Primary breast cancer induces pulmonary vascular hyperpermeability and promotes metastasis via the VEGF–PKC pathway

Jiang, Man; Qin, Chengyong; Han, Mingyong

doi:10.1002/mc.22352

Cited by 30 publications

(30 citation statements)

References 34 publications

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“…It is accepted that endothelial cell disconnection or endothelial barrier breakdown is essential for cancer cell leakage into vessels. 15 A number of growth factors are known to influence endothelial cell integrity, including vascular endothelial growth factor (VEGF) and angiopoietin/TIE family members. 16,17 For example, downregulation of barrier function of lymphatic endothelial monolayer has been shown to facilitate sarcoma cell entry into the lymphatic circulation by VEGF-D. 18 However, these data are not sufficient to explain the mechanisms by which cancer cells disseminate into vessels surrounding tumors.…”

Section: Introductionmentioning

confidence: 99%

Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion

Cao

Liu

et al. 2016

OncoImmunology

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Endothelial integrity defects initiate lymphatic metastasis of tumor cells. Low-molecular-weight hyaluronan (LMW-HA) derived from plasma and interstitial fluid was reported to be associated with tumor lymphatic metastasis. In addition, LMW-HA was proved to disrupt lymphatic vessel endothelium integrity, thus promoting lymphatic metastasis of tumor cells. Until now, there are few reports on how LMW-HA modulates lymphatic endothelial cells adhesion junctions and affects cancer cells metastasizing into lymph vessels. The aim of our study is to unravel the novel mechanism of LMW-HA in mediating tumor lymphatic metastasis. Here, we employed a melanoma metastasis model to investigate whether LMW-HA facilitates tumor cells transferring from foci to remote lymph nodes by disrupting the lymphatic endothelial integrity. Our data indicate that LMW-HA significantly induces metastasis of melanoma cells to lymph nodes and accelerates interstitial-lymphatic flow in vivo. Further experiments show that increased migration of melanoma cells across human dermal lymphatic endothelial cell (HDLEC) monolayers is accompanied by impaired lymphatic endothelial barrier function and increased permeability. The mechanism study reveals that VE-cadherin-b-catenin pathway and relevant signals are involved in modulating the interactions between endothelial cells and that a significant inhibition of lymphatic endothelium disruption is observed when antibodies to the LMW-HA receptor (LYVE-1) are present. Thus, our findings demonstrate a disruptive effect of LMW-HA on lymphatic endothelium continuity which leads to a promotion on melanoma lymphatic metastasis and also suggest a cellular signaling mechanism associated with VE-cadherin-mediated lymphatic intercellular junctions.

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Section: Introductionmentioning

confidence: 99%

Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion

Cao

Liu

et al. 2016

OncoImmunology

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“…It is well documented that tight junctions undergo an array of molecular changes in response to pathological cues 18 with post-translational degradation 19 and redistribution/internalisation of tight junction proteins reported in response to inflammatory mediators, [20][21][22] kinases, 23 and microbiota changes. 24,25 Internalization is described most commonly for ZO-1, as it resides in the cytoplasm adjacent to the plasma membrane of the cell.…”

Section: Discussionmentioning

confidence: 99%

A novelin vitroplatform for the study of SN38-induced mucosal damage and the development of Toll-like receptor 4-targeted therapeutic options

Wardill

Gibson

Sebille

et al. 2016

Exp Biol Med (Maywood)

