Profiles of chemokine receptors in melanocytic lesions: de novo expression of CXCR6 in melanoma

Seidl, Hannes; Richtig, Erika; Tilz, Hemma; Stefan, Martina; Schmidbauer, Ulrike; Asslaber, Martin; Zatloukal, Kurt; Herlyn, Meenhard; Schaider, Helmut

doi:10.1016/j.humpath.2006.11.013

Cited by 55 publications

(42 citation statements)

References 39 publications

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“…Because the latter all had substantial amounts of both proteins on the cell surface, and because the carcinoma specimens contained at least 50% carcinoma cells, the microarray data indicate that the carcinoma cells in the tumors had surface levels comparable with the cell lines. CXCR6 has also been detected in nasopharyngeal carcinomas (39), gliomas (40), melanomas (41), and part of colon carcinomas (42). We observed neither receptor nor ligand in normal mouse mammary epithelial cells and, except for very low levels of CXCL16, in nontransformed MCF10 human mammary carcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

The Chemokine Receptor CXCR6 and Its Ligand CXCL16 Are Expressed in Carcinomas and Inhibit Proliferation

Meijer¹,

Ogink²,

Kreike

et al. 2008

Cancer Research

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The chemokine receptor CXCR6 and its ligand CXCL16 are involved in inflammation. Thus far, they were known to be expressed mainly by T cells and macrophages, respectively. However, we detected both in all of 170 human primary mammary carcinomas and at similar levels in all 8 human mammary carcinoma cell lines tested by microarray analysis. Expression was confirmed by reverse transcription-PCR and for the cell lines also by fluorescence-activated cell sorting analysis. CXCR6 and CXCL16 were also detected in several mouse and human mammary, colon, and pancreatic carcinoma cell lines. CXCL16 is a transmembrane protein from which the soluble chemokine can be cleaved off. The transmembrane form is present on the surface of the carcinoma cells. Surprisingly, suppression of either CXCR6 or CXCL16 led to greatly enhanced proliferation in vitro as well as in vivo, indicating that their interaction inhibits proliferation. This notion was verified using inhibitory antibodies and by introduction of CXCL16 into a rare CXCL16-negative cell line. The effect was mediated by the G protein-coupled receptor CXCR6 because it was blocked by the G i protein inhibitor pertussis toxin. In contrast, the soluble CXCL16 chemokine enhanced proliferation, and this was also mediated by CXCR6 but not via G i protein. It is remarkable that both CXCR6 and CXCL16 are expressed by all mammary carcinomas because cells that lose either acquire a growth advantage and should be selected during tumor progression. This suggests an unknown important role in tumor formation. Proteases, possibly macrophage derived, might convert inhibitory transmembrane CXCL16 into the stimulatory chemokine.

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Section: Discussionmentioning

confidence: 99%

The Chemokine Receptor CXCR6 and Its Ligand CXCL16 Are Expressed in Carcinomas and Inhibit Proliferation

Meijer¹,

Ogink²,

Kreike

et al. 2008

Cancer Research

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“…Studies have now shown that migration of primary tumor cells to distant organs can occur through several chemokineligand signaling pathways (35,38). Although metastases to organ sites such as bone marrow, lymph nodes, lung, and liver are largely due to specific anatomic pathways such as lymphatic or vascular channels that mechanically direct tumor cell migration, specific chemokine-ligand axes are a promising answer to the puzzling questions that surround organ-specific metastasis (39,40).…”

Section: Discussionmentioning

confidence: 99%

“…ah integrin molecules have also been described as being important factors in mucosal homing. These adhesion molecules have been identified in gut-associated lymphoid tissue and T cells in the lamina propria of the small intestine (28,40,43). Investigators have proposed that expression of CCR9 and a 4 h 7 together on lymphocytes serves as a homing mechanism whereby circulating intestinal memory T-cells induced in response to intestinal immunoreactivity preferentially migrate to the small intestine (28,43).…”

Section: Discussionmentioning

confidence: 99%

Activation of CCR9/CCL25 in Cutaneous Melanoma Mediates Preferential Metastasis to the Small Intestine

