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Immunohistochemical analysis indicates that the anatomical location of B-cell non-Hodgkin's lymphoma is determined by differentially expressed chemokine receptors, sphingosine-1-phosphate receptors and integrins.

Middle S, Coupland SE, Taktak A, Kidgell V, Slupsky JR, Pettitt AR, Till KJ - Exp Hematol Oncol (2015)

Bottom Line: Finally, leukaemic lymphomas (6 FL, 5 MCL and 2 MZL) were characterised by aberrant expression of the egress receptor S1PR1 and low expression of molecules required for tissue entry/retention.In summary, our study strongly suggests that anatomical location in B-NHL is governed by the differential expression of specific adhesion/motility molecules.This novel observation has important implications for therapeutic strategies that aim to disrupt protective micro-environmental interactions.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, England.

ABSTRACT

Background: The aim of this study was to elucidate the mechanisms responsible for the location of B-cell non-Hodgkin's lymphoma (B-NHL) at different anatomical sites. We speculated that the malignant B cells in these disorders have the potential for trafficking between blood and secondary lymphoid organs (SLO) or extranodal sites and that their preferential accumulation at different locations is governed by the expression of key molecules that regulate the trafficking of normal lymphocytes.

Methods: Biopsy or blood samples from 91 cases of B-NHL affecting SLO (n = 27), ocular adnexae (n = 51) or blood (n = 13) were analysed by immunohistochemistry or flow cytometry for the expression of the following molecules: CCR7, CCL21 and αL (required for the entry of normal lymphocytes into SLO); CXCR4, CXCL12 and α4 (required for entry into extranodal sites); CXCR5, CXCL13 and S1PR2 (required for tissue retention); S1PR1 and S1PR3 (required for egress into the blood). The expression of each of these molecules was then related to anatomical location and histological subtype.

Results: The expression of motility/adhesion molecules varied widely between individual patient samples and correlated much more strongly with anatomical location than with histological subtype. SLO lymphomas [comprising 10 follicular lymphoma (FL), 8 diffuse large B-cell lymphoma (DLBCL), 4 mantle-cell lymphoma (MCL) and 5 marginal-zone lymphoma (MZL)] were characterised by pronounced over-expression of S1PR2, suggesting that the malignant cells in these lymphomas are actively retained at the site of clonal expansion. In contrast, the malignant B cells in ocular adnexal lymphomas (10 FL, 9 DLBCL, 4 MCL and 28 MZL) expressed a profile of molecules suggesting a dynamic process of trafficking involving not only tissue retention but also egress via S1PR3 and homing back to extranodal sites via CXCR4/CXCL12 and α4. Finally, leukaemic lymphomas (6 FL, 5 MCL and 2 MZL) were characterised by aberrant expression of the egress receptor S1PR1 and low expression of molecules required for tissue entry/retention.

Conclusions: In summary, our study strongly suggests that anatomical location in B-NHL is governed by the differential expression of specific adhesion/motility molecules. This novel observation has important implications for therapeutic strategies that aim to disrupt protective micro-environmental interactions.

No MeSH data available.


Related in: MedlinePlus

Representative cases of SLO and OAL showing different expression of molecules involved in lymphocyte homing. TMA cores for CCL21, S1PR2 and S1PR3 from MCL; CXCR4, CXCL12 and α4 are from DLBCL. (Other histological types are shown in Additional file 2: Figure S1). Bar = 60 μM.
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Fig2: Representative cases of SLO and OAL showing different expression of molecules involved in lymphocyte homing. TMA cores for CCL21, S1PR2 and S1PR3 from MCL; CXCR4, CXCL12 and α4 are from DLBCL. (Other histological types are shown in Additional file 2: Figure S1). Bar = 60 μM.

Mentions: In order to elucidate the mechanisms responsible for the preferential localisation of lymphomas at different anatomical sites, we first analysed the molecules involved in the entry of lymphocytes into LN, namely CCR7, its ligand CCL21 and the integrin αLβ2. The cases were initially grouped according to anatomical location irrespective of lymphoma subtype (Figures 2 and 3A; Table 1A). CCR7 was expressed at low levels in lymphomas affecting the SLO, ocular adnexae and blood, the highest expression being observed in leukaemic lymphomas (P < 0.001). In contrast, CCL21 was expressed at much higher levels in lymphomas affecting the SLO compared to OAL (P < 0.001), thereby providing greater potential for receptor-ligand interaction and, consequently, tissue entry. αL was expressed by lymphomas affecting all three anatomical sites but at different levels, being highest in OAL (P < 0.001) and lowest in leukaemic lymphomas (P < 0.001). Comparison between individual lymphoma entities irrespective of anatomical location (Figure 3B; Table 1B) showed that the expression of CCR7, CCL21 and αL was remarkably constant, although levels of αL were higher in MZL than MCL, in keeping their respective associations with OAL and leukaemic lymphoma.Figure 2


Immunohistochemical analysis indicates that the anatomical location of B-cell non-Hodgkin's lymphoma is determined by differentially expressed chemokine receptors, sphingosine-1-phosphate receptors and integrins.

