Fibroblast nemosis arrests growth and induces differentiation of human leukemia cells

Abstract

Interactive signaling between cancer cells and stroma plays an important role in determining tumor development. We recently found tumor cell-derived factors to induce fibroblast clustering, and that the high amounts of hepatocyte growth factor/scatter factor (HGF/SF) produced by these cell-cell contact-activated fibroblasts enhanced the invasiveness of c-Met-expressing cancer cells. We now observed that leukemia cells lacking c-Met respond to this novel type of fibroblast activation, nemosis, with growth arrest and differentiation to a dendritic cell-like phenotype. This effect was counteracted by introduction of c-Met expression into these cells. Moreover, those leukemia cell lines harboring properly processed c-Met showed no effect in response to nemosis. We propose this effect to be mediated by nemosis-derived cytokine signals, and present the potential candidates induced in the nemotic fibroblasts: interleukins-1, -6, -8, -11, leukemia inhibitory factor and granulocyte-macrophage-colony-stimulating factor. Our results emphasize the role of activated stromal fibroblasts in controlling progression of certain hematologic malignancies in a c-Met expression-dependent manner. ' 2007 Wiley-Liss, Inc.

Inflammatory environment created by fibroblast aggregates induces growth arrest and phenotypic shift of human myeloma cells

“…Previously, we have shown that the contact-activated fibroblast cells are characterized by massive induction of genes that are exclusively exhibiting proinflammatory activity [20]. The unique feature of this system is that sterile inflammatory conditions are gained in culture dish without addition of any exogenous stimulus as an inducer of the inflammation.…”

“…Our previous results showed that leukemic cells achieved altered phenotypic characteristics due to regulatory signals coming from stromal microenvironment only when they are growth arrested [20]. Therefore, we performed phenotypic characterization of tested myeloma cell lines after exposure to the inflammatory conditions with focus on the RPMI 8226 cells.…”

“…Nemosis, which is triggered solely by cell-cell contacts, is programmed process of cell activation and subsequent death, the most distinctly observed in human dermal fibroblasts [19]. These activated fibroblasts are characterized by production of inflammation-associated cytokines and growth factors, e.g., IL-1, IL-6, IL-8, IL-11, LIF, GM-CSF, as well as, COX-2 related-secretion of prostaglandins [20]. In order to functionally evaluate the myeloma cells' capacity to respond to stromal inflammation, we utilized an in vitro model of the nemosis-induced inflammation of fibroblasts in a threedimensional culture setting, where analysed MM cells were cocultured with the fibroblast spheroids.…”

COX-2 expression in fibroblast aggregates as a functional indicator for the anti-inflammatory activity of leukemia patients’ bone marrow-derived hematopoietic cells

“…IL-1, IL-6, IL-8; cell growth factors like HGF, amphiregulin, and FGF7, as well as, inducers of differentiation: IL-11, LIF, and GM-CSF [5,7,8]. Although this mixture of cytokines is similar to that produced by stromal cells isolated from BM [9] and we have shown bone marrow stromal cells (BMSCs) to react in a similar manner upon aggregation [10], fibroblast reactivity is preferred for sensitive functional in vitro testing due to the prompt and prominent induction of COX-2.…”

Aberrant Proliferative and Apoptotic Pathways in Acute Lymphoblastic Leukemia (ALL): Molecular Therapies to Overcome Chemo-Resistance

“…Another study by Aref et al (2007) described in B-ALL an abnormal expression of matrix metalloproteinases (MMP), which is a further class of angiogenesis and tumor progression regulators produced by both stromal and leukemic cells (Aref et al, 2007) A further interesting aspect related to BM microenvironment and leukemia cells interactions regards the role of BM microenvironment on lineage commitment and differentiation. Several studies have indeed demonstrated that BM microenvironment can drive lineagespecific differentiation in leukemia by modulating different cytokines and other soluble components (Kankuri et al, 2008;Wei et al, 2008). In an elegant study performed on a human MLL-AF9 leukemia model transplanted into immunodeficient mice, Wei J et al (2008) showed that ALL, AML or mixed-lineage leukemia were generated by altering the cytokine milieu of human CD34+ cells expressing MLL-AF9, thus demonstrating the importance of the microenvironment in driving leukemia phenotype.…”