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Research Corner
Annotations by
Tom Swartz
Transforming growth factor ß (TGF-ß) is a multifunctional growth factor that variably affects proliferation, differentiation, and extracellular matrix formation. Little information is currently available on the TGF-ß expression in malignant fibrous histiocytoma (MFH). The investigators of this study examined the expression of TGF-ß isoforms and their receptors in human MFH specimens. The investigators found an association of the TGF-ß ligand/receptor system with a significantly higher MIB-1 index in human MFHs.
The RB1 Gene Is the Target of Chromosome 13 Deletions in Malignant Fibrous Histiocytoma In this study, forty-four malignant fibrous histiocytomas (MFHs) were studied by comparative genomic hybridization. Among the observed imbalances, losses of the 13q14–q21 region were observed in almost all tumors (78%), suggesting that a gene localized in this region could act as a tumor suppressor gene and that its inactivation could be relevant for MFH oncogenesis and/or progression. In an attempt to further characterize these chromosome 13 imbalances, the investigators undertook further molecular analysis, and a consensus region of deletion focusing on the RB1 region was delineated. The investigators thus believe that the high correlation between chromosome 13 losses and absence of RB1 protein expression and the mutations detected strongly suggest that RB1 gene inactivation is a pivotal event in MFH oncogenesis.
The validity of the malignant fibrous histiocytoma (MFH) pathological entity has been recurrently questioned by pathologists. Recently, analyses by comparative genomic hybridization (CGH) of a large series of MFHs suggested that MFHs consist of morphologic modulation of other poorly differentiated sarcomas like leiomyosarcomas (LMS) or dedifferentiated liposarcomas (DLPS). The investigators of this study report an analysis by CGH of 22 myxoid MFHs (mMFH), one of the five histological subtypes of MFH, and of nine pleomorphic liposarcomas (pLPS), a rare poorly differentiated LPS. The chromosome imbalances encountered in the series of mMFH were very similar to those observed in the series of pLPS studied in the laboratory and in the series of 14 pLPS published in the literature. The most frequent gains involved chromosome subregions: pericentromeric regions of 1, 5p, 19p, 19q and 20q. Losses found in the chromosomal arms 1q, 2q, 3p, 4q, 10q, 11q and 13q were also recurrent. The use of a clustering software did not separate the two pathological groups (mMFH and pLPS) on the basis of genomic data. Moreover, pLPS-mMFH represented, according to the clustering software results, an entity clearly distinguished from other soft tissue sarcomas, LMS in particular, with which they share common genetic aberrations. Additional studies are needed to identify genes targeted by these genomic aberrations, and implicated in the oncogenesis of these tumor subtypes. The characterization of common gene alterations in both tumor groups would suggest a closer relationship between these two types of soft tissue sarcomas.
Malignant fibrous histiocytoma of soft tissue: an abandoned diagnosis Malignant fibrous histiocytoma (MFH) has been regarded as the most common soft-tissue sarcoma of adult life. Since it was first recognized in the early 1960s, however, MFH has been plagued by controversy in terms of both its histogenesis and its validity as a clinicopathologic entity. The latest World Health Organization classification no longer includes MFH as a distinct diagnostic category but rather as subtypes of an undifferentiated pleomorphic sarcoma. In this article, the authors review the current understanding of the histologic subtype classification of tumors previously diagnosed as MFH and its relation to clinical outcomes.
Inhibitory effect of STI571 on cell proliferation of human malignant fibrous histiocytoma cell lines ST1571 is a tyrosine kinase inhibitor that was initially developed as a BCR/ABL inhibitor for chronic myeloid leukemia patients. STI571 also selectively inhibits platelet-derived growth factor receptors (PDGFRs) and c-kit. The investigators of this study examined the expression of PDGFRs and c-kit in human malignant fibrous histiocytoma (MFH) cell lines, and the effect of STI571 on cell proliferation. Four human MFH cell lines (TNMY1, GBS-1, Nara-F and Nara-H) were used. The results were as follows. PDGFRalpha mRNA was expressed in TNMY1 and GBS-1, and PDGFRbeta and c-kit mRNAs were expressed in TNMY1, GBS-1 and Nara-F. All three of these mRNAs were absent in Nara-H. In addition, STI571 inhibited cell proliferation of TNMY1, GBS-1 and Nara-F in a dose- and time-dependent manner, but cell proliferation of Nara-H was not inhibited by ST1571 at concentrations of 10 microM or less. The investigators concluded that STI571 significantly inhibited proliferation of the three human MFH cell lines that expressed mRNAs of target receptor tyrosine kinases. They believe that the inhibitory effect of ST1571 on cell proliferation in these three cell lines might be due to decreased tyrosine kinase activity. Thus, STI571 might be a potent chemotherapeutic agent for human MFHs.
Cyclooxygenase-2 (COX-2) has been found to be up-regulated in several types of human malignant tumors and proposed to have a role in the angiogenic process. This study examined the expression of COX-2 in two human malignant fibrous histiocytoma (MFH) cell lines. Immunohistochemistry was conducted in 35 MFHs and 30 benign fibrohistiocytic tumors (BFHTs), comparing the expression of vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP), as well as intratumoral microvessel density (IMVD). COX-2 expression was noted in 22 (62.9%) MFHs, but in no BFHT. IMVD values were significantly higher in the MFHs (90.6+/-8.0) than BFHTs (27.9+/-3.1), and also in the COX-2 positive (104.5+/-11.3) than negative (67.2+/-5.8) MFHs. VEGF and TP expression was also associated with a significantly higher level of COX-2, as well as greater IMVD. The highest IMVD values were noted in the 17 MFHs (120.8+/-11.5) expressing all three factors. Clinical analysis demonstrated poorer survival in the 18 COX-2 positive MFHs than in the 10 negative ones, although the small number of cases did not reveal a significant difference. Thus, the investigators believe the results overall indicate that COX-2 expression is associated with intratumoral angiogenesis, which might provide favorable conditions for tumor progression in human MFHs.
