The oxidized‐LDL/LOX‐1 axis in tumor endothelial cells enhances metastasis by recruiting neutrophils and cancer cells

Tsumita, Takuya; Maishi, Nako; Annan, Dorcas A.; Towfik, Mohammad Alam; Matsuda, Aya; Onodera, Yasuhito; Nam, Jwa Min; Hida, Yasuhiro; Hida, Kyoko

doi:10.1002/ijc.34134

Cited by 19 publications

(23 citation statements)

References 49 publications

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“…Additionally, studies proved that both DU145 (Sangrajrang et al, 1998 ; Edmondson et al, 2016 ) and MDA468 (Jones et al, 2014 ; Ibrahim et al, 2018 ) cell lines express tubulin protein. Furthermore, research studies showed that LDL-receptors are highly expressed in cancer cells more than in healthy cells (Song et al, 2009 ; Alhadad et al, 2020 ; Jaragh Alhadad, 2021 ) and induce cancer cell proliferation (Antalis et al, 2010 ; Gallagher et al, 2017 ), metastasis, and angiogenesis (Lu et al, 2017 ; Zhang et al, 2021 ; Tsumita et al, 2022 ). Based on that, pyrimidine heterocyclic anticancer agents were tested for the cytotoxicity effects with 48 hr.…”

Section: Resultsmentioning

confidence: 99%

“…Third, our anticancer agents’ sizes were proved to be in the nano levels based on zeta data and scanning electron microscope data proved their morphologies. Agents’ morphology disrupts the microtubule's stability (Tsumita et al, 2022 ) and the nano-size particles increase the cellular uptake. A study, stated that rode shape anticancer agents increase the cellular uptake in-vitro and stimulate anticancer activity in-vivo (Xiupeng et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

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Cancer targeted drug delivery using active low-density lipoprotein nanoparticles encapsulated pyrimidines heterocyclic anticancer agents as microtubule inhibitors

2022

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Recently, nanomedicine had the potential to increase the delivery of active compounds to specific cell sites. Nano-LDL particles are recognized as an excellent active nano-platform for cancer-targeted delivery. Loading of therapeutic agents into nano-LDL particles achieved by surface loading, core loading, and apolipoprotein-B100 interaction. Therefore, loading nano-LDL particles’ core with pyrimidine heterocyclic anticancer agents will increase cancer cytotoxic activity targeting tubulin protein. First, by mimicking the native LDL particle's metabolic pathway, and second the agent’s chemical functional groups like the native amino acids cytosine and thymine structures will not be recognized as a foreign entity from the cell’s immune system. Nano-LDL particles will internalize through LDL-receptors endocytosis and transport the anticancer agent into the middle of the cancer cell, reducing its side effects on other healthy cells. Generally, the data revealed that pyrimidine heterocyclic anticancer agents’ size is at the nano level. Agents’ morphological examination showed nanofibers, thin sheets, clusters, and rod-like structures. LDL particles’ size became bigger after loading with pyrimidine heterocyclic anticancer agents and ranged between 121.6 and 1045 nm. Then, particles were tested for their cytotoxicity against breast (MDA468) and prostate (DU145) cancer cell lines as surrogate models with dose-response study 10, 5, 1 µM. The IC 50 values of the agents against DU145 and MDA468 possessed cell growth inhibition even at the 1 µM concentration ranges of 3.88 ± 1.05 µM and 3.39 ± 0.97 µM, respectively. In sum, nano-LDL particles proved their efficiency as active drug delivery vehicles to target tubulin in cancer cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cancer targeted drug delivery using active low-density lipoprotein nanoparticles encapsulated pyrimidines heterocyclic anticancer agents as microtubule inhibitors

2022

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“…Tumor endothelial cells (TECs) and normal endothelial cells (NECs) were isolated as previously reported [ 28 , 29 ].…”

