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

Abstract

SUMMARY 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 germinal centre of lymph nodes—the 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 cell (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.

Breast cancer stem cells: Multiple capacities in tumor metastasis

“…For example, breast and pancreatic cancer cells expressing CD44 increase metastatic ability [87]. However, this does not simply mean that only the CD44 + /CD24 −/low BCSCs are able to metastasize, several BCSC phenotypes are found to co-exist in a tumor and each phenotype shows its own unique metastatic potential and sensitivity to therapeutic regimens [88].…”

Disruption of Follicular Dendritic Cells–Follicular Lymphoma Cross-talk by the Pan-PI3K Inhibitor BKM120 (Buparlisib)

“…Among the genes modulated, CXCL12 (mean fold change 24 h (FDC-HK vs. C) ¼ 31.9) stands out as a prominent factor in chemotactic responses. Both lymphoma cells and stromal cells, including FDCs, secrete CXCL12 (34,35). Moreover, drug-resistant cancer hours, and then were subjected to adhesion assays on plates precoated with BSA 1% (nonspecific adhesion), VCAM1, or fibronectin.…”

“…stem FL cells interact with FDCs in a CXCL12/CXCR4-dependent manner to resist chemotherapy (34). In addition, PI3K inhibitors targeting p110a or p110g isoforms interfere with CXCL12-induced migration of CLL cells (36).…”

Highly Tumorigenic Diffuse Large B Cell Lymphoma Cells Are Produced by Coculture with Stromal Cells

“…High degrees of intrafollicular CD68+ and programmed cell death ligand 1+ macrophage infiltration are associated with a shorter time to transformation in FL [14]. Furthermore, cancer stem cells or the tumor-initiating cells of BCL maintain their tumorigenic potential via interplay with the TME [15, 16]. Previous studies have demonstrated that the protective effect of the TME was mediated through tumor-stroma cell interactions, especially direct cell-to-cell contact between tumor cells and stromal cells [17-19].…”