Fibroblasts mediate induction of high mobility group box protein 1 in lung epithelial cancer cells by diffusible factors

Bartling, Babett; Fuchs, Christine; Silber, Rolf-Edgar; Simm, Andreas

doi:10.3892/ijmm.20.2.217

Cited by 5 publications

(8 citation statements)

References 33 publications

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“…Moreover, engagement of RAGE by its ligands results in a sustained NFκB and various inflammatory gene activation in all cell types studied thus far, such as endotheliums, fibroblasts, monocytes, macrophages, and lymphocytes [5,6,[9][10][11][12], and RAGE expression itself is controlled by NFκB [23,37]. Furthermore, the finding of Yamagishi et al suggest that circulating sRAGE levels may reflect tissue RAGE expression and may be elevated in parallel with RAGE ligands, such as HMGB-1, as a counter-system against RAGE ligand-elicited tissue damage [23,38].…”

Section: Discussionmentioning

confidence: 99%

“…HMGB-1 released from damaged, necrotic, and apoptotic cells binds to receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)2, TLR4, and also TLR9. HMGB-1 system induces the nuclear factor-κB (NFκB) phosphorylation and productions of several cytokines and chemokines, such as TNF-α, IL-1β, IL-6, macrophage inflammatory protein-1α, and 6 transforming growth factor-β by endothelial cells, fibroblasts, and various immune cells, such as macrophages, monocytes, T cells, and B cells [5,6,[9][10][11][12]. RAGE, the first receptor that was identified for HMGB-1, is encoded in the MHC class III region, together with the genes encoding the receptors for several complement components, as well as the genes encoding TNF, lymphotoxin, and heat-shock protein 70 [9].…”

Section: Introductionmentioning

confidence: 99%

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Clinical Significance of Serum HMGB-1 and sRAGE Levels in Systemic Sclerosis: Association with Disease Severity

et al. 2008

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The high mobility group box 1 protein (HMGB-1)/adcanced glycation end products (RAGE) system is recently shown to play an important part in immune/inflammatory disorders. However, the association of this system in systemic sclerosis (SSc) remains unknown. To determine clinical association of serum levels of HMGB-1 and soluble RAGE (sRAGE) in patients with SSc, sera from 70 patients with SSc and 25 healthy controls were examined by enzyme-linked immunosorbent assay. Sera from Tight-skin mice and bleomycin-induced scleroderma mice, animal models for SSc, were also examined. Skin HMGB-1 and RAGE expression was assessed by immunohistochemistry. Serum HMGB-1 and sRAGE levels in SSc were higher than those in controls. Similarly, HMGB-1 and sRAGE levels in animal SSc models were higher than those in control mice. SSc patients with elevated HMGB-1 and sRAGE levels had more frequent involvement of several organs and immunological abnormalities compared to those with normal levels. Furthermore, HMGB-1 and sRAGE levels correlated positively with modified Rodnan total skin thickness score and negatively with pulmonary function test. HMGB-1 and sRAGE expression in the sclerotic skin was more intense than normal skin. These results suggest that elevated serum HMGB-1 and sRAGE levels are associated with the disease severity and

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical Significance of Serum HMGB-1 and sRAGE Levels in Systemic Sclerosis: Association with Disease Severity

et al. 2008

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“…Tumor-associated stromal cells have been shown to protect tumor cells from cell death and the cytotoxic effects of chemotherapeutic drugs [ 31 , 32 ]. Recently, the impact of cancer-associated fibroblasts on the expression and localization of HMGB1 in lung cancer cells has been demonstrated to operate via the release of diffusible factors from fibroblasts [ 28 ]. The extracellular HMGB1 protein behaves as a cytokine, promotes inflammation and participates in the pathogenesis of several disorders in peripheral organs.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, factors diffusing from stromal fibroblasts have recently been shown to up-regulate intracellular HMGB1 in lung cancer cells [ 28 ]. HMGB1 may then be released from cancer cells during radiotherapy or chemotherapy and act upon surviving cancer cells to promote regrowth and metastasis [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Cancer-associated fibroblasts induce high mobility group box 1 and contribute to resistance to doxorubicin in breast cancer cells

