Editors' ChoiceCancer

Reciprocal Aggression

Sci. Signal.  01 Apr 2014:
Vol. 7, Issue 319, pp. ec85
DOI: 10.1126/scisignal.2005315

Tumor growth is partially fueled by nutrients and oxygen supplied through blood vessels in the tumor microenvironment. The proliferation of lymphoma and leukemia cells is also induced by activation of Notch signaling, which can occur because of the secretion of NOTCH ligands from neighboring vascular endothelial cells (see Radojcic and Maillard). Using engineered VeraVec endothelial cells that enable serum-free culture without the influence of medium-derived growth factors, Cao et al. identified a reciprocal crosstalk between B cell lymphoma cells and neighboring endothelial cells that promoted chemoresistance. Lymphoma cells from Eµ-Myc mice proliferated and formed colonies to a greater extent when cocultured with endothelial cells than when cultured with serum alone. Lymphoma cells cocultured with endothelial cells had enhanced tumor growth in immunodeficient mice, were less sensitive to doxorubicin both in culture and in mice, and showed increased abundance of transcripts and proteins that are characteristic of lymphoma-initiating cells. Various methods supported previous observations that the Notch2-Hey1 pathway in lymphoma cells was increased by secretion of the Notch ligand Jagged1 from endothelial cells; moreover, coculture with lymphoma cells increased Jagged1 abundance in endothelial cells. Microarray analysis showed that the expression of FGF4, which encodes fibroblast growth factor 4, was increased in mouse and human lymphoma cells cocultured with endothelial cells. Human Burkitt’s lymphoma tissue, in which JAG1-positive endothelial cells were more frequently located adjacent to HEY1-positive lymphoma cells, had increased abundance of FGF4 compared with normal lymph node tissue, and activation of FGF receptor 1 (FGFR1) was increased in tumor-associated endothelial cells. Knockdown of FGFR1 in endothelial cells or FGF4 in lymphoma cells blocked the coculture-induced increase in JAG1 abundance in endothelial cells; JAG1 abundance was not increased in endothelial cells associated with hepatic lymphomas formed from FGF4-deficient lymphoma cells; and conditional endothelial cell–specific deletion of Fgfr1 sensitized lymphoma-bearing Eµ-Myc mice to doxorubicin therapy. Together, findings suggest a feed-forward loop between endothelial and lymphoma cells that is mediated by Notch and FGF signaling, indicating new therapeutic targets for B cell lymphoma.

Z. Cao, B.-S. Ding, P. Guo, S. B. Lee, J. M. Butler, S. C. Casey, M. Simons, W. Tam, D. W. Felsher, K. Shido, A. Rafii, J. M. Scandura, S. Rafii, Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance. Cancer Cell 25, 350–365 (2014). [PubMed]

V. Radojcic, I. Maillard, A jagged road to lymphoma aggressiveness. Cancer Cell 25, 261–263 (2014). [PubMed]