Endotoxin/Lipopolysaccharide Activates NF-κB and Enhances Tumor Cell Adhesion and Invasion Through a β1 Integrin-Dependent Mechanism

Wang, Jiang Huai; Manning, Brian J.; Wu, Qiong; Blankson, Siobhan; Bouchier‐Hayes, David; Redmond, H. P.

doi:10.4049/jimmunol.170.2.795

Cited by 134 publications

(109 citation statements)

References 60 publications

(58 reference statements)

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“…Previously, it was shown that bacterial LPS can increase colorectal carcinoma adhesion to, and subsequent invasion of cultured endothelial monolayers. 52 Thus, we assessed the influence of systemic inflammation on the early events in metastatic progression of lung carcinoma cells in vivo, and found that LPS-mediated systemic inflammation significantly increased the adhesion of H-59 cells within the liver sinusoids. These findings provide in vivo evidence that inflammation can increase the metastatic potential of circulating tumor cells by enhancing their ability to infiltrate the liver.…”

Section: Discussionmentioning

confidence: 99%

Systemic inflammation increases cancer cell adhesion to hepatic sinusoids by neutrophil mediated mechanisms

McDonald

Spicer

Giannais

et al. 2009

Intl Journal of Cancer

197

163

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Interactions between endothelial selectins and selectin ligands expressed on tumor cells have been implicated in the binding of circulating metastatic cancer cells to the vascular endothelium during extravasation. Moreover, there is mounting evidence that inflammatory environments can accelerate the progression of metastasis by neutrophil mediated mechanisms. In this study, a physiologically relevant in vivo model of early metastasis coupled with intravital microscopy was used to visualize the trafficking of tumor cells within the liver vasculature in real time. Using GFPlabeled Lewis lung carcinoma subline H-59 cells, we show here that disrupting the interactions between endothelial selectins and tumor cell selectin ligands diminished tumor cell recruitment to the liver. Furthermore, systemic inflammation induced by intravenous injection of lipopolysaccharide significantly enhanced the metastatic potential of these lung carcinoma cells by increasing their propensity to adhere to the liver sinusoidal endothelium. Confocal microscopy revealed frequent colocalization of cancer cells with neutrophils and neutrophil depletion in vivo significantly attenuated the lipopolysaccharide-induced increase in H-59 cell adhesion. Although direct selectin-selectin ligand interactions contributed significantly to tumor cell adhesion to sinusoidal endothelial cells, we show here that in addition, interactions between adherent neutrophils within the inflamed sinusoids and circulating tumor cells may further increase tumor cell arrest in the liver. ' 2009 UICC Key words: cancer; metastasis; lung; rodent; adhesion molecules; e-selectin; neutrophil; sialyl Lewis X Lung cancer is the leading cause of cancer-related deaths worldwide. 1 A high proportion of patients harbor metastasis to regional lymph nodes upon presentation, and over half of all patients who undergo curative intent surgical resection of the lung will develop metastatic recurrence. 2 The liver is a common site of metastasis for lung cancer, with autopsy studies showing hepatic metastases in over 50% of lung cancer patients. 3 The hematogenous dissemination of cancer cells from a primary tumor to distant organs involves a cascade of sequential steps (reviewed in Refs. 4,5). The adhesion of circulating tumor cells to the vascular endothelium of distant organs is a key step in the metastatic cascade that may determine the organ tropism and extent of metastasis. Interactions between endothelial selectins and tumor cell selectin ligands have been implicated in the metastatic process. [5][6][7][8] Selectins are a family of transmembrane glycoproteins possessing an extracellular lectin domain that binds to carbohydrate moieties present on their ligands. 9 The three known selectins that function as cell adhesion molecules are expressed on the surface of endothelial cells (E-selectin and P-selectin), platelets (P-selectin) and leukocytes (L-selectin). E-selectin has been shown to contribute to the metastatic spread of multiple cancers, including lung and colon carcinoma, and m...

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Section: Discussionmentioning

confidence: 99%

Systemic inflammation increases cancer cell adhesion to hepatic sinusoids by neutrophil mediated mechanisms

McDonald

Spicer

Giannais

et al. 2009

Intl Journal of Cancer

197

163

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“…Although it has been extensively demonstrated that bacterial endotoxin (LPS), analysed in both in vitro and in vivo experimental settings, reduces apoptosis (Andrews et al, 2001;Wang et al, 2003) and increases proliferation in metastatic tumour cells (Coffey et al, 2006), the role of extracellular matrix (ECM)-degrading enzyme systems remains to be elucidated in this phenomenon.…”

mentioning

confidence: 99%

Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-κB-dependent activation of the urokinase plasminogen activator system

