The role of activated stromal fibroblasts in regulation of progression of human hematopoietic malignancies

Interactive paracrine signaling between cancer cells and their activated stroma plays an important role in tumor development. Signals from cancer cells can induce stromal fibroblast hyperproliferation associated with increased cell-cell contacts and nemosis. Fibroblast nemosis is a unique novel type of mesenchymal cell activation that leads to production of a distinct set of signaling molecules: HGF/SF, IL-1b, IL-6, IL-8,IL-11, LIF, GM-CSF and prostaglandins. Since the growth factors and cytokines produced are associated with differentiation of hematopoietic cells, we evaluated the effect of nemosis on human leukemia cell lines. Analysis of leukemic cells was carried out after coculture with preformed fibroblast spheroids. Nemotic fibroblasts induced a dramatic growth inhibition of those leukemia cell lines lacking expression of c-Met, whereas growth of c-Met-positive cells was unaffected. Moreover, the responding cells showed increased adherence, motility, and chemotaxis. The cell cycle of the c-Met-negative cell lines stimulated by nemosis was arrested at the G0G1 phase. Since the growth arrest was accompanied by morphological changes such as cell elongation and formation of stellate pseudopodia, cell surface phenotype was further determined by FACS. New populations with enhanced expression of CD11c, CD13, CD45RA, CD54 and CD86 were identified in the nemosis-responsive cells. Our results show that stromal fibroblast nemosis produces signals that not only stimulate cell motility and chemotaxis but also induce differentiation to a dendritic-cell-like phenotype. We provide here the first evidence that nemosis can produce specific signaling to arrest growth and induce differentiation of human leukemia cells. Differentiation of leukemic cells into dendritic cell lineage may stimulate T-cells and influence responses of the immune system to malignancy.