Colon Cancer Cell–Derived Tumor Necrosis Factor-α Mediates the Tumor Growth–Promoting Response in Macrophages by Up-regulating the Colony-Stimulating Factor-1 Pathway

Zins, Karin; Abraham, Dietmar; Sioud, Mouldy; Aharinejad, Seyedhossein

doi:10.1158/0008-5472.can-06-2295

Cited by 111 publications

(94 citation statements)

References 30 publications

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“…The complex interactions between the neoplastic and inflammatory cells, which are mediated by inflammatory cytokines, are essential features of the tumor microenvironment [14] . Tumor necrosis factor-a (TNF-a) is a proinflammatory cytokine predominantly produced by macrophages as well as tumor cells [15,16] , and is a cytokine ligand of the TNF family that interacts with different receptors of the TNF receptor superfamily. The activity of this system may be one of the drivers of progression in CRC [17] .…”

Section: Introductionmentioning

confidence: 99%

“…It has multiple effects on cell function by binding to specific high-affinity, cell-surface receptors. Apart from its apoptosis-inducing mechanisms, TNF-a may promote tumor growth at lower levels during cancer progression [15,16] . A mounting body of evidence has suggested that TNF-a mediates many critical processes of tumor progression, including oncogene activation, DNA damage, and tumor metastases [18,19] .…”

Section: Introductionmentioning

confidence: 99%

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Increased expression of tumor necrosis factor-α is associated with advanced colorectal cancer stages

Obeed

Al‐Khayal

Sheikh

et al. 2014

WJG

112

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METHODS:Archival tissue specimens were collected from 30 patients with CRC who had undergone surgical intervention at King Khalid University Hospital. Patient demographic information, including age and gender, tumor sites, and histological type of CRC, was recorded. To measure TNF-a mRNA expression in CRC, total RNA was extracted from tumor formalin-fixed, paraffinembedded, and adjacent normal tissues. Reverse transcription and reverse transcription polymerase chain reaction were performed. Colorectal tissue microarrays were constructed to investigate the protein expression of TNF-a by immunohistochemistry. RESULTS:The relative expression of TNF-a mRNA in colorectal cancer was significantly higher than that seen in adjacent normal colorectal tissue. High TNF -a gene expression was associated with Stage Ⅲ and Ⅳ neoplasms when compared with earlier tumor stages (P = 0.004). Eighty-three percent of patients (25/30) showed strong TNF-a positive staining, while only 10% (n = 3/30) of patients showed weak staining, and 7% (n = 2/30) were negative. We showed the presence of elevated TNF-a gene expression in cancer cells, which strongly correlated with advanced stages of tumor. CONCLUSION:High levels of TNF-a expression could be an independent diagnostic indicator of colorectal cancer, and targeting TNF-a might be a promising prognostic tool by assessment of the clinical stages of CRC.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased expression of tumor necrosis factor-α is associated with advanced colorectal cancer stages

Obeed

Al‐Khayal

Sheikh

et al. 2014

WJG

112

View full text Add to dashboard Cite

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“…TNF has a critical role in the pathogenesis of inflammatory bowel diseases (IBD) and is a therapeutic target for treatment of these disorders (54,67). Furthermore, mounting evidence suggests that TNF signaling is important in the pathogenesis of GI cancers (47,50,78). Specifically, an altered balance between prosurvival and apoptotic signaling stimulated by TNF may be critical for tumorigenesis (5,57).…”

mentioning

confidence: 99%

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

Hobbs¹,

Goettel

Liang³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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TNF and epidermal growth factor (EGF) are well-known stimuli of cyclooxygenase (COX)-2 expression, and TNF stimulates transactivation of EGF receptor (EGFR) signaling to promote survival in colon epithelial cells. We hypothesized that COX-2 induction and cell survival signaling downstream of TNF are mediated by EGFR transactivation. TNF treatment was more cytotoxic to COX-2−/−mouse colon epithelial (MCE) cells than wild-type (WT) young adult mouse colon (YAMC) epithelial cells or COX-1−/−cells. TNF also induced COX-2 protein and mRNA expression in YAMC cells, but blockade of EGFR kinase activity or expression inhibited COX-2 upregulation. TNF-induced COX-2 expression was reduced and absent in EGFR−/−and TNF receptor-1 (TNFR1) knockout MCE cells, respectively, but was restored upon expression of the WT receptors. Inhibition of mediators of EGFR transactivation, Src family kinases and p38 MAPK, blocked TNF-induced COX-2 protein and mRNA expression. Finally, TNF injection increased COX-2 expression in colon epithelium of WT, but not kinase-defective EGFRwa2and EGFRwa5, mice. These data indicate that TNFR1-dependent transactivation of EGFR through a p38- and/or an Src-dependent mechanism stimulates COX-2 expression to promote cell survival. This highlights an EGFR-dependent cell signaling pathway and response that may be significant in colitis-associated carcinoma.

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“…The results seem reasonable because those factors have been thought to be upregulated in vivo in the TME via the activation of macrophages and other immune cells. [34,35] However we confined this study to the tumor fibroblast interaction and compensated for the immune cell derived factors with extrinsic factors in the following experi ments, to limit the complexity of our model system.…”

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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Colon Cancer Cell–Derived Tumor Necrosis Factor-α Mediates the Tumor Growth–Promoting Response in Macrophages by Up-regulating the Colony-Stimulating Factor-1 Pathway

Abstract: The interplay between malignant and stromal cells is essential in tumorigenesis. We have previously shown that colonystimulating factor (CSF)-1, matrix metalloprotease

Cited by 111 publications

References 30 publications

Increased expression of tumor necrosis factor-α is associated with advanced colorectal cancer stages

Increased expression of tumor necrosis factor-α is associated with advanced colorectal cancer stages

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

Biomimetic Model of Tumor Microenvironment on Microfluidic Platform

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