et al. 2009

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Perioperative exposure to lipopolysaccharide (LPS) is associated with accelerated metastatic colorectal tumour growth. LPS directly affects cells through Toll-like receptor 4 (TLR-4) and the transcription factor NF-kB. The urokinase plasminogen activator (u-PA) system is intimately implicated in tumour cell extracellular matrix (ECM) interactions fundamental to tumour progression. Thus we sought to determine if LPS directly induces accelerated tumour cell ECM adhesion and invasion through activation of the u-PA system and to elucidate the cellular pathways involved. Human colorectal tumour cell lines were stimulated with LPS. u-PA concentration, u-PA activity, active u-PA, surface urokinase plasminogen activator receptor (u-PAR) and TLR-4 expression were assessed by ELISA, colorimetric assay, western blot analysis and flow cytometry respectively. In vitro tumour cell vitronectin adhesion and ECM invasion were analysed by vitronectin adhesion assay and ECM invasion chambers. u-PA and u-PAR function was inhibited with anti u-PA antibodies or the selective u-PA inhibitors amiloride or WXC-340, TLR-4 by TLR-4-blocking antibodies and NF-kB by the selective NF-kB inhibitor SN-50. LPS upregulates u-PA and u-PAR in a dose-dependent manner, enhancing in vitro tumour cell vitronectin adhesion and ECM invasion by 440% (Po0.01). These effects were ameliorated by u-PA and u-PAR inhibition. LPS activates NF-kB through TLR-4. TLR-4 and NF-kB inhibition ameliorated LPS-enhanced u-PA and u-PAR expression, tumour cell vitronectin adhesion and ECM invasion. LPS promotes tumour cell ECM adhesion and invasion through activation of the u-PA system in a TLR-4-and NF-kB-dependent manner.

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“…Another important factor that regulates cancer physiology in the TME is integrin receptor signaling of the cancer cells. [28][29][30] Fibroblasts are known to be a rich source of ECM components, such as fibronectin, which is a ligand for the integrin signaling in various cellular responses. [31] Because both collagen and fibrin are important in fibronectin fibrogen esis, [32] our results might suggest that a combination of ECM integrin signaling and ECM rigidity could affect such signaling.…”

Section: Angiogenesismentioning

confidence: 99%

Biomimetic Model of Tumor Microenvironment on Microfluidic Platform

Chung

Ahn

Son

et al. 2017

Adv Healthcare Materials

107

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COMMUNICATION (1 of 7)© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Biomimetic Model of Tumor Microenvironment on Microfluidic PlatformMinhwan Chung, Jungho Ahn, Kyungmin Son, Sudong Kim, and Noo Li Jeon* DOI: 10.1002/adhm.201700196 "cure." [4,5] The TME is a complex, inter acting system including the tumor itself, other noncancerous cell types such as immune, stromal and endothelial cells, and the extracellular matrix surrounding these cells. [6,7] This complexity has largely prevented a comprehensive understanding of TME in conventional in vitro models, which have been too simple to recapitulate the intricate interactions ( Figure 1A). [8,9] During recent decades, microfabrication technologies have been shown to be valu able tools in the exploration of tumor pro gression. Recently, several studies using microfluidic platform have been reported that recreate the 3D context of each aspect of the TME and metastasis in vitro. [10][11][12][13] However, to our knowledge, no versatile in vitro experimental model that reconstitutes direct interplay between constituents of the TME during tumorigenesis has yet been reported. Here we describe a biomimetic TME model to mimic the complex inter actions of the tumor, stromal, and endothe lial cells, all of which are essential components of the TME that hinder the effective treatment of cancers. [14][15][16] We used a micro fluidic platform from our previous studies. [17,18] Various effects of extracellular matrix (ECM) and the stroma on the physiology of tumor cells and angiogenesis were tested. Finally, we could mimic simultaneous angiogenesis and lymphangiogenesis in the TME with interactions between the tumor cells.Although the cancer stroma is well known for its many roles in multiple cancer stages, direct interactions between cancer and stromal cells have remained largely unknown. [19] Addition ally, cancer cell interaction with the ECM is another TME factor that regulates the behavior of the cancer cells and their resist ance to drugs. [20] Recently, in vitro activation of tumor stoma and corresponding ECM remodeling have been reported using a microfluidic platform. [21] However, single cell responses of the cancer cells in response to the stroma coculture and ECM composition has not yet been described. To examine cancer stromal cell interaction with a 3D ECM, we used a micro fluidic 3D cell culture platform previously reported from our group. [17,18] The array of microposts in the platform enabled straightforward micropatterning of the hydrogel which allowed flexible experimental configurations. We first cocultured cancer and stromal cells within fibrin gel in different microchannels, which still allowed the cells to interact with each other in a par acrine manner ( Figure 1B). Twice as many fibroblasts as cancer cells were patterned to exclude an autocrine or indirect effectThe "Tumor microenvironment" (TME) is a complex, interacting system of the tumor and its surrounding environment. The TME has drawn more attention recently in attempts to overcome current drug...

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Endotoxin/Lipopolysaccharide Activates NF-κB and Enhances Tumor Cell Adhesion and Invasion Through a β1 Integrin-Dependent Mechanism

Cited by 134 publications

References 60 publications

Systemic inflammation increases cancer cell adhesion to hepatic sinusoids by neutrophil mediated mechanisms

Systemic inflammation increases cancer cell adhesion to hepatic sinusoids by neutrophil mediated mechanisms

Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-κB-dependent activation of the urokinase plasminogen activator system

Biomimetic Model of Tumor Microenvironment on Microfluidic Platform

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