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This Month in AJP |
More on Vasculogenic Mimicry: Invasive Ovarian Cancers
The term vasculogenic mimicry was used recently to describe a pattern of matrix-rich networks of vascular channels formed by aggressive melanoma tumor cells. These findings have generated considerable controversy as reported in The American Journal of Pathology. Sood et al (Am J Pathol 2001, 158:1279–1288) investigated whether invasive ovarian carcinoma cells could engage in molecular vasculogenic mimicry. The data revealed that the invasive ovarian cancer cells, but not normal ovarian surface epithelial cells, formed patterned networks containing solid and hollow matrix channels when grown in three-dimensional cultures containing Matrigel or Type I collagen, in the absence of endothelial cells or fibroblasts. Immunohistochemical analysis showed that matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, and MT1-MMP were discretely localized to these networks, and the formation of the networks was inhibited by treatment with MMP inhibitors. In sections from patients with high grade ovarian cancers, 7 to 10% of channels containing red blood cells were lined by tumor cells. By comparison, all vascular areas in benign tumors and low stage cancers were endothelial lined. These results offer an interesting insight into potential mechanisms of vasculogenesis in aggressive tumors.
Hyperglycemia, the VEGF/VEGF Receptor System, and Congenital Malformations
Major congenital malformations are the leading cause of mortality and morbidity in infants of diabetic mothers. Targeted mutations of several genes, including VEGF and VEGF receptors, that cause embryonic death during organogenesis are associated with a failure in the formation and/or maintenance of a functional vitelline circulation. Given the similarities in the pathology of the abnormal vitelline circulation in many of these defects, Pinter et al (Am J Pathol 2001, 158:1199–1206) hypothesized that the hyperglycemia may cause the resultant abnormalities in the vitelline circulation by affecting VEGF/VEGF receptor signaling pathway(s). Induction of hyperglycemia in pregnant mice resulted in reduced levels of VEGF-A in the conceptus, causing abnormal VEGF receptor signaling and ultimately leading to vitelline vasculopathy. The results support the notion the VEGF levels can be modulated by glucose levels and be related to congenital abnormalities associated with diabetes.
Angiogenesis and Vascular Repair during Menstruation
Regeneration of the endometrium after
menstruation requires a rapid and highly organized vascular response.
Potential regulators of this process include members of the VEGF family
of proteins and their receptors, but the relationships between VEGF
production, receptor activation and endothelial cell proliferation
during the endometrial cycle is poorly understood. Graubert et al (Am J
Pathol 2001, 158:1399–1410) found that VEGF is significantly increased
at onset of menstruation, apparently as a consequence of the additive
effects of hypoxia, TGF-
, and IL-Iß. Similarly, the VEGF receptors
FLT-1 and KDR increased at the onset of menstruation. However,
functional activation of KDR as determined by phosphorylation studies
occurred in the late menstrual and early proliferative phases and had
an inverse correlation with the presence of sFLT-1. Endothelial cell
proliferation in endometrium reached a peak during the later menstrual
and early proliferative phases in association with the increase in
VEGF, VEGF receptor phosphorylation, and decrease of sFLT-1. The
results suggest that VEGF receptor activation and the subsequent
modulation of sFLT-1 may contribute to the onset of angiogenesis and
endothelial repair during menstruation.
Differentiation of Erythroid Progenitors into Megakaryocytes
In myelodysplasias and acute myeloid leukemias, abnormalities in erythroid development often parallel abnormalities in megakaryocytic development. It is known that erythroleukemic cells undergo megakaryocytic differentiation in response to a variety of stimuli, but it is unclear whether or not this capacity is a consequence of the leukemic phenotype of these cells. Goldfarb et al (Am J Pathol 2001, 158:1191–1198) purified primary human erythroid progenitor cells and treated the cells with conditions known to induce megakaryocytic differentiation in the erythroleukemic cells. Like erythroleukemic cells, the primary erythroid progenitors responded rapidly with morphological and immunophenotypic evidence of megakaryocytic differentiation. Even erythroblasts expressing high levels of hemoglobin showed partial megakaryocytic differentiation. The results indicate that the megakaryocytic differentiation capacity of erythroleukemic cells is an intrinsic property of erythroid precursors and not a consequence of leukemic transformation.