Treatment results and prognostic factors in patients with malignant fibrous histiocytoma The objective of this study was to investigate the treatment results, prognostic factors, the role of postoperative radiotherapy, and the usefulness of the American Joint Committee on Cancer (AJCC) Staging System (2002) for soft tissue sarcomas in malignant fibrous histiocytoma (MFH). Between November 1987 and December 2000, 76 patients with localized MFH underwent surgery as the primary treatment modality with or without radiotherapy in the authors’ institution and were reviewed retrospectively. Patients with regional nodal disease, distant metastases or retroperitoneal disease were excluded from the study. All patients had at least 27 months of follow-up. The 5-year overall survival rate, local control rate, and distant metastasis-free rate were 74%, 62%, and 87%, respectively. In multivariate analysis, AJCC 2002 staging system was the only independent prognostic factor for overall survival rates. Postoperative radiotherapy was the only significant factor for local control rates. The authors concluded that the AJCC staging system is a prognostic predictor for overall survival rates, and postoperative radiotherapy can improve local control.
Leiomyosarcoma and malignant fibrous histiocytoma share similar allelic imbalance pattern at 9p The investigators of study analyzed samples from 45 soft tissue sarcomas for allelic imbalance/loss of heterozygosity (AI/LOH) of chromosome 9. The specimens consisted of 17 cases of soft tissue leiomyosarcoma (LMS), 4 cases of cutaneous LMS, 22 cases of conventional malignant fibrous histiocytoma (MFH) and 2 cases of angiomatoid fibrous histiocytoma. The frequency of allelic imbalance at different loci on chromosome 9p was analyzed in LMS and MFH and then compared with values previously examined in synovial sarcoma and malignant peripheral nerve sheath tumor. The investigators found that although AI/LOH and microsatellite instability (MSI) were more frequent in MFH, LMS and MFH groups showed similar patterns of allelic imbalance at the 9p region. Alterations of chromosome 9p have been reported in many cell lines and tumors including LMS and MFH. The 9p21 region encodes p16(INK4A) and p15(INK4B). The investigators state that the allelic imbalance observed at 9p21 in this study suggests that alterations of the negative cell cycle regulators may be an important step in the pathogenesis of MFH and LMS. However, they further found that the most frequent allelic imbalance was observed at 9p24 at D9S230. Alterations of this locus were very rare in synovial sarcoma and malignant peripheral nerve sheath tumors and were absent in cutaneous LMS and angiomatoid fibrous histiocytoma. Thus, the investigators believe that this locus may point to the existence of a genetically altered tumor suppressor gene involved in the pathogenesis of LMS and MFH. The investigators believe their results support the hypothesis that MFHs may represent a morphological pathway in tumor progression of LMSs.
Soft tissue sarcomas frequently carry p53 mutations reducing chemotherapeutical response. Malignant fibrous histiocytoma (MFH) especially reveals a reduced ifosfamide (IF) chemosensitivity when compared to other sarcomas. This study analyzed MFH cells for the effects of IF on the expression of the pathways P16-CDK4-Rb and P14ARF-MDM2-P73 regulating cell cycle. The aim was to identify candidate genes possibly involved in the anti-apoptotic response of p53-deficient MFH cells during chemotherapy. The MFH cell cultures were treated with different concentrations of IF. A non-treated MFH culture served as negative control. A threshold concentration of IF (100 microM) was determined sparing the majority of the cells (99%), whereas higher IF quantities caused complete apoptosis. The data collected showed that the MFH cells surviving 100 microM IF overexpressed the kinase gene CDK4 and oncogene MDM2 by a factor of 63. A similar strong increase was observed at the protein level for both proteins. In contrast, the other proteins analyzed were not detectable. Additionally, the MFH cells induced complex patterns of MDM2 mRNA splicing and an abnormal mRNA transcript carrying a novel MDM2 missense mutation. These effects were neither observed in the non-treated culture nor in cultures completely inducing spontaneous apoptosis. Therefore, the investigators speculate that the induction of the gene CDK4, and especially of MDM2, is involved in anti-apoptotic mechanisms of p53-negative MFH cells tolerating IF in vitro. The investigators state that further experiments are necessary to test whether the novel candidate genes favor development of chemoresistance and whether MDM2 mRNA splicing variants contribute to this process in vivo.
Antigens recognized by autologous antibodies of patients with soft tissue sarcoma Identification of cancer antigens that are potential targets for immune response is an important new area of cancer research. SEREX (serological expression of cDNA expression libraries) is an antigen identification method which involves the screening of complementary DNA (cDNA) expression libraries with serum from cancer patients, which contains the antibody products of the immune system. SEREX has been widely used to discover multiple novel tumor antigens in diverse types of cancer. In this study, the investigators used the SEREX method to identify tumor antigens in soft tissue sarcoma (STS). Specifically, sera from four patients with malignant fibrous histiocytoma, gastrointestinal stromal tumor, pleomorphic liposarcoma, and dedifferentiated liposarcoma were screened against cDNA libraries derived from autologous tumor. The investigators identified 18 antigens encoded by 15 different genes, including genes implicated in neoplastic transformation. The investigators state that these genes are attractive targets for future development of immune therapy in STS but further studies are warranted.
V2N2 ESUN Copyright © 2005 Liddy Shriver Sarcoma Initiative
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