The chemokine receptor CXCR4 is expressed in pancreatic intraepithelial neoplasia

Thomas, Ryan M.; Kim, Joseph; Revelo-Penafiel, Monica P.; Angel, Rita; Dawson, David D.; Lowy, Andrew M.

doi:10.1136/gut.2007.143941

Cited by 67 publications

(73 citation statements)

References 23 publications

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“…This is particularly significant, as other studies have ascribed important pathobiological roles to both the CXCR4 and hedgehog pathways in pancreatic cancer (7,22). Data from human clinical specimens and transgenic mouse models of spontaneous pancreatic cancer progression have suggested a role for these signaling nodes in early development and progression of pancreatic cancer (13,34). Interestingly, in pancreatic cancer, both CXCL12 and SHH act predominantly in a paracrine manner.…”

Section: Discussionmentioning

confidence: 87%

“…The CXCL12/CXCR4 pathway is critical for many normal cellular processes, including hematopoiesis, organogenesis, and vascularization, and is also utilized by the cancer cells to promote the processes of metastasis, growth, and survival (10,11). CXCR4 expression is elevated in majority of pancreatic cancers and preinvasive neoplastic lesions, suggesting its role in the pathogenesis and progression of pancreatic neoplasia (12,13). CXCL12, the sole ligand for CXCR4, is also abundantly produced by tumor-associated stromal cells and promotes pancreatic cancer progression and metastasis through CXCR4 activation (14,15).…”

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confidence: 99%

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CXCL12/CXCR4 Protein Signaling Axis Induces Sonic Hedgehog Expression in Pancreatic Cancer Cells via Extracellular Regulated Kinase- and Akt Kinase-mediated Activation of Nuclear Factor κB

Singh

Arora

Bhardwaj

et al. 2012

Journal of Biological Chemistry

109

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Background: CXCL12/CXCR4 and hedgehog pathways, predominantly acting in paracrine fashion, play important roles in pancreatic cancer pathobiology. Results: CXCL12/CXCR4 signaling regulates the expression of hedgehog ligand, the sonic hedgehog, in pancreatic cancer cells. Conclusion: Our findings indicate a novel molecular link between CXCL12/CXCR4 and hedgehog pathways. Significance: Our data provide a molecular basis for an active bidirectional tumor-stromal interaction in pancreatic cancer.

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Section: Discussionmentioning

confidence: 87%

mentioning

confidence: 99%

CXCL12/CXCR4 Protein Signaling Axis Induces Sonic Hedgehog Expression in Pancreatic Cancer Cells via Extracellular Regulated Kinase- and Akt Kinase-mediated Activation of Nuclear Factor κB

Singh

Arora

Bhardwaj

et al. 2012

Journal of Biological Chemistry

109

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“…CXCR4 expression is elevated in a majority of pancreatic cancers and preinvasive neoplastic lesions, suggesting its role in the pathogenesis and progression of pancreatic neoplasia (27,28). CXCL12, the sole ligand of CXCR4, is also produced abundantly by tumor-associated stromal cells and at common sites of metastasis, thus indicating an important role of CXCL12/ CXCR4 signaling in pancreatic cancer progression and metastasis (9,29).…”

Section: Discussionmentioning

confidence: 99%

An Undesired Effect of Chemotherapy

Arora

Bhardwaj

Singh

et al. 2013

Journal of Biological Chemistry

144

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Background: CXCR4 signaling protects pancreatic cancer cells from gemcitabine toxicity. However, the effect of gemcitabine on this resistance mechanism is unclear. Results: Gemcitabine up-regulates CXCR4 expression in pancreatic cancer cells and promotes their invasiveness. Conclusion: CXCR4 signaling serves as a counterdefense mechanism against gemcitabine. Significance: These findings are significant for the formulation of effective therapeutic strategies against pancreatic cancer.

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“…Both SDF-1 and its receptor, CXCR4, have been shown to be expressed in human pancreatic intraepithelial neoplasia (PanIN) and PDAs, and mouse PanIN lesions developed in PDX-Cre/LSL-Kras G12D mice (15,22,23). The expression of CXCR4 increases with the progression from low-grade to high-grade PanIN lesions and has been detected in 71.2% of PDA samples by immunohistochemistry (22).…”

Section: Introductionmentioning

confidence: 99%

High Levels of Expression of Human Stromal Cell–Derived Factor-1 Are Associated with Worse Prognosis in Patients with Stage II Pancreatic Ductal Adenocarcinoma

Liang

Zhu

Bruggeman

et al. 2010

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, have been shown to mediate invasiveness and metastatic behavior in a number of cancers, including ovarian, prostate, bladder, breast, and pancreatic cancers. The expression and significance of SDF-1 in pancreatic ductal adenocarcinoma (PDA) have not been systematically studied.Methods: We examined the expression of SDF-1 by immunohistochemistry using a mouse anti-human SDF-1/CXCL12 antibody (dilution 1:300) and a tissue microarray consisting of 72 stage II PDAs from pancreaticoduodenectomy specimens. The staining results were categorized as SDF-1-high (SDF-1-H; cytoplasmic staining of ≥10% of tumor cells) or SDF-1-low (SDF-1-L; no staining or staining of <10% of tumor cells). The results of SDF-1 expression were correlated with clinicopathologic parameters and survival. Statistical analyses were done using SPSS software.Result: Of the 72 stage II PDAs, 25 (35%) showed high levels of SDF-1 expression. The median overall and recurrence-free survival for patients with SDF-1-H PDAs were 26.1 and 11.1 months, respectively, compared with 44.3 and 22.3 months for patients with SDF-1-L tumors (log-rank test, P = 0.047 and P = 0.021). In multivariate analysis, high SDF-1 expression correlated with poor overall and disease-free survival (P = 0.02 and P = 0.02) independent of tumor size, differentiation, and lymph node status.Conclusion: High levels of SDF-1 expression were associated with poor overall and disease-free survival in patients with stage II PDA. SDF-1 may serve as a useful prognostic marker for stage II PDA.Impact: Our results suggest that SDF-1-CXCR4 or SDF-1-CXCR7 pathways may represent a potential target for therapeutic intervention as well as prediction of prognosis in PDA. Cancer Epidemiol Biomarkers Prev; 19(10);

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The chemokine receptor CXCR4 is expressed in pancreatic intraepithelial neoplasia

Cited by 67 publications

References 23 publications

CXCL12/CXCR4 Protein Signaling Axis Induces Sonic Hedgehog Expression in Pancreatic Cancer Cells via Extracellular Regulated Kinase- and Akt Kinase-mediated Activation of Nuclear Factor κB

CXCL12/CXCR4 Protein Signaling Axis Induces Sonic Hedgehog Expression in Pancreatic Cancer Cells via Extracellular Regulated Kinase- and Akt Kinase-mediated Activation of Nuclear Factor κB

An Undesired Effect of Chemotherapy

High Levels of Expression of Human Stromal Cell–Derived Factor-1 Are Associated with Worse Prognosis in Patients with Stage II Pancreatic Ductal Adenocarcinoma

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