The CXCR4/SDF-1 Chemokine Receptor Axis: A New Target Therapeutic for Non-small Cell Lung Cancer

Otsuka, Shannon; Bebb, Gwyn

doi:10.1097/jto.0b013e31818dda9d

Cited by 56 publications

(33 citation statements)

References 63 publications

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“…The CXCL12/CXCR4 axis is involved in several aspects of tumor progression including angiogenesis, metastasis, and survival (1,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). The bone marrow microenvironment facilitates the survival, differentiation, and proliferation of normal hematopoietic cells, malignant hematopoietic cells, and epithelial tumor cell bone metastasis.…”

Section: Cxcr4 and Cancermentioning

confidence: 99%

CXCL12 (SDF-1)/CXCR4 Pathway in Cancer

Teicher¹,

Fricker²

2010

Clinical Cancer Research

1,205

1,067

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Chemokines, small proinflammatory chemoattractant cytokines that bind to specific G-proteincoupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. The chemokine CXCL12 [stromal cell-derived factor-1 (SDF-1)] binds primarily to CXC receptor 4 (CXCR4; CD184). The binding of CXCL12 to CXCR4 induces intracellular signaling through several divergent pathways initiating signals related to chemotaxis, cell survival and/or proliferation, increase in intracellular calcium, and gene transcription. CXCR4 is expressed on multiple cell types including lymphocytes, hematopoietic stem cells, endothelial and epithelial cells, and cancer cells. The CXCL12/CXCR4 axis is involved in tumor progression, angiogenesis, metastasis, and survival. This pathway is a target for therapeutics that can block the CXCL12/CXCR4 interaction or inhibit downstream intracellular signaling.

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Section: Cxcr4 and Cancermentioning

confidence: 99%

CXCL12 (SDF-1)/CXCR4 Pathway in Cancer

Teicher¹,

Fricker²

2010

Clinical Cancer Research

1,205

1,067

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“…In fact, neutralization of CXCL12 by anti-CXCL12 or anti- CXCR4 monoclonal antibody in preclinical in vivo studies results in a significant decrease in NSCLC metastases [164]. Activation of the CXCR4/CXCL12 (SDF-1) axis also induces nuclear export of the heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 [165].…”

Section: Inflammatory Mediators In Copd and Lung Cancer Chemokines Tmentioning

confidence: 99%

Chronic Obstructive Pulmonary Disease and Lung Cancer: New Molecular Insights

2011

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Both chronic obstructive pulmonary disease (COPD) and lung cancer are major causes of death worldwide. In most cases this reflects cigarette smoke exposure which is able to induce an inflammatory response in the airways of smokers. Indeed, COPD is characterized by lower airway inflammation, and importantly, the presence of COPD is by far the greatest risk factor for lung cancer amongst smokers. Cigarette smoke induces the release of many inflammatory mediators and growth factors including TGF-β, EGFR, IL-1, IL-8 and G-CSF through oxidative stress pathways and this inflammation may persist for decades after smoking cessation. Mucus production is also increased by these inflammatory mediators, further linking airway inflammation to an important mechanism of lung cancer. A greater understanding of the molecular and cellular pathobiology that distinguishes smokers with lung cancer from smokers with and without COPD is needed to unravel the complex molecular interactions between COPD and lung cancer. By understanding the common signalling pathways involved in COPD and lung cancer the hope is that treatments will be developed that not only treat the underlying disease process in COPD, but also reduce the currently high risk of developing lung cancer in these patients.

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“…Thus, CXCR7 appears to be the critical receptor for SDF-1 in the developing heart, whereas the CXCR4 receptor appears to be involved in hematopoietic and gastrointestinal development (Sierro et al 2007). Other models of SDF-1/CXCR4 inhibition involve the use of antibodies and indicate roles for this signaling complex in neonatal hypoxia-induced pulmonary hypertension (Young et al 2009) and in non-small cell lung cancer (for a review, see Otsuka and Bebb 2008). However, specific details of the roles of SDF-1 signaling in the lung during development and in adults have not been characterized.…”

Section: Introductionmentioning

confidence: 96%

Lung defects in neonatal and adult stromal-derived factor–1 conditional knockout mice

Chen

Tzeng

et al. 2010

Cell Tissue Res

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Stromal-derived factor (SDF)-1/CXCL12 is a cytokine that is involved in organogenesis, hematopoiesis, chemoattraction, and wound healing. An SDF-1 knockout mouse (SDF-1(-/-)) has provided important insights into the role of SDF-1 in fetal development. Because the SDF-1 knockout is lethal in the perinatal period, we have created a conditional SDF-1 knockout mouse. In the present study, we induced conditionally knocked out SDF-1 in neonatal mice and found that lung development was compromised; neonatal lungs showed increased alveolar airspace and abnormal ultrastructure. Conditional knockout of SDF-1 in adult mice resulted in an emphysemic morphology, with increased alveolar airspace and thickened alveolar septa. Fluorescence angiography showed pulmonary vessel hyperdilation. To determine whether the hyperdilation involved nitric oxide, we inhibited endothelial nitric oxide synthase (eNOS) with N (G)-nitro-L- arginine methyl ester. This resulted in the inhibition of pulmonary vessel hyperdilation. Western blot results showed increased phosphorylation of eNOS in our induced SDF-1 knockout mice, indicating that eNOS is normally repressed in the presence of SDF-1, and that activation of eNOS contributes to pulmonary pathology. Thus, a conditional knockout mouse has been successfully created for SDF-1; initial characterization indicates that SDF-1 is intimately involved in lung development and physiology.

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The CXCR4/SDF-1 Chemokine Receptor Axis: A New Target Therapeutic for Non-small Cell Lung Cancer

Cited by 56 publications

References 63 publications

CXCL12 (SDF-1)/CXCR4 Pathway in Cancer

CXCL12 (SDF-1)/CXCR4 Pathway in Cancer

Chronic Obstructive Pulmonary Disease and Lung Cancer: New Molecular Insights

Lung defects in neonatal and adult stromal-derived factor–1 conditional knockout mice

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