Pancreatic Stellate Cells Increase the Invasion of Human Pancreatic Cancer Cells through the Stromal Cell-Derived Factor-1/CXCR4 Axis

Gao, Zhihua; Wang, Xingpeng; Wu, Kai; Zhao, Yan; Hu, Guoyong

doi:10.1159/000236012

Cited by 106 publications

(68 citation statements)

References 39 publications

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“…The microarray expression analysis of FAT10 overexpressing NeHepLxHT and HCT116 cells by Gao et al (2014) revealed that the chemokine receptors CXCR4 and CXCR7 were highly up-regulated in FAT10 overexpressing NeHepLxHT cells, consistent with other data showing that NF-B is a transcription factor for both genes (Katoh and Katoh, 2010;Tarnowski et al, 2010). CXCR4 and −7 are both described to promote invasion and tumor growth in several cancer types (Gao et al, 2010;Heinrich et al, 2012;Liang et al, 2005;Zheng et al, 2010). In accordance with these data, an siRNA-mediated knockdown of p65 or overexpression of I B␣ in FAT10 overexpressing NeHepLxHT cells significantly attenuated cell invasion and migration in vitro, precisely as silencing of CXCR4 and CXCR7 did.…”

Section: What Are the Mechanisms Behind Fat10 Overexpression?supporting

confidence: 85%

The ubiquitin-like modifier FAT10 in cancer development

Aichem

Groettrup

2016

The International Journal of Biochemistry & Cell Biology

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a b s t r a c tDuring the last years it has emerged that the ubiquitin-like modifier FAT10 is directly involved in cancer development. FAT10 expression is highly up-regulated by pro-inflammatory cytokines IFN-␥ and TNF-␣ in all cell types and tissues and it was also found to be up-regulated in many cancer types such as glioma, colorectal, liver or gastric cancer. While pro-inflammatory cytokines within the tumor microenvironment probably contribute to FAT10 overexpression, an increasing body of evidence argues that pro-malignant capacities of FAT10 itself largely underlie its broad and intense overexpression in tumor tissues. FAT10 thereby regulates pathways involved in cancer development such as the NF-B-or Wnt-signaling. Moreover, FAT10 directly interacts with and influences downstream targets such as MAD2, p53 or ␤-catenin, leading to enhanced survival, proliferation, invasion and metastasis formation of cancer cells but also of non-malignant cells. In this review we will provide an overview of the regulation of FAT10 expression as well as its function in carcinogenesis.

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Section: What Are the Mechanisms Behind Fat10 Overexpression?supporting

confidence: 85%

The ubiquitin-like modifier FAT10 in cancer development

Aichem

Groettrup

2016

The International Journal of Biochemistry & Cell Biology

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“…Previous studies suggested overexpression of the CXCL12 receptor CXCR4 in PDAC (14,15). Furthermore, CXCL12 was previously detected on tumor-associated fibroblasts (16) and on FAP + fibroblasts (17), and its receptor CXCR4 was detected on pancreatic stellate cells (18) and also on endothelial cells (14). However, no studies have focused on the distribution of CXCL12/CXCR4/CXCR7 in pancreatic nerves.…”

Section: Resultsmentioning

confidence: 85%

Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells

Demir

Kujundzic

Pfitzinger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic ductal adenocarcinoma (PDAC) cells (PCC) have an exceptional propensity to metastasize early into intratumoral, chemokine-secreting nerves. However, we hypothesized the opposite process, that precancerous pancreatic cells secrete chemokines that chemoattract Schwann cells (SC) of nerves and thus induce ready-to-use routes of dissemination in early carcinogenesis. Here we show a peculiar role for the chemokine CXCL12 secreted in early PDAC and for its receptors CXCR4/CXCR7 on SC in the initiation of neural invasion in the cancer precursor stage and the resulting delay in the onset of PDAC-associated pain. SC exhibited cancer-or hypoxia-induced CXCR4/CXCR7 expression in vivo and in vitro and migrated toward CXCL12-expressing PCC. Glia-specific depletion of CXCR4/CXCR7 in mice abrogated the chemoattraction of SC to PCC. PDAC mice with pancreas-specific CXCL12 depletion exhibited diminished SC chemoattraction to pancreatic intraepithelial neoplasia and increased abdominal hypersensitivity caused by augmented spinal astroglial and microglial activity. In PDAC patients, reduced CXCR4/CXCR7 expression in nerves correlated with increased pain. Mechanistically, upon CXCL12 exposure, SC down-regulated the expression of several pain-associated targets. Therefore, PDAC-derived CXCL12 seems to induce tumor infiltration by SC during early carcinogenesis and to attenuate pain, possibly resulting in delayed diagnosis in PDAC.Schwann cells | pancreatic cancer | CXCL12 | CXCR4 | CXCR7

