Biomedical subjects
Publications and source records attributed to Richard M Terek.
Chondrosarcoma are a heterogeneous group of tumors whose treatment is limited to surgical removal. Molecular genetic analysis of these tumors has revealed some of the abnormalities responsible for the traits of the malignant phenotype.
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Differential display-polymerase chain reaction was used to compare gene expression between human chondrosarcoma cell lines and normal cartilage. A new gene, CSAGE, has been cloned and belongs to a gene family that includes the taxol resistance associated gene (TRAG)-3. CSAGE, like TRAG-3, does not confer resistance to taxol when transfected in vitro. Both genes have alternatively spliced variants. CSAGE and TRAG-3 are expressed in chondrosarcoma, melanoma, and cartilage and testis, but not in other normal tissues. TRAG-3 has been reported to be a cancer/testis antigen. Our results suggest that CSAGE belongs to the growing list of cancer/testis antigens as well. In all of the CSAGE positive samples, the melanoma antigen gene family was also expressed. This is the first report on the expression of cancer/testis antigens in chondrosarcoma.
Pathologic neovascularization has been described in numerous types of cancers. The angiogenic cytokines vascular endothelial growth factor and basic fibroblast growth factor are thought to be the primary inducers of angiogenesis in these tumors. Hypoxia-inducible transcription factor is a nuclear transcription factor that promotes vascular endothelial growth factor expression. Prior studies have shown pathologic neovascularization in chondrosarcoma, which correlates with pathologic grade of the tumor. Angiogenic and nonangiogenic cartilage tumors were studied for expression of vascular endothelial growth factor, basic fibroblast growth factor and hypoxia-inducible transcription factors by immunohistochemistry and Northern blot analysis. Expression of vascular endothelial growth factor and hypoxia-inducible transcription factor were increased significantly in angiogenic tumors. Fibroblast growth factor expression was similar in angiogenic and nonangiogenic specimens. This may have implications for tumor grading and surgical decision-making, and potential treatment with antiangiogenesis chemotherapeutic agents.
Tumor-induced angiogenesis is necessary to sustain radial growth of tumors. Increased microvascularity has been correlated with increased metastatic potential in breast, gastrointestinal, and gynecologic tumors, but has not been well studied in cartilaginous tumors. Grade II and Grade III chondrosarcomas have increased metastatic potential compared with Grade I tumors. One reason for this may be pathologic neovascularization. The purpose of the current study was to quantify the microvessel density of cartilage tumors. Seven Grade III, 17 Grade II, and eight Grade I chondrosarcomas, and 22 benign cartilage tumors were examined. Specimens were stained with antiCD34 antibody. Microvessel densities then were determined by direct counting and estimated using the Chalkley technique. Microvessel densities for Grade III and Grade II chondrosarcomas were 45.9 and 46.2 per high-power field and for Grade I and benign tumors the microvessel densities were 9.3 and 10.3. Microvessel densities of the aggressive tumors (Grades III and II) were greater than the microvessel densities of the nonaggressive tumors (Grade I and benign). Chalkley estimates confirmed the results. Microvascularity in cartilage tumors correlates with their biologic aggressiveness and seems promising as a variable to help with histopathologic grading and as a target for new treatment modalities.
Chondrosarcoma is the second most common primary malignant neoplasm of bone in adults, but the major genetic events involved in the progression of this often-fatal cancer remain to be elucidated. Loss of heterozygosity of chromosome 10q has been reported in 67% of chondrosarcoma. The tumor suppressor gene PTEN is located on chromosome 10q, specifically 10q23, raising the possibility that the loss of PTEN function is responsible for some chondrosarcomas. The authors examined 40 chondrosarcoma tumors and tumor-derived cell lines for alterations in PTEN. Only one mutation resulting in a truncated PTEN protein was detected, which was in a metastasized extraskeletal myxoid chondrosarcoma. Thus, mutated PTEN is an uncommon event in the development of chondrosarcoma. The high frequency of loss of heterozygosity on 10q suggests the presence of additional tumor suppressor genes at these loci.