Mechanosensitive TRPV4 channels stabilize VE-cadherin junctions to regulate tumor vascular integrity and metastasis

Cappelli, Holly C.; Kanugula, Anantha Koteswararao; Adapala, Ravi K.; Amin, Vibhatsu; Sharma, Priya; Midha, Priya; Paruchuri, Sailaja; Thodeti, Charles K.

doi:10.1016/j.canlet.2018.07.042

Cited by 43 publications

(38 citation statements)

References 27 publications

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“…VE-cad is a transmembrane glycoprotein that can maintain an intercellular connection and is expressed only in highly aggressive tumors. It has been demonstrated that the downregulation of VE-cad can inhibit VM formation 48. TGF-β1 is a cytokine which is secreted by epithelial cells, macrophages and fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

<p>Inhibition of tumor metastasis by targeted daunorubicin and dioscin codelivery liposomes modified with PFV for the treatment of non-small-cell lung cancer</p>

Wang¹,

Fu²,

Liu³

et al. 2019

IJN

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Background: Chemotherapy for non-small-cell lung cancer (NSCLC) still leads to unsatisfactory clinical prognosis because of poor active targeting and tumor metastasis. Purpose: The objective of this study was to construct a kind of PFV peptide modified targeted daunorubicin and dioscin codelivery liposomes, which could enhance tumor targeting and inhibit tumor cell metastasis. Methods and results: Targeted daunorubicin and dioscin codelivery liposomes were prepared by film dispersion and the ammonium sulfate gradient method. With the ideal physicochemical properties, targeted daunorubicin and dioscin codelivery liposomes exhibited enhanced cellular uptake and showed strong cytotoxicity to tumor cells. The encapsulation of dioscin increased the inhibitory effects of daunorubicin on A549 cells, vasculogenic mimicry (VM) channels and tumor metastasis. The enhanced antimetastatic mechanism of the targeted liposomes was attributed to the downregulation of matrix metalloproteinase-2 (MMP-2), vascular endothelial cadherin (VE-Cad), transforming growth factor-β1 (TGF-β1) and hypoxia inducible factor-1α (HIF-1α). Meanwhile, the targeted daunorubicin and dioscin codelivery liposomes exhibited significant antitumor effects in tumor-bearing mice. H&E staining, immunohistochemistry with Ki-67 and TUNEL assay also showed the promoted antitumor activity of the targeted liposomes. Conclusion: Targeted daunorubicin and dioscin codelivery liposomes may provide an effective strategy for the treatment of NSCLC.

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Section: Discussionmentioning

confidence: 99%

<p>Inhibition of tumor metastasis by targeted daunorubicin and dioscin codelivery liposomes modified with PFV for the treatment of non-small-cell lung cancer</p>

Wang¹,

Fu²,

Liu³

et al. 2019

IJN

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“…Subcutaneous injection of Lewis Lung Carcinoma cells in TRPV4 knockout mice leads to increased vascular density, higher vessel diameter, and reduced pericyte coverage, overall resulting in enhanced tumor growth ( Adapala et al, 2016 ). More recently, it has also been shown by the same group that TRPV4 silencing causes a significant decrease in VE-cadherin expression at cell-to-cell junctions, with the subsequent increase in vascular leakage ( Cappelli et al, 2019 ). Accordingly, overexpression or pharmacological stimulation of TRPV4 with GSK1016790A has been shown to lead to a “normalization” of the vascular endothelium, enhancing the permeability of chemotherapeutic drugs, and basically blocking tumor growth ( Adapala et al, 2016 ).…”

Section: Introductionmentioning

confidence: 93%

TRP Channels and Small GTPases Interplay in the Main Hallmarks of Metastatic Cancer

