CXCR4/CXCL12 Axis in Non Small Cell Lung Cancer (NSCLC) Pathologic Roles and Therapeutic Potential

Wald, Ori; Shapira, Oz M.; Izhar, Uzi

doi:10.7150/thno.4922

Cited by 114 publications

(105 citation statements)

References 81 publications

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“…In cancer, the CCR7-CCL19/CCL21 axis is primarily responsible for lymph node metastasis formation by recruiting tumor cells to the T cell zone of lymph nodes (25). CCR7 overexpression has been observed in a large number of malignant tumors, including esophageal squamous cell carcinoma, gastric carcinoma, colon carcinoma and NSCLC, which was confirmed to be associated with lymph node metastasis, tumor growth, angiogenesis and invasion (6,26,27). However, the underlying mechanisms of these associations remained to be elucidated, although they were thought to involve integrins or phosphoinositide 3-kinase (26,28).…”

Section: Discussionmentioning

confidence: 99%

“…CXCL12/SDF-1, the only ligand of CXCR4, is a homeostatic chemokine and is continuously produced in numerous types of tissues, including those where metastases commonly occur (6). CXCL12/SDF-1 interactions with CXCR4 initiate divergent downstream signaling pathways, which may lead to various responses, including chemotaxis, cell survival and/or proliferation, increased intracellular calcium levels and gene transcription.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies regarding CXCL12-CXCR4 focus on its pathologic role and the potential therapeutic implications of targeting this axis for the treatment of lung cancer (2,3,6,7). In addition, CXCL8/interleukin-8 (IL-8), a potent angiogenic and autocrine growth factor, was reported to be associated with metastasis of lung cancer (8).…”

Section: Introductionmentioning

confidence: 99%

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Association of chemokine and chemokine receptor expression with the invasion and metastasis of lung carcinoma

Liu

Geng

et al. 2015

Oncology Letters

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Abstract. The chemokine system has been reported to be utilized and manipulated by tumor cells in order to promote local tumor growth and distant dissemination. The present study aimed to investigate the expression of three chemokine ligand-receptor axes in lung carcinoma tissues. Tumor and healthy normal tissue samples were obtained from 120 lung carcinoma patients following surgical resection. Immunohistochemistry and reverse transcription quantitative polymerase chain reaction were used in order to identify the protein and messenger (m)RNA expression of chemokines, including chemokine (C-X-C motif) ligand (CXCL)12/stromal cell-derived factor (SDF)-1, CXCL8/interleukin (IL)-8, chemokine (C-C motif) ligand (CCL)19 and CCL21, and the corresponding chemokine receptors, chemokine (C-X-C motif) receptor (CXCR)4, CXCR1, CXCR2 and chemokine (C-C motif) receptor (CCR)7, respectively. The results revealed that compared with the normal lung tissues, lung carcinoma tissues expressed significantly higher mRNA levels of CXCL12/SDF-1, CXCR4, CXCL8/IL-8, CXCR2, CCL19 and CCR7 (P<0.01). In four histological subtypes, adenocarcinoma presented dominant expression of CXCR4, CXCR2, CXCL8/IL-8 and CCL19 (P<0.05). In addition, it was demonstrated that tumor staging was inversely correlated with chemokine receptor CCR7 and CXCR2 mRNA expression as well as positively correlated with CXCL12/SDF-1, CXCL8/IL-8 and CCL19 mRNA levels (P<0.05). Lymph node metastasis presented a positive correlation with CXCR4, CXCR2 and CXCL8/IL-8 expression and a negative correlation with CCL19 and CCR7 expression (P<0.05). Furthermore, vascular invasion was more prevalent in patients with higher expression levels of CXCR4, CCR7 or CCL19 (P<0.01). In conclusion, these data suggested that the ligand-receptor interaction of CXCL8-CXCR2, CXCL12-CXCR4 and CCL19-CCR7 may be involved in the tumorigenesis of lung carcinoma. Higher expression levels of chemokines and lower expression of chemokine receptors indicated poor tumor staging. The CXC chemokine receptors, CXCR4 and CXCR2, promoted lymphatic metastasis through the activation of their specific ligands, while CCL19 and its receptor CCR7 had an essential role in hematogenous metastasis of lung carcinoma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Association of chemokine and chemokine receptor expression with the invasion and metastasis of lung carcinoma

