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Single Nucleotide Polymorphisms in Breast Cancer Epithelial Cells
Analysis of loss of heterozygosity in breast cancer has been difficult because of the heterogeneity of the tissue, the small amount of tissue available for analysis, and the relatively small number of polymorphic markers. To overcome these limitations, Schubert et al (Am J Pathol 2002, 160:73–79) purified epithelial cells from breast cancer tissue blocks using flow cytometry. They used a PCR-based whole genome amplification method referred to as "primer-extension preamplification," which increased template availability by approximately 30-fold. Using this technique, the authors generated informative single nucleotide polymorphisms at 379 genome-wide loci. This technique is a very powerful tool to identify genome-wide allelic imbalances in breast cancer using routinely processed pathology specimens.
Identification of Prostate Cell Populations Using Cell Surface Antigens
The prostate gland contains various types of epithelial cells, neuroendocrine cells, as well as stromal fibroblasts and smooth muscle cells. Because the prostate is a solid organ, isolation of specific cell types and the examination of patterns of gene expression in specific cell types are particularly difficult. Liu and True (Am J Pathol 2002, 160:37–43) used monoclonal antibodies to cluster designation (CD) cell surface molecules to identify populations of cells in prostatic carcinoma. CD molecules were originally found in human leukemic cells but are also present in other cell types. Liu and True show that prostatic epithelial cells have unique patterns of CD expression. The patterns of CD expression shown by these cells can be used to separate specific cell populations by flow cytometry or laser capture microdissection. Furthermore, expression of CD antigens may be helpful in the diagnosis of prostate cancer.
Overexpression of S100A4 (Calvasculin) Is Associated with Poor Differentiation and Hypomethylation in Pancreatic Ductal Adenocarcinomas
S100A4 is a member of the family of S100 calcium-binding proteins. It has been suggested that the protein may be associated with metastatic capacity in some cancer cell lines. Rosty et al(Am J Pathol 2002, 160:45–50) surveyed a series of normal pancreas and pancreatic cancer gene libraries and found that S100A4 was expressed in 5 of 7 cancer libraries but not in normal pancreas. Further analyses demonstrated S100A4 expression in 93% of invasive pancreatic carcinomas, but no expression was detected in low-grade lesions or chronic pancreatitis. Three CpG sites, which are 90% methylated in microdissected normal pancreatic tissue, were 100% hypomethylated in 11 of 12 pancreatic cancer cell lines. The data indicate that S100A4 may be a useful marker to detect pancreatic carcinoma and that pancreatic cancer cells selectively overexpress hypomethylated S100A4.
Role of Neuropilin-1 in Wound Angiogenesis
Vascular endothelial growth factor (VEGF) is a potent mediator of angiogenesis during embryonic development and in wound healing and tumorigenesis of adult tissues. There are three soluble forms of VEGF ligands that induce angiogenesis through binding to the cell surface receptors VEGFR1 and VEGFR2. The two receptors are expressed on endothelial cells of sprouting vessels, but a third receptor, neuropilin-1, was recently identified. Neuropilin-1, originally characterized as a semaphorin receptor involved in nerve guidance during development, plays a role in vasculogenesis. Its absence causes cardiovascular defects and embryonic lethality in mice, suggesting that neuropilin-1 may serve as a co-receptor for VEGF. Matthies et al (Am J Pathol 2002, 160:289–296) found that neuropilin-1 is abundantly expressed on new vasculature of healing wounds and that mice treated with anti-neuropilin-1 antibodies showed an almost 70% decrease in vascular density in these wounds. In vitro experiments demonstrated that the antibodies inhibited VEGF-mediated formation of endothelial cord-like structures, as well as endothelial cell migration. The results provide strong evidence for a critical role of neuropilin-1 in wound angiogenesis, as well as in VEGF-mediated effects in endothelial cell migration.
C-KIT and Gastrointestinal Stromal Tumors: A Complex Relationship
Gastrointestinal stromal tumors (GIST) have received increased attention because of the possibility of inhibiting tumors and growth through the blockage of C-KIT activity. Nevertheless, there are few comprehensive analyses of the spectrum of C-KIT mutations in these tumors. Andersson et al (Am J Pathol 2002, 160:15–22)analyzed 14 GIST from 12 patients and found a much wider spectrum of C-KIT mutations than anticipated. They found 11 different in-frame mutations involving exons 11, 14, and 15 and lack of mutations in four tumors. Spectral karyotype analyses revealed clonal abnormalities in eight tumors, including deletions and chromosome losses. Neither the C-KIT mutation status nor the chromosome aberrations correlated with tumor phenotype or clinical behavior. The significance of the diverse changes reported by Andersson et al is not known at this time, but it indicates that relationships between C-KIT mutations, as well as chromosomal abnormalities in GIST pathogenesis, are complex and require further study.
Characterization of Fetal Cells Circulating in Maternal Blood
Fetal trophoblastic cells, which circulate in the peripheral blood of pregnant women, might be of potential use for genetic analyses without requiring invasive methods for collection of fetal cells. Vona et al (Am J Pathol 2002, 160:51–58) enriched circulating trophoblastic cells from women at 11 to 12 weeks of pregnancy. They used a method to separate cells by taking advantage of the larger size of trophoblastic cells compared with peripheral blood leukocytes. The method required 2 ml of blood for analysis. Fetal cell identification was confirmed by PCR analysis with short tandem repeats and Y chromosome-specific primers. The technique also permits the performance of FISH analyses to detect DNA point mutations in single microdissected cells. The technique may have wide applicability for non-invasive prenatal diagnoses of genetic diseases.
Lack of ERBB2 Involvement in Prostate Cancer
Potentially promising results with anti-ERBB2 antibodies in the management of advanced breast cancer has led to the suggestion that the same approach may be of value in other forms of cancer. Savinainen et al (Am J Pathol 2002, 160:339–345) show that only 1 of 126 prostatic tumors contained ERBB2 amplification and that ERBB2 protein expression was not detectable in any of the tumors examined. As determined by RT-PCR, ERBB2 mRNA expression in prostate tumors was about 20-fold less than in breast tumors with ERBB2 amplification. The data demonstrate that expression of ERBB2 in prostate cancer is low and unmodified during disease progression, indicating that this gene is unlikely to be a good target for prostate cancer treatment.
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