Interaction between neoplastic cells and cancer-associated fibroblasts through the CXCL12/CXCR4 axis: Role in non–small cell lung cancer tumor proliferation

Wald, Ori; Izhar, Uzi; Amir, Gail; Kirshberg, Sophie; Shlomai, Zipora; Zamir, Gideon; Peled, Amnon; Shapira, Oz M.

doi:10.1016/j.jtcvs.2010.11.056

Cited by 69 publications

(54 citation statements)

References 28 publications

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“…In the present study, it was observed that higher CXCR4 mRNA expression occurred in lung carcinomas with lymph node metastasis or with vascular invasion, which was in concurrence with the previous consensus of the role of CXCR4 in promotion of invasion and metastasis (13,17,18). Previous studies have reported an association between high CXCL12/SDF-1 expression and high T scores as well as an increased tendency to form lymph node metastases (18,19). In the present study, CXCL12/SDF-1 mRNA expression was significantly associated with higher TNM staging, but inversely correlated with vascular invasion.…”

Section: Discussionsupporting

confidence: 92%

“…The IL-8 receptors, CXCR1 and CXCR2, have been identified in numerous tumor cells; however, the presence of these receptors has not yet been reported in lung cancer. Chemokine (C-C motif) receptor (CCR)7, which is the receptor for two major chemokines, chemokine (C-C motif) ligand (CCL) 19 and CCL21, was also demonstrated to have an important role in tumor metastasis and was associated with poor prognosis (9,10). The aim of the present study was to investigate the role of three chemokine ligand-receptor pairs, CXCL12-CXCR4, CXCL8-CXCR1/CXCR2, CCL19/CCL21-CCR7, in the malignant progression and metastasis of lung carcinoma.…”

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: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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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“…Sporadic studies indicated that CXCL12 mediated the proliferation of cancer cells, which may be related to activation of Akt, Erk, Akt-1/FOXO-3␣, Stat-3, and etc. (7,20,21,30,31). Although additional study is warranted to elucidate the correlation between rapamycin anti-proliferation activity and cxcl12 expression, this finding further supports that mTOR inhibitor may be useful for gastric cancer therapy.…”

Section: Discussionmentioning

confidence: 53%

Inhibition of Chemokine (CXC Motif) Ligand 12/Chemokine (CXC Motif) Receptor 4 Axis (CXCL12/CXCR4)-mediated Cell Migration by Targeting Mammalian Target of Rapamycin (mTOR) Pathway in Human Gastric Carcinoma Cells

Chen

Wang

et al. 2012

Journal of Biological Chemistry

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CXCL12/CXCR4 plays an important role in metastasis of gastric carcinoma. Rapamycin has been reported to inhibit migration of gastric cancer cells. However, the role of mTOR pathway in CXCL12/CXCR4-mediated cell migration and the potential of drugs targeting PI3K/mTOR pathway remains unelucidated. We found that CXCL12 activated PI3K/Akt/mTOR pathway in MKN-45 cells. Stimulating CHO-K1 cells expressing pEGFP-C1-Grp1-PH fusion protein with CXCL12 resulted in generation of phosphatidylinositol (3,4,5)-triphosphate, which provided direct evidence of activating PI3K by CXCL12. Down-regulation of p110β by siRNA but not p110α blocked phosphorylation of Akt and S6K1 induced by CXCL12. Consistently, p110β-specific inhibitor blocked the CXCL12-activated PI3K/Akt/mTOR pathway. Moreover, CXCR4 immunoprecipitated by anti-p110β antibody increased after CXCL12 stimulation and Gi protein inhibitor pertussis toxin abrogated CXCL12-induced activation of PI3K. Further studies demonstrated that inhibitors targeting the PI3K/mTOR pathway significantly blocked the chemotactic responses of MKN-45 cells triggered by CXCL12, which might be attributed primarily to inhibition of mTORC1 and related to prevention of F-actin reorganization as well as down-regulation of active RhoA, Rac1, and Cdc42. Furthermore, rapamycin inhibited the secretion of CXCL12 and the expression of CXCR4, which might form a positive feedback loop to further abolish upstream signaling leading to cell migration. Finally, we found cells expressing high levels of cxcl12 were sensitive to rapamycin in its activity inhibiting migration as well as proliferation. In summary, we found that the mTOR pathway played an important role in CXCL12/CXCR4-mediated cell migration and proposed that drugs targeting the mTOR pathway may be used for the therapy of metastatic gastric cancer expressing high levels of cxcl12.

