Lysyl oxidase-like 2 (LOXL2) and E47 EMT factor: novel partners in E-cadherin repression and early metastasis colonization

Canesin, Giacomo; Cuevas, Eva P.; Santos, Vanesa; López-Menéndez, Celia; Moreno‐Bueno, Gema; Huang, Yujie; Csiszár, Katalin; Portillo, Francisco; Peinado, Héctor; Lyden, David; Cano, Amparo

doi:10.1038/onc.2014.23

Cited by 80 publications

(84 citation statements)

References 42 publications

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“…CCL9 is induced through TGF-β signaling in myeloid cells in the pre-metastatic lungs, whereas it enhances tumor cell survival and promotes metastasis (25). Another recent study has found that lysyl oxidase-like 2 (LOXL2) and the bHLH transcription factor E47, which function together to induce EMT, also contribute to the recruitment of BMDCs to pre-metastatic lungs through transcriptional regulation of fibronectin and cytokines including GM-CSF (26). TNFα, TGFβ, and VEGF-A secreted by the primary tumor can induce the expression of S100A8 and S100A9 in pre-metastatic lung endothelial cells which act as potent chemoattractants for Mac-1 + myeloid cells and cancer cells through SAA3-induces TLR4 signaling (17, 18).…”

Section: Traits Of a Pre-metastatic Nichementioning

confidence: 99%

“…More recent work has shown that factors secreted by hypoxic tumor cells, including LOX, LOXL2, and G-CSF, direct a pro-metastatic niche reprogramming (60–62). LOXL2 has also been shown to collaborate with E47 to induce EMT and increase the secretion of GM-CSF to recruit BMDCs to pre-metastatic lungs (26). VEGF, another hypoxia-induced factor, has been known to play an important role in cancer growth and metastasis through the induction of angiogenesis in the primary tumor.…”

Section: Tumor-derived Formation Of a Pre-metastatic Nichementioning

confidence: 99%

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Cancer Tills the Premetastatic Field: Mechanistic Basis and Clinical Implications

Chin

Wang

2016

Clinical Cancer Research

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A growing body of work has demonstrated that cancer metastasis is not a random spontaneous event; rather it is the culmination of a cascade of priming steps through which a sub-population of the tumor cells acquires invasive traits while readying a permissive environment, termed the pre-metastatic niche, in which distant metastases can occur. Signals from the primary tumor mobilize and adapt immune cells as well as directly communicate with distant niche cells to induce a broad spectrum of adaptations in target organs, including the induction of angiogenesis, inflammation, extracellular matrix remodeling, and metabolic reprogramming. Together these interactions facilitate the formation of a pre-metastatic niche composed of a variable mix of resident and recruited immune cells, endothelial cells, and stromal cells connected through a complex signaling network that we are only beginning to understand. Here we summarize the latest findings on how cancer induces and guides the formation of this pre-metastatic niche as well as potential prognostic markers and therapeutic targets that may lead to a better understanding and effective treatment of metastatic disease.

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Section: Traits Of a Pre-metastatic Nichementioning

confidence: 99%

Section: Tumor-derived Formation Of a Pre-metastatic Nichementioning

confidence: 99%

Cancer Tills the Premetastatic Field: Mechanistic Basis and Clinical Implications

Chin

Wang

2016

Clinical Cancer Research

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“…So, Grhl3 may directly bind to this motif to repress E-cadherin expression. Additionally, several E-cadherin transcriptional repressors, such as Twist, Zeb1, Snail, Slug, Loxl2, and E47 that directly interact with the proximal E-boxes of the promoter, have been identified in recent years [17,[26][27][28][29]. Grhl3 may also interact with these factors and bind to the E-boxes, and indirectly repress E-cadherin expression.…”

Section: Discussionmentioning

confidence: 99%

Grhl3 induces human epithelial tumor cell migration and invasion via downregulation of E-cadherin

Zhao¹,

Guo²,

Tu³

et al. 2016

ABBS

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Grainyhead genes are involved in wound healing and developmental neural tube closure. Metastasis is a multistep process during which cancer cells disseminate from the site of primary tumors and establish secondary tumors in distant organs. The adhesion protein E-cadherin plays an essential role in metastasis. In light of the high degree of similarity between the epithelial-mesenchymal transition (EMT) occurring in wound-healing processes and the EMT occurring during the acquisition of invasiveness in skin or breast cancer, we investigated the role of the Grainyhead genes in cancer invasion. Here, we show that there is an inverse relationship between Grainyhead-like 3 (Grhl3) and E-cadherin expression in some epithelial tumor cell lines. Overexpression of Grhl3 in the E-cadherin-positive epithelial tumor cell line, characterized by less invasiveness, generated a transcriptional blockage of the E-cadherin gene and promoted cell migration and cell invasion. Conversely, Grhl3 depletion inhibited cell migration and cell invasion and was associated with a gain of E-cadherin expression. To further explore the mechanism by which Grhl3 regulated E-cadherin expression, an E-cadherin promoter report analysis was performed and results showed that Grhl3 repressed E-cadherin gene expression by directly or indirectly binding to the E-boxes present in the proximal E-cadherin promoter. Taken together, our findings define a major role for Grhl3 in the induction of migration and invasion by the downregulation of E-cadherin in cancer cells.

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“…Antibodies against MMP and lysyl-oxidase like 2 (LOXL2) (simtuzumab) [81] are tested for liver fibrosis.…”

Section: Anti-fibrotic Therapiesmentioning

confidence: 99%

Where are we heading to in pharmacological IBD therapy?

Rogler

2015

Pharmacological Research

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Lysyl oxidase-like 2 (LOXL2) and E47 EMT factor: novel partners in E-cadherin repression and early metastasis colonization

Cited by 80 publications

References 42 publications

Cancer Tills the Premetastatic Field: Mechanistic Basis and Clinical Implications

Cancer Tills the Premetastatic Field: Mechanistic Basis and Clinical Implications

Grhl3 induces human epithelial tumor cell migration and invasion via downregulation of E-cadherin

Where are we heading to in pharmacological IBD therapy?

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