Mechanisms of Mesangial Cell Proliferation in Glomerular Disease
Proliferation of mesangial cells is a hallmark of glomerular disease, but the mechanisms that regulate the proliferation of these cells are not completely understood. Previous studies done in cell cultures showed that the protein coded by the growth arrest-specific gene 6 (Gas6) stimulates mesangial cell proliferation by binding to its cell surface receptor Axl and that warfarin, as well as the extracellular domain of Axl conjugated with the Fc portion of human IgGl (Axl-Fc), inhibit mesangial cell proliferation by interfering with the Gas6/Axl pathway. Yanagita et al (Am J Pathol 2001, 158:1423–1432) examined the potential role of Gas6 and Axl in an experimental model of mesangial proliferative glomerulonephritis induced by the injection of anti-Thy1.1 antibody (Thy1 GN) in rats. In these animals, expression of Gas6 and Axl was markedly increased in glomeruli and correlated with progression of mesangial cell proliferation. Administration of relatively small doses of warfarin or daily injection of Axl-Fc inhibited mesangial cell proliferation and abolished the induction of PDGF-B mRNA and protein. These findings indicate that the Gas6/Axl pathway may play an important role in mesangial cell proliferation in glomerular disease.
Matriptase, an Extracellular Matrix-Degrading Protease, and its Inhibitor HAI-1 Are Expressed by Normal and Transformed Epithelial Cells
Matriptase and its serine protease inhibitor HAI-1 are a newly characterized extracellular matrix-degrading protease system that may function as an epithelial membrane activator for other proteases and latent growth factors. To test the hypothesis that this system is expressed by epithelial cells, both normal and transformed, Oberst et al (Am J Pathol 2001, 158:1301–1310) analyzed matriptase and HAI-1 expression in cultured cells as well as human tumors. Both the enzyme and its inhibitor were detected at the protein and mRNA level in hormone-dependent and -independent cultured breast cancer cells together with the expression of the epithelial markers E-cadherin or ZO-1, but were absent in breast cancer cell lines expressing the mesenchymal marker vimentin. Matriptase, as determined by Western blot analysis, was detected in human primary breast, gynecological, and colon carcinomas, but not in stromal-derived ovarian tumors and sarcomas of various origins and histological grades. In breast cancers, matriptase and HAI-1 were detected by in situ hybridization and immunohistochemistry in the carcinoma cells and surrounding normal breast epithelia. These results indicate that matriptase and HAI-1 are expressed by normal and transformed epithelial cells from various tissues. A potential role for this system in normal physiology, as well as in invasion and metastasis, remains to be established.
Relationships between Microsatellite Instability and Gene Mutations in Colon Cancer
There is considerable controversy about whether the frequency of p53 and K-ras mutations is inversely correlated with microsatellite instability in colon cancer. Samowitz et al (Am J Pathol 2001, 158:1517–1524) examined a population-based sample of 496 individuals with colon cancer. Microsatellite instability was determined by several established criteria. The authors also determined the presence of mutations in K-ras codons 12 and 13 by sequencing and examined p53 expression by immunohistochemistry. K-ras mutations were present in 33.2% of tumors, p53 overexpression in 51.5%, and microsatellite instability (as determined by the Bethesda consensus panel) in 12.5%. K-ras mutations were significantly less common in unstable tumors than stable tumors (11.8% vs. 36.9%, P < 0.001). p53 overexpression was significantly less common in unstable tumors than in stable tumors (20.0% vs. 55.7%, P < 0.01). These inverse relationships between microsatellite instability and ras gene mutations and p53 overexpression were independent of tumor site. In contrast, coding mononucleotide repeat mutations in five different genes were significantly more common in unstable tumors than stable tumors (85.7% vs. 1.0%, P < 0.001). The results suggest the molecular profile of colon cancers with microsatellite instability is characterized by relatively infrequent mutations in K-ras and p53 overexpression as well as relatively frequent mutations in coding mononucleotide repeats.
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