Amersi

Terando

Goto

et al. 2008

Clinical Cancer Research

144

110

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Purpose: Specific chemokines and their respective receptors have been implicated in distant tumor cell metastasis. Cutaneous melanoma has a distinct pattern of metastasis, preferentially targeting the submucosa of the small intestine. However, the underlying pathogenic mechanism remains unknown. Migration of CCR9(+) lymphocytes to the small intestine is known to occur in response to the chemoattractant effects of CCL25 (thymus-expressed chemokine). The integrin heterodimers ah are also known to be important mediators of cellular adhesion. We hypothesize that the mechanism of small intestinal metastasis by melanoma is via the CCR9-CCL25 axis and specific integrins. Experimental Design: Quantitative reverse transcription-PCR, flow cytometry, and immunohistochemistry were used to assess melanoma tumors for CCR9 and CCL25. Integrin expression was assessed using flow cytometry. CCR9 expression by quantitative reverse transcription-PCR was assessed in primary (n = 23) and metastatic (n = 198) melanomas, and melanoma lines derived from small intestinal metastases (n = 23). Results: We showed CCR9 expression in 88 of 102 paraffin-embedded metastatic melanomas from the small intestine, 8 of 8 melanoma lines derived from metastases in the small intestine, and 0 of 96 metastatic melanomas from other sites. In vitro migration and invasion studies done on CCR9(+) melanoma lines showed migration in response to CCL25 that was inhibited by anti-CCR9 antibody or by short interfering RNA CCR9. Flow cytometric analysis confirmed CCR9 expression by melanomas to the small intestine and showed concomitant a 4 h 1 integrin expression. Conclusions: Our findings show that functionally active CCR9 on melanoma cells facilitates metastasis to the small intestine. The CCR9-CCL25 axis may explain the high incidence of melanoma metastasis to this specific location.Human cutaneous melanoma is the most common cancer to metastasize to the small intestine (1, 2), for reasons that remain unclear. However, small intestinal metastases from other solid tumors are rare when compared with their incidence of hepatic and other organ metastases (3, 4). In the largest reported series of melanoma patients with gastrointestinal metastases, lesions were more common in the small intestine than the stomach, colon, or rectum (5). Diagnosis and management of patients with small intestinal metastases is often difficult due to their insidious nature. Most patients initially have nonspecific symptoms; symptoms caused by gastrointestinal hemorrhage or bowel obstruction are highly specific but also represent a surgical emergency. Several prognostic markers have been investigated for patients with clinically localized primary cutaneous melanoma, but none has been linked to organspecific metastasis. A biomarker for the risk of gastrointestinal metastasis would allow a tailored postoperative follow-up program to identify visceral spread of melanoma at an early, nonemergent stage.Metastasis to certain organ sites, such as bone marrow, lung, and liver, are primari...

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“…15,16 The real-time PCR and calculation of the expression levels were performed according to a protocol previously reported by Seidl et al 17 The nucleotide acid sequences for the primers and probes used for the determination of the expression levels of 19 chemokine receptors are shown in the Supplementary Table S1.…”

Section: Rna Isolation Cdna Synthesis and Real-time Pcrmentioning

confidence: 99%

Chemokine receptors in gastric MALT lymphoma: loss of CXCR4 and upregulation of CXCR7 is associated with progression to diffuse large B-cell lymphoma

et al. 2013

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Chemokine receptors have a crucial role in the development and progression of lymphoid neoplasms. To determine the chemokine receptor expression profile in gastric mucosa-associated lymphoid tissue (MALT) lymphoma, we performed an expression analysis of 19 chemokine receptors at mRNA levels by using real-time RT-PCR, as well as of five chemokine receptors-CCR8, CCR9, CXCR4, CXCR6 and CXCR7-by immunohistochemistry on human tissue samples of Helicobacter pylori-associated gastritis, gastric MALT lymphoma and gastric extranodal diffuse large B-cell lymphoma originating from MALT lymphoma (transformed MALT lymphoma). Following malignant transformation from H. pylori-associated gastritis to MALT lymphoma, an upregulation of CCR7, CXCR3 and CXCR7, and a loss of CXCR4 were detected. The transformation of gastric MALT lymphomas to gastric extranodal diffuse large B-cell lymphoma was accompanied by upregulation of CCR1, CCR5, CCR7, CCR8, CCR9, CXCR3, CXCR6, CXCR7 and XCR1. Remarkably, CXCR4 expression was exclusively found in nodal marginal B-cell lymphomas and nodal diffuse large B-cell lymphomas but not at extranodal manifestation sites, ie, in gastric MALT lymphomas or gastric extranodal diffuse large B-cell lymphomas. Furthermore, the incidence of bone marrow infiltration (16/51 with bone marrow involvement vs 35/51 with bone marrow involvement; Spearman q ¼ 0467 Po0.001) positively correlated with CXCR4 expression. CXCL12, the ligand of CXCR4 and CXCR7, was expressed by epithelial, endothelial and inflammatory cells, MALT lymphoma cells and was most strongly expressed by extranodal diffuse large B-cell lymphoma cells, suggesting at least in part an autocrine signaling pathway. Our data indicate that CXCR4 expression is associated with nodal manifestation and a more advanced stage of lymphomas and hence, might serve as useful clinical prognostic marker.

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Profiles of chemokine receptors in melanocytic lesions: de novo expression of CXCR6 in melanoma

Cited by 55 publications

References 39 publications

The Chemokine Receptor CXCR6 and Its Ligand CXCL16 Are Expressed in Carcinomas and Inhibit Proliferation

The Chemokine Receptor CXCR6 and Its Ligand CXCL16 Are Expressed in Carcinomas and Inhibit Proliferation

Activation of CCR9/CCL25 in Cutaneous Melanoma Mediates Preferential Metastasis to the Small Intestine

Chemokine receptors in gastric MALT lymphoma: loss of CXCR4 and upregulation of CXCR7 is associated with progression to diffuse large B-cell lymphoma

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