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Loss of a Tumor Suppressor Gene Causes Polycystic Kidney Disease
Homozygous deficiency of the tuberous sclerosis 2 (Tsc2) gene causes embryonic lethality in rats. Heterozygous animals for a mutant Tsc2 allele develop renal cell carcinomas in frequencies close to 100%, after inactivation of the normal Tsc2 allele. Loss of the normal allele occurs in preneoplastic lesions and coincides with increased expression of transforming growth factor 
, similar to human renal cell carcinomas. Cai et al (Am J Pathol 2003, 162:457–468) report that loss of heterozygosity (LOH) at the Tsc2 locus during embryonic development caused severe polycystic kidney disease in Eker rats. In addition, spleen and uterine tumors developed in young animals. Tsc2 interacts with Pkd1, the polycystic kidney disease 1 gene product. In the affected rats, Pkd1 was intact, demonstrating a direct relationship between Tsc2 and polycystic renal disease. A commentary by D.M. Hockenberry (Am J Pathol 2003, 162:369–371) discusses this important finding in more detail.
Profiling of Vascular and Lymphatic Endothelial Cells
There has been enormous progress in understanding the mechanisms of angiogenesis and endothelial cell functions. Most of this work involves the blood vascular system, but much less information is available on lymphatic vessels. A major barrier for studies on lymphatic vessels is the difficulty of developing adequate experimental procedures for the required analyses. Hirakawa et al (Am J Pathol 2003, 162:575–586) obtained lymphatic endothelial cells (LEC) by immunomagnetic selection of CD34-/CD31+ cells directly from human skin. These cells, as well as blood vascular endothelial cells, were placed in culture and analyzed for their transcriptional profiles. LEC, but not blood vascular cells, expressed the lymphatic marker Prox1 as well as LYVE-1, a marker that was also expressed in vascular structures produced by implantation of LEC in vivo. The work identified patterns of gene expression in blood vascular and lymphatic endothelium and is of great importance for the understanding of vasculogenesis in embryonic development and in adults.
Direct Role of the Alternative Complement Pathway in Intestinal Ischemia/Reperfusion Injury
It has been firmly established that the complement system is involved in ischemia/reperfusion (I/R) injury in various organs. However, there is no precise information about the role by different pathways of complement activation in I/R injury. Factor D cleavage of factor B to form the C3bBb convertase is the rate-limiting step for the activation of the complement alternative pathway. Stahl et al (Am J Pathol 2003, 162:449–455) used factor D knockout and heterozygous mice to study the role of the alternative complement pathway in I/R injury in the intestine. Injury after I/R, as measured by LDH and intestinal myeloperoxidase activity, was much higher in factor D knockout animals than in heterozygous mice. Addition of factor D to knockout mice restored a normal response to intestinal I/R injury and could be prevented by factor D antibodies. The data demonstrate that factor D may be an important target for the control of I/R injury. The role of complement pathways in I/R is discussed in a commentary by Riedemann and Ward (Am J Pathol 2003, 162:363–367).
The Shh (Sonic Hedgehog) Gene May Be Involved in Pulmonary Hypoplasia
The Shh gene is involved in many steps of embryonic development including branching morphogenesis in the lung. Shh acts by binding to the receptor molecule called "Patched," which releases the repression of a second membrane receptor ("Smoothened") activating at least three lung transcription factors. The mortality of babies with congenital diaphragmatic hernia (CDH) is primarily attributed to lung hypoplasia, although the mechanisms of this defect, which causes a 20 to 40% mortality rate, are not known. Unger et al (Am J Pathol 2003, 162:547–555) studied Shh expression in human and rat developing normal lungs and compared the patterns of expression to those in lungs with pulmonary hypoplasia secondary to CDH and in an animal model for the disease. Shh expression was highest once the tracheobronchial tree has been formed and was diminished in hypoplastic lungs at early stages of development. It reached a maximum at much later stages in hypoplastic lungs, at a time in which Shh expression had already declined in normal lungs. The results suggest that Shh may be important in the pathogenesis of pulmonary hypoplasia associated with CDH, although more studies are needed to prove a causal relationship.
TGFß Is Required for Healing of the Intestinal Mucosa
TGFß has a multitude of biological effects and can mediate cell differentiation, migration, proliferation, fibrogenesis, and healing. Investigators have attempted to sort out these various mechanisms using TGFß1 knockout mice. However, these animals die rapidly with multi-focal inflammation and thus do not constitute an adequate tool to analyze tissue-specific abnormalities caused by TGFß1 deficiency. Beck et al (Am J Pathol 2003, 162:597–608) produced mice that overexpress a dominant negative form of TGFß receptor type II under the regulation of a modified liver fatty acid binding promoter. The truncated TGFß receptor was expressed in intestinal cells and made these cells unable to respond to TGFß (the truncation produces a molecule that binds the receptor but does not signal). The transgenic mice showed no changes in epithelial cell proliferation and developed and survived normally. However, they were highly susceptible to dextran sodium sulfate-induced colitis and had poor recovery from the injury. The results demonstrate that TGFß is required for healing of the intestinal mucosa after injury.
Genomic Instability Is Present in Normal and Abnormal Regions of the Colon of Ulcerative Colitis Patients with Dysplasia and Cancer
The development of colon cancer in patients with ulcerative colitis (UC) differs from that of sporadic colon cancer primarily because dysplasia in UC patients is multi-focal. Recent data have identified field effects in areas of normal appearing mucosa adjacent to tumors suggesting that in UC patients, chromosomal instability may involve large segments of the colon when cancer and/or dysplasia are present. Chen et al (Am J Pathol 2003, 162:665–672) developed a PCR method (ISSR-PCR or intersimple sequence repeat) and used it together with arbitrarily primed PCR to determine the variation in DNA sequences in biopsies from UC patients containing non-dysplastic, dysplastic, and neoplastic tissues. Patients with dysplasia/cancer had significant levels of genomic instability in both dysplastic and non-dysplastic colonic mucosa. Instability was detectable only at low frequency in UC patients without dysplasia/cancer. The work demonstrates that there is generalized genomic instability in the colon mucosa of UC patients who develop dysplasia or cancer.
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