Middle S, Coupland SE, Taktak A, Kidgell V, Slupsky JR, Pettitt AR, Till KJ - Exp Hematol Oncol (2015)

Representative cases of SLO and OAL showing different expression of molecules involved in lymphocyte homing. TMA cores for CCL21, S1PR2 and S1PR3 from MCL; CXCR4, CXCL12 and α4 are from DLBCL. (Other histological types are shown in Additional file 2: Figure S1). Bar = 60 μM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4416323&req=5

Fig2: Representative cases of SLO and OAL showing different expression of molecules involved in lymphocyte homing. TMA cores for CCL21, S1PR2 and S1PR3 from MCL; CXCR4, CXCL12 and α4 are from DLBCL. (Other histological types are shown in Additional file 2: Figure S1). Bar = 60 μM.
Mentions: In order to elucidate the mechanisms responsible for the preferential localisation of lymphomas at different anatomical sites, we first analysed the molecules involved in the entry of lymphocytes into LN, namely CCR7, its ligand CCL21 and the integrin αLβ2. The cases were initially grouped according to anatomical location irrespective of lymphoma subtype (Figures 2 and 3A; Table 1A). CCR7 was expressed at low levels in lymphomas affecting the SLO, ocular adnexae and blood, the highest expression being observed in leukaemic lymphomas (P < 0.001). In contrast, CCL21 was expressed at much higher levels in lymphomas affecting the SLO compared to OAL (P < 0.001), thereby providing greater potential for receptor-ligand interaction and, consequently, tissue entry. αL was expressed by lymphomas affecting all three anatomical sites but at different levels, being highest in OAL (P < 0.001) and lowest in leukaemic lymphomas (P < 0.001). Comparison between individual lymphoma entities irrespective of anatomical location (Figure 3B; Table 1B) showed that the expression of CCR7, CCL21 and αL was remarkably constant, although levels of αL were higher in MZL than MCL, in keeping their respective associations with OAL and leukaemic lymphoma.Figure 2

Bottom Line: Finally, leukaemic lymphomas (6 FL, 5 MCL and 2 MZL) were characterised by aberrant expression of the egress receptor S1PR1 and low expression of molecules required for tissue entry/retention.In summary, our study strongly suggests that anatomical location in B-NHL is governed by the differential expression of specific adhesion/motility molecules.This novel observation has important implications for therapeutic strategies that aim to disrupt protective micro-environmental interactions.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, England.

ABSTRACT

Background: The aim of this study was to elucidate the mechanisms responsible for the location of B-cell non-Hodgkin's lymphoma (B-NHL) at different anatomical sites. We speculated that the malignant B cells in these disorders have the potential for trafficking between blood and secondary lymphoid organs (SLO) or extranodal sites and that their preferential accumulation at different locations is governed by the expression of key molecules that regulate the trafficking of normal lymphocytes.

Methods: Biopsy or blood samples from 91 cases of B-NHL affecting SLO (n = 27), ocular adnexae (n = 51) or blood (n = 13) were analysed by immunohistochemistry or flow cytometry for the expression of the following molecules: CCR7, CCL21 and αL (required for the entry of normal lymphocytes into SLO); CXCR4, CXCL12 and α4 (required for entry into extranodal sites); CXCR5, CXCL13 and S1PR2 (required for tissue retention); S1PR1 and S1PR3 (required for egress into the blood). The expression of each of these molecules was then related to anatomical location and histological subtype.

Results: The expression of motility/adhesion molecules varied widely between individual patient samples and correlated much more strongly with anatomical location than with histological subtype. SLO lymphomas [comprising 10 follicular lymphoma (FL), 8 diffuse large B-cell lymphoma (DLBCL), 4 mantle-cell lymphoma (MCL) and 5 marginal-zone lymphoma (MZL)] were characterised by pronounced over-expression of S1PR2, suggesting that the malignant cells in these lymphomas are actively retained at the site of clonal expansion. In contrast, the malignant B cells in ocular adnexal lymphomas (10 FL, 9 DLBCL, 4 MCL and 28 MZL) expressed a profile of molecules suggesting a dynamic process of trafficking involving not only tissue retention but also egress via S1PR3 and homing back to extranodal sites via CXCR4/CXCL12 and α4. Finally, leukaemic lymphomas (6 FL, 5 MCL and 2 MZL) were characterised by aberrant expression of the egress receptor S1PR1 and low expression of molecules required for tissue entry/retention.

Conclusions: In summary, our study strongly suggests that anatomical location in B-NHL is governed by the differential expression of specific adhesion/motility molecules. This novel observation has important implications for therapeutic strategies that aim to disrupt protective micro-environmental interactions.

No MeSH data available.


Related in: MedlinePlus