Section: Methodsmentioning

confidence: 99%

Bovine Lactoferrin Suppresses Tumor Angiogenesis through NF-κB Pathway Inhibition by Binding to TRAF6

et al. 2023

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Tumor angiogenesis is essential for tumor progression. The inhibition of tumor angiogenesis is a promising therapy for tumors. Bovine lactoferrin (bLF) has been reported as an anti-tumor agent. However, bLF effects on tumor angiogenesis are not well demonstrated. This study evaluated the inhibitory effects of bLF on tumor angiogenesis in vivo and in vitro. Herein, tumor endothelial cells (TECs) and normal endothelial cells (NECs) were used. Proliferation, migration, tube formation assays, RT-PCR, flow cytometry, Western blotting, siRNA experiments and immunoprecipitation were conducted to clarify the mechanisms of bLF-induced effects. CD-31 immunoexpression was examined in tumor tissues of oral squamous cell carcinoma mouse models with or without Liposomal bLF (LbLF)-administration. We confirmed that bLF inhibited proliferation/migration/tube formation and increased apoptosis in TECs but not NECs. TNF receptor-associated factor 6 (TRAF6), p-p65, hypoxia inducible factor-α (HIF-1α) and vascular endothelial growth factor (VEGF) were highly expressed in TECs. In TECs, bLF markedly downregulated VEGF-A, VEGF receptor (VEGFR) and HIF-1α via the inhibition of p-p65 through binding with TRAF6. Since NECs slightly expressed p-p65, bLF–TRAF-6 binding could not induce detectable changes. Moreover, orally administrated LbLF decreased CD31-positive microvascular density only in TECs. Hence, bLF specifically suppressed tumor angiogenesis through p-p65 inhibition by binding to TRAF6 and suppressing HIF-1α activation followed by VEGF/VEGFR down-regulation. Collectively, bLF can be an anti-angiogenic agent for tumors.

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“…Tumor cell migration toward the S. mutans ‐stimulated ECs was assessed using transwell chambers (Corning, Life Sciences) as described previously, 20 , 22 , 23 with some modifications. Briefly, MS1 suspensions were placed into the lower compartment.…”

Section: Methodsmentioning

confidence: 99%

The oral bacterium Streptococcus mutans promotes tumor metastasis by inducing vascular inflammation

Maishi

Akahori

et al. 2022

Cancer Science

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Recent studies have demonstrated a relationship between oral bacteria and systemic inflammation. Endothelial cells (ECs), which line blood vessels, control the opening and closing of the vascular barrier and contribute to hematogenous metastasis; however, the role of oral bacteria‐induced vascular inflammation in tumor metastasis remains unclear. In this study, we examined the phenotypic changes in vascular ECs following Streptococcus mutans (S. mutans) stimulation in vitro and in vivo. The expression of molecules associated with vascular inflammation and barrier‐associated adhesion was analyzed. Tumor metastasis was evaluated after intravenous injection of S. mutans in murine breast cancer hematogenous metastasis model. The results indicated that S. mutans invaded the ECs accompanied by inflammation and NF‐κB activation. S. mutans exposure potentially disrupts endothelial integrity by decreasing vascular endothelial (VE)‐cadherin expression. The migration and adhesion of tumor cells were enhanced in S. mutans‐stimulated ECs. Furthermore, S. mutans‐induced lung vascular inflammation promoted breast cancer cell metastasis to the lungs in vivo. The results indicate that oral bacteria promote tumor metastasis through vascular inflammation and the disruption of vascular barrier function. Improving oral hygiene in patients with cancer is of great significance in preventing postoperative pneumonia and tumor metastasis.

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The oxidized‐LDL/LOX‐1 axis in tumor endothelial cells enhances metastasis by recruiting neutrophils and cancer cells

Cited by 19 publications

References 49 publications

Cancer targeted drug delivery using active low-density lipoprotein nanoparticles encapsulated pyrimidines heterocyclic anticancer agents as microtubule inhibitors

Cancer targeted drug delivery using active low-density lipoprotein nanoparticles encapsulated pyrimidines heterocyclic anticancer agents as microtubule inhibitors

Bovine Lactoferrin Suppresses Tumor Angiogenesis through NF-κB Pathway Inhibition by Binding to TRAF6

The oral bacterium Streptococcus mutans promotes tumor metastasis by inducing vascular inflammation

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