Excellent translational research in oncology: A journey towards novel and more effective anti-cancer therapies.

Comprehensive Cancer Centres (CCCs) serve as critical drivers for improving cancer survival. In Europe, we have developed an Excellence Designation System (EDS) consisting of criteria to assess "excellence" of CCCs in translational research (bench to bedside and back), with the expectation that many European CCCs will aspire to this status.

Natural killer cell-target cell interactions.

Research into the molecular mechanisms of target cell recognition by natural killer (NK) cells has recently progressed rapidly. NK cells express several MHC I recognizing receptors that inactivate the NK cells' functions. In pathological alterations of MHC I expression, the NK cell inhibitory receptors do not engage and thus permit the lysis of the target cell. The receptors that trigger the cytolytic machinery of NK cells, after the permission of lysis from the inhibitory receptors, are poorly characterized. Some candidate triggering receptors have been identified and it seems that triggering of NK cell killing is mediated by multiple receptors, as is the inhibition of cytotoxicity.

The ezrin protein family: membrane-cytoskeleton interactions and disease associations.

Ezrin, radixin, moesin and merlin form a subfamily of conserved proteins in the band 4.1 superfamily. Ezrin protein subfamily members act as linkers between the plasma membrane and the cytoskeleton. Members of the subfamily have been shown to interact with each other, with cell adhesion molecules such as CD44 and with F-actin. Recent data indicate that intercellular adhesion molecules 1 and 2 also interact with ezrin. The proteins are also involved in the redistribution of intercellular adhesion molecules and the organization of cell membrane structures. Merlin is a tumor suppressor that is involved in tumorigenesis of schwannomas and meningiomas. Merlin has the same overall protein structure as the other proteins in the subfamily but may have partially distinct functions.

ICAM-2 redistributed by ezrin as a target for killer cells.

Very little is known about the receptors and target molecules involved in natural killer (NK) cell activity. Here we present a model system in which interleukin-2-activated killing by NK cells depends on the intercellular adhesion molecule ICAM-2 and is regulated by the distribution of ICAM-2. The level of ICAM-2 expression in NK-sensitive and resistant cells is similar, but in sensitive cells ICAM-2 is concentrated into bud-like cellular projections known as uropods, whereas in resistant cells it is evenly distributed. The cytoskeletal-membrane linker protein ezrin is also localized in uropods. Transfection of human ezrin into NK-resistant cells induces uropods formation, redistribution of ICAM-2 and ezrin, and sensitizes target cells to interleukin-2-activated killing. These results reveal a new mechanism of target-cell recognition: cytotoxic cells recognize adhesion molecules that are already present on normal cells, but in diseased cells are concentrated into a biologically active cell-surface region by cytoskeletal reorganization. The results also highlight the importance of cytoskeletal interactions in the regulation of ICAM-2-mediated adhesive phenomena.

Involvement of natural killer cells in chronic myeloid leukemia.

We assessed the involvement of natural killer (NK) cells in chronic myeloid leukemia (CML). We adopted the MAC (morphology antibody chromosomes) method, which allows simultaneous assessment of cell morphology, immunophenotype, and chromosome aberrations in the same mitotic or interphase cells. We examined three patients with CML in chronic phase and two patients with the disease in blast crisis. Patients in the chronic phase of the disease showed no involvement of NK cells, but involvement was detected in one of the patients in blast crisis. In this patient, a proportion of the B cells and lymphoid stem cells was also neoplastic, whereas mature postthymic T cells were normal.

Recognition of chromosome 6-associated target structures by human lymphokine-activated killer cells.

Different populations of unstimulated and IL-2-activated PBL were used in binding and killing assays against somatic mouse/human lymphocyte cell hybrids containing different human chromosomes. Unstimulated PBL effector cells showed low binding and killing activity to both cell hybrids and mouse parental cell lines. However, IL-2-activated killer (LAK) cells bound strongly to, and effectively killed, cell hybrids carrying human chromosome 6, but were inefficient in both assays to mouse parental cells and to cell hybrids not carrying human chromosome 6. These results show that human LAK cells but not endogenous NK cells bind and kill mouse/human lymphocyte hybrids containing human chromosome 6. We thus suggest that LAK cells recognize ligands encoded by genes on chromosome 6.