Molecular Signals from Neighboring Dendritic Cells Drive Leukemia Growth

Noncancerous cells in the immediate tumor microenvironment supply signals that drive T-cell acute lymphoblastic leukemia (T-ALL) growth, and may become attractive therapeutic targets to control the disease.

T-ALL cells require signals derived from noncancerous cells to survive. Although many studies have identified alterations in signaling pathways that promote T-ALL growth, the identity of endogenous stromal cells and their associated signals in the tumor microenvironment that support T-ALL remains unknown.

In order to identify the cells that provide growth signals to T-ALL, investigators at the University of Texas (Austin, USA) examined the thymic tumor microenvironments in multiple murine T-ALL models and in human patient samples.

They reported in the February 9, 2016, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) that systematic evaluation of the functional capacity of tumor-associated stromal cells revealed that myeloid cells, primarily dendritic cells (DCs), were necessary and sufficient to support T-ALL survival. DCs supported T-ALL growth both in primary thymic tumors and at secondary tumor sites.

To identify a molecular mechanism by which DCs supported T-ALL growth, the investigators performed gene expression (transcriptome) profiling. Results of these studies revealed up-regulation of platelet-derived growth factor receptor beta (Pdgfrb) and insulin-like growth factor I receptor (Igf1r) on T-ALL cells, with concomitant expression of their ligands by tumor-associated DCs. Both Pdgfrb and Igf1r were activated in T-ALL cell cultures. Co-culture with tumor-associated, but not normal thymic DCs, sustained IGF1R activation. Furthermore, IGF1R signaling was necessary for DC-mediated T-ALL survival.

"It is only more recently that people have really appreciated that tumors are complex organs in and of themselves with all of the heterogenous cell types that can talk to each other and promote each other's survival and proliferation," said senior author Dr. Lauren Ehrlich, assistant professor of molecular biosciences at the University of Texas.

The current paper provides the first evidence that endogenous tumor-associated DCs supply signals driving T-ALL growth, and implicate tumor-associated DCs and their mitogenic signals as attractive therapeutic targets. "If we can find directed therapies to more specifically target the tumors without being overly toxic to the person, that would obviously be much better," said Dr. Ehrlich.

Related Links:
University of Texas