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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

Expression of molecules involved in retention within LN. A. Box and whiskers plots show lymphomas analysed according by tissue of origin and B. Box and whiskers plots show lymphomas according to histology. Statistically significant differences in expression are shown.
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Fig5: Expression of molecules involved in retention within LN. A. Box and whiskers plots show lymphomas analysed according by tissue of origin and B. Box and whiskers plots show lymphomas according to histology. Statistically significant differences in expression are shown.

Mentions: Having analysed the molecules involved in the entry of lymphocytes into tissues, we next turned our attention to factors involved primarily in retention within tissues, i.e. CXCR5, CXCL13 and S1PR2. Grouping lymphomas according to anatomical location (Figure 2 and 5A, Table 1A) showed that CXCR5 was expressed at higher levels in lymphomas affecting the SLO and ocular adnexae (P < 0.001) than in leukaemic lymphomas (P < 0.001). CXCL13 was also expressed, albeit at low levels, in ocular adnexal and SLO lymphomas, expression being higher in OAL (P < 0.001). Of particular note, S1PR2 was expressed at very high levels in lymphomas of the SLO but was virtually absent in OAL (P < 0.001) and leukaemic lymphomas (P < 0.001). This profile of CXCR5, CXCL13 and S1PR2 expression strongly suggests that the malignant B-cells in lymphomas of the SLO (and to a lesser extent OAL) are actively retained in the tissues, whereas the malignant cells in leukaemic lymphoma are allowed unimpeded passage through the tissues and back into the blood. Comparison between individual histological subtypes irrespective of anatomical location (Figure 5B; Table 1B) revealed no significant differences in the expression of CXCL13. However, levels of CXCR5 were highest in DLBCL in keeping with its negative association with leukaemic lymphoma, whereas S1PR2 expression was lowest in MZL in keeping with the fact that only a minority of these cases affected the SLO.Figure 5


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)

Expression of molecules involved in retention within LN. A. Box and whiskers plots show lymphomas analysed according by tissue of origin and B. Box and whiskers plots show lymphomas according to histology. Statistically significant differences in expression are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: Expression of molecules involved in retention within LN. A. Box and whiskers plots show lymphomas analysed according by tissue of origin and B. Box and whiskers plots show lymphomas according to histology. Statistically significant differences in expression are shown.
Mentions: Having analysed the molecules involved in the entry of lymphocytes into tissues, we next turned our attention to factors involved primarily in retention within tissues, i.e. CXCR5, CXCL13 and S1PR2. Grouping lymphomas according to anatomical location (Figure 2 and 5A, Table 1A) showed that CXCR5 was expressed at higher levels in lymphomas affecting the SLO and ocular adnexae (P < 0.001) than in leukaemic lymphomas (P < 0.001). CXCL13 was also expressed, albeit at low levels, in ocular adnexal and SLO lymphomas, expression being higher in OAL (P < 0.001). Of particular note, S1PR2 was expressed at very high levels in lymphomas of the SLO but was virtually absent in OAL (P < 0.001) and leukaemic lymphomas (P < 0.001). This profile of CXCR5, CXCL13 and S1PR2 expression strongly suggests that the malignant B-cells in lymphomas of the SLO (and to a lesser extent OAL) are actively retained in the tissues, whereas the malignant cells in leukaemic lymphoma are allowed unimpeded passage through the tissues and back into the blood. Comparison between individual histological subtypes irrespective of anatomical location (Figure 5B; Table 1B) revealed no significant differences in the expression of CXCL13. However, levels of CXCR5 were highest in DLBCL in keeping with its negative association with leukaemic lymphoma, whereas S1PR2 expression was lowest in MZL in keeping with the fact that only a minority of these cases affected the SLO.Figure 5

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