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“…In vitro studies revealed that SDF-1 was secreted by cancer associated fibroblasts (CAFs) or myofibroblasts and bound to its receptors (CXCR4 and CXCR7) on cancer cell surface to activate downstream intracellular signal pathways that regulate the metastasis, angiogenesis, and drug-resistant of cancer cells (18). Gao et al and Jiang et al both demonstrated that the proliferation, migration and invasion of pancreatic cancer cells and epithelial ovarian cancer cells were enhanced through SDF-1/CXCR4 axis after treating with certain concentrations of SDF-1 (19,20). Kang et al overexpressed SDF-1 in MDA-MB-231 cells to create an autocrine loop of SDF-1/CXCR4 and found that SDF-1 boosted the invasiveness and migration of breast cancer cells (21).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of SDF-1 activates the NF-κB pathway to induce epithelial to mesenchymal transition and cancer stem cell-like phenotypes of breast cancer cells

Kong

Guo

Liu

et al. 2016

International Journal of Oncology

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Abstract. The formation of EMT and EMT-induced CSC-like phenotype is crucial for the metastasis of tumor cells. The stromal cell-derived factor-1 (SDF-1) is upregulated in various human carcinomas, which is closely associated with proliferation, migration, invasion and prognosis of malignancies. However, limited attention has been directed towards the effect of SDF-1 on epithelial to mesenchymal transition (EMT) or cancer stem cell (CSC)-like phenotype formation in breast cancer cells and the related mechanism. In the present study, we screened MCF-7 cells with low SDF-1 expression level for the purpose of evaluating whether SDF-1 is involved in EMT and CSC-like phenotype formation in MCF-7 cells. The pEGFP-N1-SDF-1 plasmid was transfected into MCF-7 cells, and the stably overexpressed SDF-1 in MCF-7 cells was confirmed by real-time PCR and western blot analysis. Colony formation assay, MTT, wound healing assay and Transwell invasion assay demonstrated that overexpression of SDF-1 significantly boosted the proliferation, migration and invasion of MCF-7 cells compared with parental (P<0.05). Flow cytometry analysis revealed a notable increase of CD44 + / CD24 -subpopulation in SDF-1 overexpressing MCF-7 cells (P<0.001), accompanied by the apparently elevated ALDH activity and the upregulation of the stem cell markers OCT-4, Nanog, and SOX2 compared with parental (P<0.01).Besides, western blot analysis and immunofluorescence assay observed the significant decreased expression of E-cadherin and enhanced expression of slug, fibronectin and vimentin in SDF-1 overexpressed MCF-7 cells in comparison with parental (P<0.01). Further study found that overexpression of SDF-1 induced the activation of NF-κB pathway in MCF-7 cells. Conversely, suppressing or silencing p65 expression by antagonist or RNA interference could remarkably increase the expression of E-cadherin in SDF-1 overexpressed MCF-7 cells (P<0.001). Overall, the above results indicated that overexpression of SDF-1 enhanced EMT by activating the NF-κB pathway of MCF-7 cells and further induced the formation of CSC-like phenotypes, ultimately promoting the proliferation and metastasis of MCF-7 cells. Therefore, SDF-1 may further be assessed as a potential target for gene therapy of breast cancer. IntroductionBreast cancer is one of the most common malignancies in women, with ~1.05 million new cases annually and 3.1% increasing rate (1,2). Currently, surgery, chemotherapy, radiotherapy and endocrine therapy are the mainstream clinical strategies for breast cancer, but 25% mortality rate still remains (3). The deterioration and poor prognosis of breast cancer are attributed to tumor invasion and metastasis (1). Epithelialmesenchymal transition (EMT) and EMT-induced acquisition of cancer stem cell (CSC)-like phenotypes are crucial for invasion and metastasis of tumor cells (4-7). Hence, finding the key molecules that regulate formation of EMT and CSCs is warranted to reveal the pathological progression of breast cancer and develop novel therapeutic approaches.The ...

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Pancreatic Stellate Cells Increase the Invasion of Human Pancreatic Cancer Cells through the Stromal Cell-Derived Factor-1/CXCR4 Axis

Cited by 106 publications

References 39 publications

The ubiquitin-like modifier FAT10 in cancer development

The ubiquitin-like modifier FAT10 in cancer development

Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells

Overexpression of SDF-1 activates the NF-κB pathway to induce epithelial to mesenchymal transition and cancer stem cell-like phenotypes of breast cancer cells

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