Modulation of macrophage antitumor potential by apoptotic lymphoma cells.

In aggressive non-Hodgkin's lymphoma (NHL), constitutive apoptosis of a proportion of the tumor cell population can promote net tumor growth. This is associated with the accumulation of tumor-associated macrophages (TAMs) that clear apoptotic cells and exhibit pro-oncogenic transcriptional activation profiles characteristic of reparatory, anti-inflammatory and angiogenic programs. Here we consider further the activation status of these TAMs.

Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma.

Background: Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer.

Pure populations of murine macrophages from cultured embryonic stem cells. Application to studies of chemotaxis and apoptotic cell clearance.

Embryonic stem cells provide a potentially convenient source of macrophages in the laboratory. Given the propensity of macrophages for plasticity in phenotype and function, standardised culture and differentiation protocols are required to ensure consistency in population output and activity in functional assays. Here we detail the development of an optimised culture protocol for the production of murine embryonic stem cell-derived macrophages (ESDM).

Cell death in the neighbourhood: direct microenvironmental effects of apoptosis in normal and neoplastic tissues.

Here we consider the impact of the physiological cell-death programme on normal tissue homeostasis and on disease pathogenesis, with particular reference to evolution and progression of neoplasia. We seek to describe the direct contributions played by apoptosis in creating the microenvironments of normal and malignant tissues and to discuss the molecular mechanisms underlying the elements of the '3Rs' that define the meaning of apoptosis: recognition, response, and removal. Apoptotic cells elicit responses in other cell types-both phagocytic and non-phagocytic-through short- and long-range signalling modes that range from direct contact to intercellular communication via membrane-bound microparticles.

Microenvironmental influences of apoptosis in vivo and in vitro.

The apoptosis program of physiological cell death elicits a range of non-phlogistic homeostatic mechanisms-"recognition, response and removal"-that regulate the microenvironments of normal and diseased tissues via multiple modalities operating over short and long distances. The molecular mechanisms mediate intercellular signaling through direct contact with neighboring cells, release of soluble factors and production of membrane-delimited fragments (apoptotic bodies, blebs and microparticles) that allow for interaction with host cells over long distances. These processes effect the selective recruitment of mononuclear phagocytes and the specific activation of both phagocytic and non-phagocytic cells.

Inhibitory effects of persistent apoptotic cells on monoclonal antibody production in vitro: simple removal of non-viable cells improves antibody productivity by hybridoma cells in culture.

Cells undergoing apoptosis in vivo are rapidly detected and cleared by phagocytes. Swift recognition and removal of apoptotic cells is important for normal tissue homeostasis and failure in the underlying clearance mechanisms has pathological consequences associated with inflammatory and auto-immune diseases. Cell cultures in vitro usually lack the capacity for removal of non-viable cells because of the absence of phagocytes and, as such, fail to emulate the healthy in vivo micro-environment from which dead cells are absent.

Apoptotic human cells inhibit migration of granulocytes via release of lactoferrin.

Apoptosis is a noninflammatory, programmed form of cell death. One mechanism underlying the non-phlogistic nature of the apoptosis program is the swift phagocytosis of the dying cells. How apoptotic cells attract mononuclear phagocytes and not granulocytes, the professional phagocytes that accumulate at sites of inflammation, has not been determined.

CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis.

Cells undergoing apoptosis are efficiently located and engulfed by phagocytes. The mechanisms by which macrophages, the professional scavenging phagocytes of apoptotic cells, are attracted to sites of apoptosis are poorly defined. Here we show that CX3CL1/fractalkine, a chemokine and intercellular adhesion molecule, is released rapidly from apoptotic lymphocytes, via caspase- and Bcl-2-regulated mechanisms, to attract macrophages.

Enhanced apoptotic cell clearance capacity and B cell survival factor production by IL-10-activated macrophages: implications for Burkitt's lymphoma.

Burkitt's lymphoma (BL) is typified by frequent tumor cell apoptosis and significant macrophage infiltration. Since BL cells have an inherent tendency to undergo apoptosis at a high rate, we reasoned that macrophages in BL are functionally enhanced in at least two activities that have implications for tumor pathogenesis: 1) engulfment of apoptotic cells, an anti-inflammatory process known to suppress immune responses, and 2) production of BL cell survival factors that limit the extent of tumor cell apoptosis. In this study, we show that the microenvironment of BL is rich in the pleiotropic cytokine IL-10, which can be produced by both tumor cells and macrophages, and that IL-10-activated human macrophages have enhanced capacity to engulf apoptotic cells in vitro.

Population depletion activates autonomous CD154-dependent survival in biopsylike Burkitt lymphoma cells.

Population size is governed through cells reacting to a variety of intrinsic and extrinsic cues. Tumors, while liberated from many of the homeostatic constraints placed on physiologic counterparts, can nonetheless remain subject to both social and environmental control. Burkitt lymphoma cells faithful to the biopsy phenotype were used to model the reliance of the colony, if any, on an inbuilt population sensor.