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“…NSCLC cells expressing CXCR4 were noticed to migrate to tissues or organs with a high level of CXCL12, such as lymph nodes, contralateral lung, liver, brain, and bone marrow (Phillips et al, 2003;Belperio et al, 2004;Su et al, 2005;Wagner et al, 2009), even if the primary tumor was resected, just as Wang et al (2014) found that a high expression level of CXCR4 correlated with brain-specific metastasis following complete resection of NSCLC. In addition, the axis can promote cell proliferation, tumor growth, and angiogenesis (Phillips et al, 2003;Wald et al, 2011), and CXCR4 also appears to have an effect on the biology of cancer stem cells, which possess high self-renewal capacities, potential recapitulation of tumors in ectopic settings, and drug-resistant properties in NSCLC (Eramo et al, 2008;Wald et al, 2011). NSCLC cells expressing CXCR4 are strong candidates for those stem cells that maintain their property of self-renewal through a CXCR4-mediated signal transducer and activator of transcription 3 (STAT3) pathway (Jung et al, 2013).…”

Section: Cxcl12/cxcr4mentioning

confidence: 99%

“…Extracellular Ub, a recently identified new ligand for CXCR4, was found to act as an anti-inflammatory immune modulator in hematopoietic cells, and to induce suppressive and apoptotic effects on these cells (Saini et al, 2010;Majetschak, 2011). Recent studies on the potential role of extracellular Ub in non-hematological cells found that it had anti-apoptotic effects via activation of the PI3K Belperio et al, 2004;Su et al, 2005;Eramo et al, 2008;Wagner et al, 2009;Damelin et al, 2011;Montuori et al, 2011;Wald et al, 2011;Almasi et al, 2013;Jung et al, 2013;Hu et al, 2014;Li and Tai, 2014;Wang et al, 2014 Nrf2: NF-E2-related factor 2; EGFR: epidermal growth factor receptor; uPAR: urokinase plasminogen activator receptor; Ub: ubiquitin; DARC: Duffy antigen receptor for chemokines; CCX-CKR: ChemocentryX chemokine receptor. References in bold: chemokines/ receptors with anti-tumor effect pathway and was related to cell migration in epithelial cells.…”

Section: Ubiquitin/cxcr4mentioning

confidence: 99%

Chemokines and their receptors in lung cancer progression and metastasis

Cheng

Shi

Yuan

et al. 2016

J. Zhejiang Univ. Sci. B

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Lung cancer is the leading cause of cancer-related mortality around the world. Despite advancements in diagnosis, surgical techniques, and neoadjuvant chemoradiotherapy over the last decade, the mortality rate is still high and the 5-year survival is a dismal 15%. Fortunately, early detection by low-dose computed tomography (LDCT) scans has reduced mortality by 20%; yet, overall, 5-year-survival remains low at less than 20%. Therefore, in order to ameliorate this situation, a thorough understanding of the underlying molecular mechanisms is urgently needed. Chemokines and their receptors, crucial microenvironmental factors, play important roles in lung tumor genesis, progression, and metastasis, and exploring the mechanisms of this might bring new insights into early diagnosis and precisely targeted treatment. Consequently, this review will mainly focus on recent advancements on the axes of chemokines and their receptors of lung cancer.

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Interaction between neoplastic cells and cancer-associated fibroblasts through the CXCL12/CXCR4 axis: Role in non–small cell lung cancer tumor proliferation

Abstract: Interaction between carcinoma-associated fibroblasts and tumor epithelial cells through the CXCL12/CXCR4 axis plays a role in non-small cell lung cancer tumor proliferation, marking this axis as a target for immune intervention.

Cited by 69 publications

References 28 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

Inhibition of Chemokine (CXC Motif) Ligand 12/Chemokine (CXC Motif) Receptor 4 Axis (CXCL12/CXCR4)-mediated Cell Migration by Targeting Mammalian Target of Rapamycin (mTOR) Pathway in Human Gastric Carcinoma Cells

Chemokines and their receptors in lung cancer progression and metastasis

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