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A rare fraction of drug‐resistant follicular lymphoma cancer stem cells interacts with follicular dendritic cells to maintain tumourigenic potential
Author(s) -
Lee ChungGi,
Das Bikul,
Lin Tara L.,
Grimes Chelsea,
Zhang Xin,
Lavezzi Tracey,
Huang Li,
Cole John,
Yau Lillian,
Li Li
Publication year - 2012
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2012.09123.x
Subject(s) - cxcr4 , follicular lymphoma , cancer research , follicular dendritic cells , cancer stem cell , stromal cell , stem cell , biology , lymphoma , germinal center , population , chemokine , b cell , immunology , medicine , t cell , antigen presenting cell , antibody , microbiology and biotechnology , immune system , environmental health
Summary Follicular lymphoma ( FL ) comprises nearly 25% of non‐ H odgkin 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 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 ABCG 2, were enriched by chemotherapy and radiation treatments. In vitro , SP cells were attracted by and adhered to FDC s through chemokine ( C ‐ X ‐ C motif) ligand 12/chemokine ( C ‐ X ‐ C motif) receptor 4 ( CXCL 12/ CXCR 4) 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 AMD 3100, a specific CXCL 12/ CXCR 4 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 ABCG 2 expressing lymphoma cells in FL clinical specimens. Thus, we found that the highly tumourigenic FL cells having CSC ‐like activities ( FL ‐ SC ) interact with FDC s in a CXCL 12/ CXCR 4 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.