JAM-A overexpression is related to disease progression in diffuse large B-cell lymphoma and downregulated by lenalidomide

Abstract

Cancer stem cells play an important role on tumor progression. Biomarkers of stem cell property and their relationship to extranodal involvement of malignant lymphocytes are undefined in diffuse large B-cell lymphoma (DLBCL). Here we showed that junctional adhesion molecule-A (JAM-A) was highly expressed in DLBCL patients with multiple extranodal lesions. JAM-A maintained B-lymphoma cell stemness and was associated with cell invasion and epithelial-to-mesenchymal transition both in vitro and in vivo. As mechanism of action, JAM-A overexpression selectively activated transforming growth factor-β (TGF-β)/NODAL signaling, thereby enhanced B-lymphoma cell aggressiveness and induced extranodal involvement to mesoendoderm-derived organs in DLBCL. Lenalidomide downregulated JAM-A and downstream NODAL expression, resulting in inhibition of B-lymphoma cell invasion and epithelial-to-mesenchymal transition. In a murine xenograft model established with subcutaneous injection of JAM-A-overexpressing B-lymphoma cells, lenalidomide retarded tumor growth and prevented cell invasion to mesoendoderm-derived organs, consistent with the downregulation of JAM-A and NODAL expression. Collectively, these findings indicated that JAM-A was related to extranodal involvement in DLBCL through modulating TGF-β/NODAL signaling. Identified as a biomarker of stem cell property, JAM-A indicated the sensitivity of B-lymphoma cells to lenalidomide. Therapeutic targeting of JAM-A/NODAL axis could thus be a promising clinical strategy to impede tumor progression in DLBCL.

New Insights into Diffuse Large B-Cell Lymphoma Pathobiology

“…Based on these findings and on several pieces of compelling evidence investigating how the deregulated adhesion-mediated system would contribute to more aggressive disease, several attempts uncovered the junctional adhesion molecule role in mediating disease aggressiveness [ 141 , 144 , 145 ]. In line with previous results [ 128 , 146 , 147 ], preliminary data from our lab demonstrate that direct contact of environmental cells with DLBCL cells would enhance adhesion molecule levels, thus preventing both direct and indirect cell invasiveness and epithelial–mesenchymal transition and extra-nodal dissemination (unpublished data). Even more interesting, the cell adhesion molecule junctional adhesion molecule-A (JAM-A) presents remarkable features [ 148 ], whereby it can interact with itself if expressed on two opposing cell types.…”

“…Mechanistically, endothelial cells, by expressing TIM-3, HB-EGF [ 120 , 121 , 122 ], and a plethora of surface and soluble factors, prompt defective immunosurveillance and, in turn, allow for the persistence and proliferation of lymphoid neoplastic cells [ 123 , 124 , 125 ], envisioning novel therapeutic windows [ 126 , 127 ]. Moreover, the initial observation that the expression level of the adhesion molecules by the malignant lymphoma cells can predict disease outcome in extranodal DLBCL [ 128 ] prompted further investigation, especially in peculiar clinical disease phenotypes, such as DLBCLs involving the central nervous system (CNS) [ 128 ]. Remarkably, CNS spreading represents a paradigmatic extranodal localization with peculiar pathobiology involving adhesion molecule deregulated expression [ 129 ] and hyperactivation of the angiogenesis fueling pathway [ 130 ] along with a truncal genomic signature [ 131 ], which can contribute to drug sensitivity and resistance [ 132 , 133 , 134 ], as in other malignancies [ 135 , 136 , 137 ].…”

“…Remarkably, CNS spreading represents a paradigmatic extranodal localization with peculiar pathobiology involving adhesion molecule deregulated expression [ 129 ] and hyperactivation of the angiogenesis fueling pathway [ 130 ] along with a truncal genomic signature [ 131 ], which can contribute to drug sensitivity and resistance [ 132 , 133 , 134 ], as in other malignancies [ 135 , 136 , 137 ]. Therefore, given that the aberrant expression of adhesion molecules on bone marrow endothelial cells of patients with lymphoid and myeloid neoplasia was also discovered to predict poor clinical outcome [ 138 , 139 , 140 , 141 ], it is tempting to speculate a vicious cycle in DLBCL by paralleling the neoplastic cell behavior [ 128 ], whereby the described molecular signature [ 36 , 142 ] has more interactions among themselves than what would be expected for a random set of gene-encoding proteins drawn from the genome [ 143 ].…”

Intravascular lymphoma forming massive aortic tumors complicated with sarcoidosis and focal segmental glomerulosclerosis: a case report and literature review

“…These molecules are known to mediate leukocyte adhesion or invasion [ 17 ], and were suggested to contribute to the invasive character of PCNSMLs. A recent report showed that junctional adhesion molecule-A was highly expressed in DLBCL patients with multiple extranodal lesions, and its overexpression may trigger transforming growth factor-β/NODAL signaling, cause B-lymphoma cell aggressiveness, and promote extranodal involvement [ 18 ]. It is possible that certain adhesion molecules and/or gelatinases caused the aortic tumor formation in our present case.…”

New developments in the pathology of malignant lymphoma: a review of the literature published from May to August 2017

“…Xu et al [ 41 ] show that junctional adhesion molecule-A (JAM-A) was highly expressed in DLBCL patients with multiple extranodal lesions. JAM-A maintains B lymphoma cell stemness and was associated with cell invasion and epithelial-to-mesenchymal transition both in vitro and in vivo.…”