Abstract 3288: The chemokine receptor CXCR4 and the cannabinoid receptor CB2R form heterodimers in non-Hodgkin lymphoma (NHL) and solid tumors leading to functional crosstalk
Authors: Guerrero Martina , Griera Rosa , Perez Maria , Roué Gaël , Bosch Joan , McCormick Peter J. , Camps Jordi , Perez-Galan Patricia 
Published: July 2016

Background: A major hallmark of cancer cells, including both solid tumors and hematological neoplasias, is the ability to disseminate and generate distant/distal metastasis.Two families of proteins that play a role in dissemination and metastasis are the cannabinoid and the chemokine receptors. Moreover, cannabinoids also impair uncontrolled cancer cell growth and induce apoptosis. Both receptors are members of the G-protein coupled receptor (GPCR) super family, and may combine among themselves to generate new and unique biochemical and functional characteristics. We have focused our study in the chemokine receptor 4 (CXCR4), overexpressed in several human cancer types and associated with an aggressive phenotype, and in the cannabinoid receptor 2 (CB2R). Recently, it has been reported that CB2R forms heterodimers with different receptors such as CB1R and HER2. In the case of CB2 with HER2, the co-expression and the formation of these heterodimers correlate with poor prognosis in breast cancer.

Aim: To characterize CXCR4 and CB2 expression and heterodimer formation in non-Hodgkin lymphoma (NHL), colorectal cancer (CRC) and pancreatic cancer, together with their role in tumor cell dissemination and proliferation.

Results: We have characterized the expression of CXCR4 and CB2 in several NHL models (Chronic Lymphocytic Leukemia (CLL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL) and Diffuse Large B-Cell Lymphoma (DLBCL)), colorectal cancer (CRC) and in pancreatic cancer. Flow cytometry analysis showed high CXCR4 expression in most of the cell lines, while CB2R expression was moderate. Noteworthy, hypoxia increased the expression of both CXCR4 and CB2. Preliminary immunohistochemistry results using primary tumors and their matched metastasis indicate that CXCR4 and CB2R expression is heterogenous. By means of Proximity Ligation Assay (PLA), we have uncovered that the formation of CXCR4-CB2R heterodimers in NHL, CRC and pancreatic cancer models. Moreover, we have confirmed that these heterodimers modulate pathway activation and function of both receptors. In this sense, using the CRC cell line SW480 and p42/p44 ERK phosphorylation a as read-out, we have proved that CXCR4 pathway activation by its agonist CXCL12 is decreased by co-treatment with the CB2R antagonist JTE907. Conversely, CB2R activation by its agonist JWH133 is hampered by the CXCR4 antagonist AMD3100. Furthermore, CB2R blockade by JTE907 interferes with CXCL12-induced cell migration assessed by wound healing assay.

Conclusions: We have described for the first time the formation of CXCR4-CB2 heterodimers in NHL, CRC and pancreatic cancer models together with its implications in downstream receptor crosstalk and cellular function. These results establish the proof-of-concept to target CXCR4-CB2 heterodimers as a new therapeutic intervention in these neoplasias.

Citation Format: Martina Guerrero, Rosa Griera, Maria Perez, Gaël Roué, Joan Bosch, Peter J. McCormick, Jordi Camps, Patricia Perez-Galan. The chemokine receptor CXCR4 and the cannabinoid receptor CB2R form heterodimers in non-Hodgkin lymphoma (NHL) and solid tumors leading to functional crosstalk. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3288.