Abstract
An effective cellular response to tissue damage or infection requires the rapid recruitment of leukocytes. Typically this involves the circulating leukocyte rolling along the endothelium, recognizing a site of tissue damage, and extravasating into the tissue. Here the authors characterized a new subset of monocytes that patrol healthy tissue in order to ensure a timely response when recruitment is necessary. The patrolling behavior was discovered using intravital confocal microscopy under steady state conditions or during inflammation in mice induced by irritants, aseptic wounding and intraperitoneal injection of Listeria monocytogenes. In steady state conditions, the average velocity of monocytes was 4–20 μm/min, and cells showed a high confinement ratio. The authors then determined that the integrin LFA-1 and chemokine receptor CX3CR1 were required for the patrolling phenotype. Upon induction of tissue damage monocytes extravasated into the adjacent tissue within one hour, with peak extravasation at two hours, long before peak recruitment of polymorphonuclear cells. This process allows rapid initiation of the innate immune response and differentiation of patrolling monocytes into tissue macrophages.
Auffray C, Fogg D, Garfa M, et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science
In recent years we have begun to appreciate how the stromal cells in the microenvironment of carcinomas may contribute to the neoplastic phenotype. Several studies indicate that stromal cells influence growth of the primary tumor, but their role in facilitating metastasis has been uncertain. In this manuscript the authors demonstrate that the tumor microenvironment does indeed play a role in allowing a metastatic phenotype, and some of the changes induced by the stromal cells may be reversible. When the authors mixed human bone marrow-derived mesenchymal stem cells with a weakly metastatic breast cancer cell line, the cell line had a much greater metastatic rate after injection into mice compared to the cell line without the addition of the mesenchymal stem cells. Furthermore, the stromal cells were found to secrete the chemokine CCL5 (RANTES) which had a paracrine effect on the epithelial cell line to increase its aggressive phenotype. Lastly, when cells from metastatic foci in the lungs were isolated and re-injected into mice, the absence of the mesenchymal stem cells allowed the cell line to revert to its normally weak metastatic phenotype, indicating that the influence of the microenvironment is potentially reversible. These experiments reinforce the need to consider the stromal component in addition to the epithelial component when evaluating tumor biology.
Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature
It is well known that prolonged ingestion of bracken fern (Pteridium aquilinum) leads to chronic enzootic hematuria (CEH) in cattle. Toxic compounds in bracken fern include ptaquiloside and quercetin, and are believed to be responsible for the development of bladder cancer in exposed cattle. In order to determine if chromosome aberrations and sister chromatid exchanges might be sequelae of bracken fern exposure, this was examined in cells from 30 cattle with CEH and 15 cattle with no bracken fern exposure (age matched controls). Chromosomal aberrations (aneuploidy, chromatid breaks, chromosome breaks and fragments) were observed more frequently in cattle with CEH, and the sister chromatid exchange test confirmed increased chromosome fragility in the affected cattle. However, it should be noted that the control group also had high numbers of aneulpoid cells, the cause of which is unknown. Also, these tests were performed using peripheral blood cells and findings may or may not be directly applicable to the urothelium.
Peretti V, Ciotola F, Albarella S, et al. Chromosomal fragility in cattle with chronic enzootic haematuria. Mutagenesis
Most mammals have a symbiotic relationship with the large population of bacteria that colonize their intestine. However, perturbations in this balance can result in chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. The authors of this study have discovered a mechanism whereby deficiency in T-bet results in a communicable ulcerative colitis. T-bet, also known as Tbx21, is a transcription factor that regulates gene expression in immune cells involved in the type 1 proinflammatory immune response. Both T-bet−/− mice as well as T-bet−/− x RAG2−/− (TRUC) mice developed a severe colitis. The colitis in TRUC mice was communicable both vertically and horizontally to mice with an intact immune system. The authors went on to show that T-bet is essential for maintaining the colonic epithelial barrier by regulating tumor necrosis factor alpha (TNF-α) in colonic dendritic cells. They dubbed T-bet the ‘peacekeeper’ of host-commensal relationships in the gut.
Garrett WS, Lord GM, Punit S, et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell
Dogs with a dorsal hair ridge, such as the Rhodesian and Thai Ridgebacks, may also have a concurrent dermoid sinus. This congenital malformation results in a tubular indentation of the skin with luminal keratin and hair. By studying only nine ridgeless and twelve ridged dogs, investigators were able to determine the genomic locus responsible for the ridged phenotype. Closer analysis of this region revealed a 133 kilobase duplication involving three fibroblast growth factor (FGF) genes, the OVAOV1 (oral cancer overexpressed 1) gene, and the 3′ end of Cylcin D1. Although the exact mechanism was not determined, the authors speculate that gene duplication of this FGF cluster leads to dysregulation of FGF expression during embryonic development which may contribute to disorganized hair follicles along the dorsal midline and an increased risk of dermoid sinus formation.
Hillbertz NH, Isaksson M, Karlsson EK, et al. Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs. Nat Genet Epub (preprint)▒ 2007