et al. 2014

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BackgroundCancer-associated fibroblasts and high mobility group box 1 (HMGB1) protein have been suggested to mediate cancer progression and chemotherapy resistance. The role of such fibroblasts in HMGB1 production in breast cancer is unclear. This study aimed to investigate the effects of cancer-associated fibroblasts on HMGB1 expression in breast cancer cells and its role in chemotherapeutic response.MethodsBreast cancer-associated fibroblasts (BCFs) and non-tumor-associated fibroblasts (NTFs) were isolated from human breast cancers or adjacent normal tissues and established as primary cultures in vitro. After confirmation of the activated status of these fibroblasts, conditioned-media (CM) were collected and applied to MDA-MB-231 human triple negative breast cancer cells. The levels of intracellular and extracellular HMGB1 were measured by real-time PCR and/or Western blot. The response of BCF-CM-pre-treated cancer cells to doxorubicin (Dox) was compared with those pre-treated with NTF-CM or control cultures. The effect of an HMGB1 neutralizing antibody on Dox resistance induced by extracellular HMGB1 from non-viable Dox-treated cancer cells or recombinant HMGB1 was also investigated.ResultsImmunocytochemical analysis revealed that BCFs and NTFs were alpha-smooth muscle actin (ASMA) positive and cytokeratin 19 (CK19) negative cells: a phenotype consistent with that of activated fibroblasts. We confirmed that the CM from BCFs (but not NTFs), could significantly induce breast cancer cell migration. Intracellular HMGB1 expression was induced in BCF-CM-treated breast cancer cells and also in Dox-treated cells. Extracellular HMGB1 was strongly expressed in the CM after Dox-induced MDA-MB-231 cell death and was higher in cells pre-treated with BCF-CM than NTF-CM. Pre-treatment of breast cancer cells with BCF-CM induced a degree of resistance to Dox in accordance with the increased level of secreted HMGB1. Recombinant HMGB1 was shown to increase Dox resistance and this was associated with evidence of autophagy. Anti-HMGB1 neutralizing antibody significantly reduced the effect of extracellular HMGB1 released from dying cancer cells or of recombinant HMGB1 on Dox resistance.ConclusionsThese findings highlight the potential of stromal fibroblasts to contribute to chemoresistance in breast cancer cells in part through fibroblast-induced HMGB1 production.

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“…Overexpression of S100 family members is related to worse prognosis and poor survival in patients with lung cancer [99][100][101]. Significant alterations in tissue and serum levels of HMGB1 (amphoterin) in lung cancer have also been reported [102][103][104][105].…”

Section: Role Of Rage In Lung Cancermentioning

confidence: 99%

Critical role of RAGE in lung physiology and tumorigenesis: a potential target of therapeutic intervention?

Marinakis

Bagkos

Piperi

et al. 2014

Clinical Chemistry and Laboratory Medicine (CCLM)

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Lung cancer is one of the most common malignancies in the world and one of the leading causes of death from cancer. In the search for molecules that may be involved in lung tumor induction and progression, the receptor of advanced glycation end products (RAGE) comes across as a critical regulator of lung physiology. RAGE is a multiligand receptor that presents a differential expression pattern in lung epithelial cells compared to other cell types being gradually increased from fetal to birth and adult life. Under stress conditions, RAGE expression and activation are rapidly elevated resulting in chronic inflammation, which, in turn, in many instances, promotes epithelial cell malignant transformation. RAGE overexpression in normal lung alveolar type I epithelial cells is followed by rapid downregulation upon malignant transformation, being associated with increased aggressiveness. This is a striking paradox, since in every other cell type the pattern of RAGE expression follows the opposite direction, suggesting the involvement of RAGE in the well-functioning of lung cells. Additionally, RAGE has been attributed with the role of adhesion molecule, since it can stabilize mature alveolar epithelial cells to their substrate (basal lamina) by interacting electrostatically with other molecules. However, the reduction of RAGE observed in lung tumorigenesis interrupts cell-to-cell and cell-to-substrate communication, which is a critical step for cancer cell induction, progression and migration. This review addresses the differential properties of RAGE in lung physiology and carcinogenesis, providing evidence of therapeutic possibilities.

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Fibroblasts mediate induction of high mobility group box protein 1 in lung epithelial cancer cells by diffusible factors

Cited by 5 publications

References 33 publications

Clinical Significance of Serum HMGB-1 and sRAGE Levels in Systemic Sclerosis: Association with Disease Severity

Clinical Significance of Serum HMGB-1 and sRAGE Levels in Systemic Sclerosis: Association with Disease Severity

Cancer-associated fibroblasts induce high mobility group box 1 and contribute to resistance to doxorubicin in breast cancer cells

Critical role of RAGE in lung physiology and tumorigenesis: a potential target of therapeutic intervention?

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