Liu

Geng

et al. 2015

Oncology Letters

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“…Cytokines mediated signals can cross talk with chemokines and multiple chemokine-receptors are shown to be associated with tumor progression and metastasis. [7][8][9][10][11][12][13][14][15][16][17] Additionally, cell cycle regulation is governed by calcium flux, which in turn is altered by chemokine signaling. In this manuscript we have presented evidence that AG exerts its anticancer effects by modulating cell cycle as well as chemokine receptors (CXCR3 and CXCR7) and their common ligand CXCL11 in PCa cells.…”

Section: Introductionmentioning

confidence: 99%

Andrographolide inhibits prostate cancer by targeting cell cycle regulators, CXCR3 and CXCR7 chemokine receptors

et al. 2016

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Despite state of the art cancer diagnostics and therapies offered in clinic, prostate cancer (PCa) remains the second leading cause of cancer-related deaths. Hence, more robust therapeutic/preventive regimes are required to combat this lethal disease. In the current study, we have tested the efficacy of Andrographolide (AG), a bioactive diterpenoid isolated from Andrographis paniculata, against PCa. This natural agent selectively affects PCa cell viability in a dose and time-dependent manner, without affecting primary prostate epithelial cells. Furthermore, AG showed differential effect on cell cycle phases in LNCaP, C4-2b and PC3 cells compared to retinoblastoma protein (RB ¡/¡ ) and CDKN2A lacking DU-145 cells. G2/M transition was blocked in LNCaP, C4-2b and PC3 after AG treatment whereas DU-145 cells failed to transit G1/S phase. This difference was primarily due to differential activation of cell cycle regulators in these cell lines. Levels of cyclin A2 after AG treatment increased in all PCa cells line. Cyclin B1 levels increased in LNCaP and PC3, decreased in C4-2b and showed no difference in DU-145 cells after AG treatment. AG decreased cyclin E2 levels only in PC3 and DU-145 cells. It also altered Rb, H3, Wee1 and CDC2 phosphorylation in PCa cells. Intriguingly, AG reduced cell viability and the ability of PCa cells to migrate via modulating CXCL11 and CXCR3 and CXCR7 expression. The significant impact of AG on cellular and molecular processes involved in PCa progression suggests its potential use as a therapeutic and/or preventive agent for PCa.

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“…The interaction between CXCR-4 and stromal cell-derived factor (SDF-1α), its ligand, is known to play an important role in tumor genesis, metastasis, and angiogenesis (6,7). This biological role is demonstrated in different types of tumors including malignant melanoma, glioblastoma, and lung, breast, pancreatic, and cholangiocellular carcinomas (8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Chemokine CXCR-4 and cyclooxygenase-2 in the pathogenesis of pterygium

Baser¹,

Sivrikoz²,

Karahan³

et al. 2017

Turk J Med Sci

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Background/aim: This study aimed to investigate the expression of chemokine receptor 4 (CXCR-4) and cyclooxygenase-2 (COX-2) in the epithelium and stroma of pterygium tissue in comparison with healthy conjunctiva. Materials and methods:The expression of CXCR4 and COX-2 was investigated by immunohistochemistry in the epithelium and stroma of the pterygium tissue of 29 eyes and compared with healthy conjunctival tissues. The correlation between CXCR4 and COX-2 expression as well as the correlation of these markers with the area of pterygium were evaluated statistically.Results: COX-2 staining scores were 1.75 ± 0.63 in the epithelium and 1.20 ± 0.62 in the stroma of the pterygium tissue. Mean CXCR-4 staining in the epithelium was 0.069 ± 0.37, whereas it was 5.0 ± 2.84 cells in the stroma. There was almost no staining of COX-2 and CXCR4 in the control samples. There was a strong positive correlation between the expression of CXCR-4 and COX-2 in the stroma of the pterygium. Conclusion:CXCR-4 and COX-2 may play important roles in the pathogenesis of pterygium.

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CXCR4/CXCL12 Axis in Non Small Cell Lung Cancer (NSCLC) Pathologic Roles and Therapeutic Potential

Cited by 114 publications

References 81 publications

Association of chemokine and chemokine receptor expression with the invasion and metastasis of lung carcinoma

Association of chemokine and chemokine receptor expression with the invasion and metastasis of lung carcinoma

Andrographolide inhibits prostate cancer by targeting cell cycle regulators, CXCR3 and CXCR7 chemokine receptors

Chemokine CXCR-4 and cyclooxygenase-2 in the pathogenesis of pterygium

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