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This Month in AJP |
Nestin Is a Diagnostic Marker for Gastrointestinal Stromal Tumors (GISTs)
Nestin is an intermediate filament protein predominantly expressed in neuroectodermal stem cells, skeletal muscle progenitor cells, and tumors that originate from these cells. Tsujimura et al (Am J Pathol 2001, 158:817–823) examined nestin expression in GISTs to determine whether GISTs originate from stem cells. Strong immunoreactivity for nestin was observed in all 18 GISTs, and its expression was confirmed by Western blot and Northern blot analyses. In contrast, 3 leiomyomas and a schwannoma that developed in the gastrointestinal tract showed no apparent immunoreactivity for nestin. Among 17 mesenchymal tumors (7 leiomyosarcomas, 5 malignant peripheral nerve sheath tumors, and 5 fibrosarcomas) that occurred in sites other than the gastrointestinal tract, only 2 malignant peripheral nerve sheath tumors were moderately immunoreactive for nestin. The results indicate that nestin may be a useful marker for diagnosis of GISTs. Moreover, because nestin expression was detected in interstitial cells of Cajal (ICCs) in the normal intestine, the data support the hypothesis that GISTs originate from stem cells that differentiate toward an ICC phenotype.
Endothelin-1 Is an Autocrine Growth Factor in Kaposi’s Sarcoma
Endothelin-1 (ET-1) is a mitogenic agent for endothelial and many tumor cells, acting through an autocrine mechanism. Bagnato et al (Am J Pathol 2001, 158:841–847) studied whether a tumorigenic Kaposi’s sarcoma (KS) cell line would respond to ET-1 mitogenic activity. KS IMM cells expressed ET-1 and ETbR mRNAs as well as functional ETAR and ETBR. These cells also released high concentrations of ET-1 in the culture medium. Expression of ET-1 and cognate receptors was detected by immunohistochemical method in vitro, in KS IMM xenograft and in tissue sections of human KS. ET-1 induced a marked dose-dependent increase in [3H]thymidine incorporation in KS cells comparable to that elicited by vascular endothelial growth factor. Addition of selective ETBR (BQ 788) and ETAR (BQ 123) antagonists completely blocked the ET-1-induced mitogenic response and reduced the basal growth rate of unstimulated cells. The results suggest that ET-1 may participate on KS pathogenesis through its action as an autocrine growth factor. ET-1 receptor antagonists may be novel candidates for therapeutic intervention in KS.
Plasminogen Activators Contribute to Tissue Repair in Acute Liver Injury
Tissue repair requires the coordination between cell proliferation and reorganization of extracellular matrix. Bezerra et al (Am J Pathol 2001, 158:921–929) explored the regulatory role of tissue- (tPA) and urokinase- (uPA) type plasminogen activators in liver repair. After acute carbon tetrachloride (CCl4) hepatic injury, tPA-deficient mice displayed a mild defect in hepatic repair, whereas livers of uPA-deficient mice had delayed repair with injury of centrilobular hepatocytes persisting up to 14 days after CCl4. There was a profound reparative defect in livers of mice lacking both tPA and uPA, with persistence of centrilobular injury for more than 1 month, suggesting that there may be functional cooperativity between the two types of plasminogen activators. The defective repair was not due to increased susceptibility of experimental mice to the toxin or to inadequate cellular proliferation. Instead, lack of plasminogen activators led to the accumulation of fibrin and fibronectin within injured areas and deficient removal of necrotic cells. These data demonstrate that tPA and uPA play a critical role in the repair of acute liver injury through proteolysis of matrix elements and clearance of cellular debris.
Multiple Methylator Phenotypes in Ovarian Carcinoma
It has been proposed that aberrant methylation of CpG islands causes inactivation of tumor suppressor genes and contributes to tumor development. Recent studies on colorectal and gastric cancer have defined a CpG island methylator phenotype (CIMP) involving the hypermethylation of promoters of multiple genes. Strathdee et al (Am J Pathol 2001, 158:1121–1127) investigated the methylation status of 93 primary ovarian tumors at 10 loci using methylation specific PCR. Seven of the loci (BRACA1, HIC1, MINT25, MINT31, MLH1, p73, and hTR) were found to be methylated in a significant proportion of the ovarian tumors and methylation of at least one of these genes was found in 71% of samples. Although concurrent methylation of multiple genes was common, no single CIMP phenotype emerged. The results suggest that ovarian tumors may have two CIMP+ phenotype groups, each susceptible to methylation of a different subset of genes. In addition, approximately 30% of the tumors showed no CpG island methylation at the loci studied.
A Transgene Murine Model for Macular Degeneration
Choroidal neovascularization in age-related macular degeneration is a frequent and not easily treated cause of vision loss and has been associated with the expression of vascular endothelial growth factor (VEGF). Schwesinger et al (Am J Pathol 2001, 158:1161–1172) wished to establish a transgenic murine model of age-related macular degeneration in which the overexpression of VEGF by the retinal pigment epithelium would induce choroidal neovascularization. A construct consisting of a tissue-specific murine retinal pigment epithelium promoter (RPE65 promoter) coupled to murine VEGF164 cDNA with a rabbit ß-globin-3' UTR was introduced into the genome of albino mice. Transgene mRNA was expressed in the retinal pigment epithelium at all ages, peaking at 4 months. Histological analysis revealed intrachoroidal neovascularization without penetration through the intact Bruch’s membrane. This animal model may be useful for the study of mechanisms of choroidal vessel growth and for screening for inhibitors of retinal vascularization.
Basic Fibroblast Growth Factor (bFGF) and Ultraviolet Light
Ultraviolet (UV) light is an epidemiological risk factor for melanoma, although its exact contribution to melanoma pathogenesis is not known. Berking et al (Am J Pathol 2001, 158:943–953) hypothesized that the uncontrolled proliferation of melanocytes might be induced by a combination of UV damage and an imbalance of bFGF production, the major autocrine growth factor associated with tumor progression in melanomas. Overexpression of bFGF through adenoviral gene transfer in human skin xenografted to severely combined-immunodeficient mice led to black pigmented macules within 3 weeks of treatment. Immunofluorescence analysis demonstrated pathological hyperpigmentation, proliferation, and hyperplasia of activated melanocytes, but no malignant transformation. However, bFGF combined with UVB exposure caused pigmented lesions with hyperplastic melanocytic cells, including a lesion with high-grade atypia resembling lentiginous malignant melanoma. The results suggest that an imbalance in the production of a physiological growth factor in the skin, in combination with UV exposure, may be a causal factor in melanoma development.
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