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Tight junction and epithelial barrier disruption is a common trait of many gastrointestinal pathologies, including chemotherapyinduced gut toxicity. Currently, there are no validated in vitro models suitable for the study of chemotherapy-induced mucosal damage that allow paralleled functional and structural analyses of tight junction integrity. We therefore aimed to determine if a transparent, polyester membrane insert supports a polarized T84 monolayer with the phenotypically normal tight junctions. T84 cells (passage 5-15) were seeded into either 0.6 cm 2 , 0.4 mm pore mixed-cellulose transwell hanging inserts or 1.12 cm 2 , 0.4 mm pore polyester transwell inserts at varying densities. Transepithelial electrical resistance was measured daily to assess barrier formation. Immunofluoresence for key tight junction proteins (occludin, zonular occludens-1, claudin-1) and transmission electron microscopy were performed to assess tight junction integrity, organelle distribution, and polarity. Reverse transcription-polymerase chain reaction was performed to determine expression of toll-like receptor 4 (TLR4). Liquid chromatography was also conducted to assess SN38 degradation in this model. Polyester membrane inserts support a polarized T84 phenotype with functional tight junctions in vitro. Transmission electron microscopy indicated polarity, with apico-laterally located tight junctions. Immunofluorescence showed membranous staining for all tight junction proteins. No internalization was evident. T84 cells expressed TLR4, although this was significantly lower than levels seen in HT29 cells (P ¼ .0377). SN38 underwent more rapid degradation in the presence of cells (À76.04 AE 1.86%) compared to blank membrane (À48.39 AE 4.01%), indicating metabolic processes. Polyester membrane inserts provide a novel platform for paralleled functional and structural analysis of tight junction integrity in T84 monolayers. T84 cells exhibit the unique ability to metabolize SN38 as well as expressing TLR4, making this an excellent platform to study clinically relevant therapeutic interventions for SN38-induced mucosal damage by targeting TLR4.

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“…According to the presence or absence of lung metastasis, the metastatic process can be divided into two phases: the premetastatic phase and the metastatic phase. Based on our previous study, days 0 to 14 was defined as the premetastatic phase …”

Section: Resultsmentioning

confidence: 99%

Primary tumor‐secreted VEGF induces vascular hyperpermeability in premetastatic lung via the occludin phosphorylation/ubiquitination pathway

Jiang

et al. 2019

Molecular Carcinogenesis

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Primary tumor can induce the formation of premetastatic niche. The hyperpermeability of the vessels in the premetastatic niche is the first step in the development of metastasis. However, the cellular and molecular mechanisms of vascular hyperpermeability remain to be elucidated. In this study, 4T1 breast cells were injected into the breasts of mice to establish a tumor model. Our results showed that primary tumors induced hyperpermeability of the vessels in the premetastatic lung. Subsequent studies showed that the level of vascular endothelial growth factor (VEGF) was elevated in the tumor‐bearing mice serum and the levels of tight junction (TJ) proteins occludin and ZO‐1 were decreased in the premetastatic lung. In vitro studies demonstrated that VEGF increased the permeability of dextran and decreased the levels of occludin and ZO‐1 in human umbilical vein endothelial cells. Moreover, the hyperpermeability of vessels and the degradation of occludin was blocked by bevacizumab. Overexpression of occludin alleviated the VEGF‐induced hyperpermeability. Further investigations revealed that VEGF‐induced occludin phosphorylation at Ser‐490 and ubiquitination. Finally, we showed that VEGF accelerated the process of occludin degradation through the ubiquitin‐proteasome system. In conclusion, primary tumor‐secrete VEGF induce the occludin phosphorylation/ubiquitination and downregulation, resulting in the disruption of TJs and hyperpermeability of vessels in premetastatic lung. The occludin phosphorylation/ubiquitination pathway may be the mechanism of VEGF‐induced vascular hyperpermeability in the lung premetastatic niche.

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Primary breast cancer induces pulmonary vascular hyperpermeability and promotes metastasis via the VEGF–PKC pathway

Cited by 30 publications

References 34 publications

Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion

Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion

A novelin vitroplatform for the study of SN38-induced mucosal damage and the development of Toll-like receptor 4-targeted therapeutic options

Primary tumor‐secreted VEGF induces vascular hyperpermeability in premetastatic lung via the occludin phosphorylation/ubiquitination pathway

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