Interleukin‐8 secreted by endothelial cells induces Chemotaxis of melanoma cells through the chemokine receptor CXCR1

Ramjeesingh, Ravi; Leung, Randy; Siu, Chi‐Hung

doi:10.1096/fj.02-0560fje

Cited by 73 publications

(49 citation statements)

References 54 publications

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“…It was shown that the migration of CXCR1-and CXCR2-expressing endothelial cells is predominantly mediated through CXCR2 (Addison et al, 2000;Loukinova et al, 2000; Heidemann et al, 2003). On the other hand, a recent report suggests that in melanoma cells, CXCL-8-mediated chemotaxis is mainly mediated through CXCR1 (Ramjeesingh et al, 2003). We, however, did not observe any significant differences in CXCL-8-dependent motility and invasion between CXCR1-or CXCR2-overexpressing cells.…”

Section: Discussioncontrasting

confidence: 77%

CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion

et al. 2009

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The aggressiveness of malignant melanoma is associated with differential expression of CXCL-8 and its receptors, CXCR1 and CXCR2. However, the precise functional role of these receptors in melanoma progression remains unclear. In this study, we investigate the precise functional role of CXCR1 and CXCR2 in melanoma progression. CXCR1 or CXCR2 were stably overexpressed in human melanoma cell lines, SBC-2 (non-tumourigenic) and A375P (low-tumourigenic) exhibiting low endogenous expression of receptors. Functional assays were performed to study the resulting changes in cell proliferation, motility and invasion, and in vivo tumour growth using a mouse xenograft model. Our data demonstrated that CXCR1-or CXCR2-overexpressing SBC-2 and A375P melanoma cells had enhanced proliferation, chemotaxis and invasiveness in vitro. Interestingly, CXCR1 or CXCR2 overexpression in SBC-2 cells induced tumourigenicity, and A375P cells significantly enhanced tumour growth as examined in vivo. Immunohistochemical analyses showed significantly increased tumour cell proliferation and microvessel density and reduced apoptosis in tumours generated from CXCR1-or CXCR2-overexpressing melanoma cells. CXCR1-or CXCR2-induced modulation of melanoma cell proliferation and migration was observed to be mediated through the activation of ERK1/2 phosphorylation.Together, these studies demonstrate that CXCR1 and CXCR2 play essential role in growth, survival, motility and invasion of human melanoma.

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Section: Discussioncontrasting

confidence: 77%

CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion

et al. 2009

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“…Previous studies have shown that the angiogenic effects of IL-8 in human microvascular endothelial cells and NSCLC were mediated by CXCR2 (Addison et al, 2000;Salcedo et al, 2000;Heidemann et al, 2003). The chemotactic response of melanoma cells to IL-8 was mediated by CXCR1 (Ramjeesingh et al, 2003), and the mitogenic activity of IL-8 was mediated by both CXCR1 and CXCR2 in colon cancer (Li et al, 2001), but only by CXCR1 in monocytes (Browning et al, 2000). Our results show that CXCR1 is the major receptor that mediates the mitogenic function of IL-8 in lung cancer.…”

Section: Discussionmentioning

confidence: 94%

Interleukin-8/CXCL8 is a growth factor for human lung cancer cells

et al. 2004

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Interleukin-8/CXCL8 (IL-8) is a chemokine and angiogenic factor. Recently, IL-8 was identified as an autocrine growth factor in several human cancers. Here, we investigated the expression and function of IL-8 in lung cancer cells. The expressions of IL-8 and its receptors, CXCR1 and CXCR2, were examined in a panel of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines. Using reverse transcription -polymerase chain reaction (RT -PCR) and enzyme-linked immunosorbent assay, we found that all NSCLC cell lines tested produced modest or high levels of IL-8 (up to 51 ng ml À1 10 6 cells À1 ). Expression of CXCR1 and CXCR2 was found by RT -PCR and flow cytometry in two out of three cell lines. In contrast, SCLC cell lines produced very low or undetectable levels of IL-8, but expressed CXCR1 and CXCR2. We next investigated whether IL-8 could act as an autocrine growth factor in two NSCLC cell lines (H460 and MOR/P) expressing both IL-8 and its receptors. We found that cell proliferation was attenuated by anti-IL-8 neutralising antibody to 71 and 76% in H460 and MOR/P, respectively (Po0.05). Exogenous IL-8 significantly stimulated cell proliferation in four SCLC cell lines tested in a dose-dependent fashion. Cell proliferation was increased by between 18% (Po0.05) and 37% (Po0.05). Stimulation of cell proliferation by IL-8 was also demonstrated by analysis of proliferating cell nuclear antigen expression and cell cycle in H69 cells. Furthermore, we investigated which receptor(s) mediated the mitogenic function of IL-8 in lung cancer cells. We found that cell proliferation was significantly reduced by anti-CXCR1 antibody but not by anti-CXCR2 antibody. In conclusion, IL-8 can act as an autocrine and/or paracrine growth factor for lung cancer cells, and the mitogenic function of IL-8 in lung cancer is mediated mainly by CXCR1 receptor.

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“…Both receptors are G protein-coupled seventransmembrane domain receptors, but different biological functions may be mediated by the different receptors. CXCR1 is believed to mediate the chemotactic activity, whereas CXCR2 mediates the angiogenic activity of CXC ELR þ chemokines such as IL-8 (Heidemann et al, 2003;Ramjeesingh et al, 2003;Bates et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Production and upregulation of granulocyte chemotactic protein-2/CXCL6 by IL-1β and hypoxia in small cell lung cancer

2006

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Small cell lung cancer (SCLC) is characterised by early and widespread metastasis. However, SCLC cells have so far been found to produce low levels of known pro-angiogenic factors. We speculated that SCLC cells might produce alternative pro-angiogenic factors. Here, we report that a panel of SCLC cell lines constitutively secrete granulocyte chemotactic protein-2 (GCP-2)/CXCL6, a CXC ELR þ chemokine. In contrast, none of the three tested NSCLC cell lines secreted GCP-2. Production of GCP-2 in vivo was also confirmed in seven out of nine specimens with SCLC. We demonstrate that expression of GCP-2 is mediated by NF-kB as ALLN, an NF-kB pathway inhibitor, almost completely abolished GCP-2 production in SCLC cell lines. We also demonstrate that GCP-2 can be significantly upregulated by IL-1b and hypoxia in SCLC cell lines. This result suggests a role for GCP-2 in promoting tumour progression in vivo under unfavourable conditions such as oxygen deprivation. As SCLC cells express both GCP-2 and its receptors CXCR1 and CXCR2, their biological significance in SCLC progression was further studied. We demonstrate that GCP-2 is an autocrine growth factor. Cell proliferation was significantly inhibited by anti-GCP-2 neutralising antibody in two high-GCP-2-producing cell lines. In addition, expression of the proliferation marker PCNA was upregulated by exogenous GCP-2 in two low-GCP-2-producing cell lines. Taken together, these results suggest an important role for GCP-2 as an autocrine mitogen in the growth and metastasis of SCLC.

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Interleukin‐8 secreted by endothelial cells induces Chemotaxis of melanoma cells through the chemokine receptor CXCR1

Cited by 73 publications

References 54 publications

CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion

CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion

Interleukin-8/CXCL8 is a growth factor for human lung cancer cells

Production and upregulation of granulocyte chemotactic protein-2/CXCL6 by IL-1β and hypoxia in small cell lung cancer

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