2020

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Transient Receptor Potential (TRP) cations channels, as key regulators of intracellular calcium homeostasis, play a central role in the essential hallmarks of cancer. Among the multiple pathways in which TRPs may be involved, here we focus our attention on the ones involving small guanosine triphosphatases (GTPases), summarizing the main processes associated with the metastatic cascade, such as migration, invasion and tumor vascularization. In the last decade, several studies have highlighted a bidirectional interplay between TRPs and small GTPases in cancer progression: TRP channels may affect small GTPases activity via both Ca 2+ -dependent or Ca 2+ -independent pathways, and, conversely, some small GTPases may affect TRP channels activity through the regulation of their intracellular trafficking to the plasma membrane or acting directly on channel gating. In particular, we will describe the interplay between TRPC1, TRPC5, TRPC6, TRPM4, TRPM7 or TRPV4, and Rho-like GTPases in regulating cell migration, the cooperation of TRPM2 and TRPV2 with Rho GTPases in increasing cell invasiveness and finally, the crosstalk between TRPC1, TRPC6, TRPM8, TRPV4 and both Rho- and Ras-like GTPases in inducing aberrant tumor vascularization.

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“…VIP significantly increased the lung metastasis of gastric cancer cells in vivo through the VPAC1/TRPV4/Ca 2+ signaling axis 113 . In vivo angiogenesis assay demonstrated that TRPV4 regulates tumor vessel integrity by maintaining VE-cadherin expression at cell–cell contacts 114 .…”

Section: Influence Of Trpv4 On Tumor Metastasis and Possible Mechanismmentioning

confidence: 99%

Transient receptor potential ion-channel subfamily V member 4: a potential target for cancer treatment

Huang

Ding

et al. 2019

Cell Death Dis

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The transient receptor potential ion-channel superfamily consists of nonselective cation channels located mostly on the plasma membranes of numerous animal cell types, which are closely related to sensory information transmission (e.g., vision, pain, and temperature perception), as well as regulation of intracellular Ca 2+ balance and physiological activities of growth and development. Transient receptor potential ion channel subfamily V (TRPV) is one of the largest and most diverse subfamilies, including TRPV1-TRPV6 involved in the regulation of a variety of cellular functions. TRPV4 can be activated by various physical and chemical stimuli, such as heat, mechanical force, and phorbol ester derivatives participating in the maintenance of normal cellular functions. In recent years, the roles of TRPV4 in cell proliferation, differentiation, apoptosis, and migration have been extensively studied. Its abnormal expression has also been closely related to the onset and progression of multiple tumors, so TRPV4 may be a target for cancer diagnosis and treatment. In this review, we focused on the latest studies concerning the role of TRPV4 in tumorigenesis and the therapeutic potential. As evidenced by the effects on cancerogenesis, TRPV4 is a potential target for anticancer therapy. Facts 1. TRPV4 is a broadly expressed, nonselective calcium permeant cation channel that perform an important role in regulating the Ca 2+ influx in the cells in which they are expressed. 2. TRPV4 is a thermosensor, activated by temperatures greater than 24-27°C, also can be activated by osmotic, mechanical, and chemical cues. 3. TRPV4 is constitutively expressed and capable of spontaneous activity in the absence of agonist stimulation, which suggests that it serves important physiological functions. Open questions 1. What is the underlying cause of TRPV4 expression levels in different types of cancer? 2. Whether it is possible to lower the toxicity and highefficiency TRPV4 inhibitors from natural products to treat various diseases? 3. How to inhibit the development of cancer by targeting TRPV4 of tumor cells without affecting the function of normal cells?

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Mechanosensitive TRPV4 channels stabilize VE-cadherin junctions to regulate tumor vascular integrity and metastasis

Cited by 43 publications

References 27 publications

<p>Inhibition of tumor metastasis by targeted daunorubicin and dioscin codelivery liposomes modified with PFV for the treatment of non-small-cell lung cancer</p>

<p>Inhibition of tumor metastasis by targeted daunorubicin and dioscin codelivery liposomes modified with PFV for the treatment of non-small-cell lung cancer</p>

TRP Channels and Small GTPases Interplay in the Main Hallmarks of Metastatic Cancer

Transient receptor potential ion-channel subfamily V member 4: a potential target for cancer treatment

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