,49 These morphological observations suggest that the microenvironment surrounding the para-apoptotic megakaryocytes is enriched for growth factors produced by these cells and activated by the neutrophil proteases.…”

Section: Myelofibrosis Is a Disease Of The Microenvironment Sustainmentioning

confidence: 99%

Novel targets to cure primary myelofibrosis from studies on Gata1^low mice

et al. 2019

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In 2002, we discovered that mice carrying the hypomorphic Gata1 low mutation that reduces expression of the transcription factor GATA1 in megakaryocytes (Gata1 low mice) develop myelofibrosis, a phenotype that recapitulates the features of primary myelofibrosis (PMF), the most severe of the Philadelphianegative myeloproliferative neoplasms (MPNs). At that time, this discovery had a great impact on the field because mutations driving the development of PMF had yet to be discovered. Later studies identified that PMF, as the others MPNs, is associated with mutations activating the thrombopoietin/JAK2 axis raising great hope that JAK inhibitors may be effective to treat the disease.Unfortunately, ruxolitinib, the JAK1/2 inhibitor approved by FDA and EMEA for PMF, ameliorates symptoms but does not improve the natural course of the disease, and the cure of PMF is still an unmet clinical need. Although GATA1is not mutated in PMF, reduced GATA1 content in megakaryocytes as a consequence of ribosomal deficiency is a hallmark of myelofibrosis (both in humans and mouse models) and, in fact, a driving event in the disease. Conversely, mice carrying the hypomorphic Gata1 low mutation express an activated TPO/JAK2 pathway and partially respond to JAK inhibitors in a fashion similar to PMF patients (reduction of spleen size but limited improvement of the natural history of the disease). These observations cross-validated Gata1 low mice as a bona fide animal model for PMF and prompted the use of this model to identify abnormalities that might be targeted to cure the disease. We will summarize here data generated in Gata1 low mice indicating that the TGF-β/P-

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

Cited by 2,641 publications

References 216 publications

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

Prognostic significance of PD‐L1 expression on cell‐surface vimentin‐positive circulating tumor cells in gastric cancer patients

Novel targets to cure primary myelofibrosis from studies on Gata1^low mice

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

Cited by 2,641 publications

References 216 publications

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

Prognostic significance of PD‐L1 expression on cell‐surface vimentin‐positive circulating tumor cells in gastric cancer patients

Novel targets to cure primary myelofibrosis from studies on Gata1low mice

Contact Info

Product

Resources

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Novel targets to cure primary myelofibrosis from studies on Gata1^low mice