A rare fraction of drug-resistant follicular lymphoma cancer stem cells interacts with follicular dendritic cells to maintain tumourigenic potential

Follicular lymphoma (FL) comprises nearly 25% of non-Hodgkin lymphoma cases and is clinically characterized by initial sensitivity to chemotherapy followed by relapse. FL stroma contains a special type of stromal cell found in the germinal centre of lymph nodesthe follicular dendritic cell (FDC). We first isolated tumourigenic cells from the FL cell line FLK-1 by side population (SP) technique, and found that SP cells, which express ABCG2, were enriched by chemotherapy and radiation treatments. In vitro, SP cells were attracted by and adhered to FDCs through chemokine (C-X-C motif) ligand 12/chemokine (C-X-C motif) receptor 4 (CXCL12/CXCR4) signalling. In vivo, limiting dilution assays showed SP cells were highly enriched in cancer stem cells (CSC), but required FDC for tumour formation in non-obese diabetic/severe combined immunodeficiency mice. Treatment with AMD3100, a specific CXCL12/CXCR4 inhibitor, eliminated tumour growth. These findings were then verified with FL cells isolated from an FL patient's ascitic fluid (FLA-1). Finally, we detected the ABCG2 expressing lymphoma cells in FL clinical specimens. Thus, we found that the highly tumourigenic FL cells having CSC-like activities (FL-SC) interact with FDCs in a CXCL12/CXCR4 dependent manner to resist chemotherapy. Our results indicate the importance of FL-SC and niche cell signalling in maintaining tumourigenicity. These signals represent novel targets for CSC eradication.