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Transcription dysregulation is common in sarcomas driven by oncogenic transcription factors. Clear cell sarcoma of soft tissue (CCSST) is a rare sarcoma with poor prognosis presently with no therapy. It is characterized by a balanced t(12;22) (q13;q12) chromosomal translocation, resulting in a fusion of the Ewing's sarcoma gene EWSR1 with activating transcription factor 1 (ATF1) to give an oncogene EWSR1-ATF1. Unlike normal ATF1, whose transcription activity is dependent on phosphorylation, EWSR1-ATF1 is constitutively active to drive ATF1-dependent gene transcription to cause tumorigenesis. No EWSR1-ATF1-targeted therapies have been identified due to the challenges in targeting intracellular transcription factors. Through proteomics screening to identify potential druggable targets for CCSST, we discovered protein arginine methyltransferase 5 (PRMT5) as a novel protein to interact with EWSR1-ATF1. PRMT5 is a type II protein arginine methyltransferase to symmetrically dimethylate arginine residues in substrate proteins to regulate a diverse range of activities including gene transcription, RNA splicing, and DNA repair. We found that PRMT5 enhances EWSR1-ATF1-mediated gene transcription to sustain CCSST cell proliferation. Genetic silencing of PRMT5 in CCSST cells resulted in severely impaired cell proliferation and EWSR1-ATF1-driven transcription. Furthermore, we demonstrate that the clinical-stage PRMT5 inhibitor JNJ-64619178 potently and efficaciously inhibited CCSST cell growth in vitro and in vivo. These results provide new insights into PRMT5 as a transcription regulator and warrant JNJ-64619178 for further clinical development to treat CCSST patients., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Clear cell sarcoma is a unique tumor which has EWSR1-ATF1 or EWSR1-CREB1 fusion. Several patterns of EWSR1-ATF1 fusion are observed in clear cell sarcoma. Since type 5-7 fusions were reported recently, they are classified as type 1-7. We examined EWSR1-ATF1 and EWSR1-CREB1 fusions in a single case of clear cell sarcoma with lung metastasis in a 36-year-old Japanese man. As a result, we found only type 1 EWSR1-ATF1 fusion in the primary site, but 4 types of EWS-ATF1 fusion (type 1, 2, 5, 6) were detected in the metastatic site. These 4 types of fusion were completely identical to the recent report, but the case had the same fusion patterns in both primary and metastatic sites. In our case, increased splicing activity in the EWSR1-ATF1 fusion might be acquired at the metastatic site. There is another possibility that metastasis might develop through the increased splicing activity in the fusion., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Clear cell sarcoma is a rare cancer primarily of tendons, fascia, and aponeuroses that can be difficult to discern from primary cutaneous malignant melanoma. The two cancers share several histological markers, with most cases of both cancers staining positively for S-100, HMB-45, and melanin. Primary therapy of both cancers involves wide local excision, but while systemic therapy has proven benefit for malignant melanoma, it has not been established for clear cell sarcoma.We report the case of a 58 year old woman with a large, ulcerated, fungating mass on her left lower leg. Frozen section of the mass showed a malignant epithelioid and spindle cell tumor confined to the subcutaneous tissue. A provisional diagnosis of soft-tissue sarcoma was made. Through in-depth study of initial biopsy with immunohistochemistry for S-100, HMB-45, MART-1, and MITF, along with karyotyping and FISH analysis for EWS gene rearrangement, the diagnosis of amelanotic malignant melanoma was confirmed. The patient then underwent systemic treatment with ipilimumab upon recurrence with good response., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1989338475107348.

Molecular techniques are increasingly important in the practice of surgical pathology. In soft tissue tumors, there are a number of tumors with recurring cytogenetic abnormalities. Knowledge of these abnormalities has furthered our understanding of these tumors and has also allowed development of molecular techniques to aid in the diagnosis. This review will focus on mesenchymal tumors with specific cytogenetic abnormalities that may present as a superficial tumor of the dermis or subcutis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Clear-cell sarcoma (CCS) is a soft-tissue neoplasm that morphologically resembles cutaneous malignant melanoma but has a distinct molecular profile. Gastrointestinal and intra-abdominal CCSs are very rare. Here, the authors present 3 cases of intra-abdominal CCS and review the literature. Of these cases, 2 involved the small bowel, and 1 involved the peritoneum. Cases 1 and 3 had the characteristic CCS morphology, but case 2 was morphologically unusual and therefore difficult to diagnose. It had relatively small cells with less prominence of clear cells; many pseudoglandular structures were also present. It also showed aberrant expression of epithelial membrane antigen (EMA). The other 2 cases also involved some diagnostic uncertainty and were therefore referred to specialized centers. The authors wish to emphasize the importance of molecular studies in making a conclusive diagnosis of intra-abdominal CCS.

Clear cell sarcoma of tendons and aponeuroses (CCSTA) is a rare, aggressive soft tissue malignancy, which is found in intimate association with tendon, aponeurosis or fascia. It has not previously been reported in association with intraarticular ligaments. We report the first case of an intraarticular CCSTA, in this case of the anterior cruciate ligament and describe the diagnostic and treatment challenges of intraarticular tumours of the knee., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: The immunomodulatory properties of polyuridylic acid (PolyU) make it a promising agent in cancer immunotherapy. However, there is limited information on its direct effects on tumor cells., Materials and Methods: TLR8 mRNA and protein expression in soft tissue sarcoma (STS) and bone sarcoma (BS) cell lines were determined by PCR and flow cytometry, respectively. Apoptosis and proliferation assays were performed using annexin V staining and BrdU incorporation assays, respectively. A relative cell enumeration was evaluated with WST-1 reagent. Expression levels of apoptotic proteins were evaluated by Western blotting., Results: We demonstrate that PolyU treatment resulted in a significant decrease in STS and BS cell count by inducing apoptosis and inhibition of cell proliferation. All cell lines examined expressed TLR8 and the effect of PolyU was partially mediated through TLR8. Several apoptotic proteins including caspases were activated or increased in STS cells after treatment with PolyU. Administration PolyU resulted in significant growth inhibition of STS without any observable adverse effects in mouse xenograft tumor models., Conclusions: These results elucidate the effect of PolyU in STS and BS cells and demonstrate that PolyU may be a potential therapeutic agent for STS and BS., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Clear cell sarcoma of soft tissue (CCSST) represents a highly malignant tumor of the musculoskeletal system that is characterized by the chromosomal translocation t(12;22)(q13;q12) of the Ewing sarcoma gene (EWSR1) and activating transcription factor 1 (ATF1). In a former microarray expression study, we identified ERBB3, a member of the epidermal growth factor receptor (EGFR) family, as a promising new diagnostic marker in the differential diagnosis of CCSST. Here we show that, besides ErbB3, all CCSST cell lines (n = 8) also express the ErbB2 receptor or the ErbB4 receptor, representing an adequate coreceptor of ErbB3. The phosphorylation status of ErbB3 revealed these receptor pairs to be either constitutively activated in CCSST cells with high neuregulin-1 (NRG1) expression (n = 4) or activatable by exogenic NRG1 in cells showing low amounts of NRG1 mRNA (n = 4). Exogenous NRG1 stimulated the growth of a subset of CCSST cells but did not affect the kinetics of another subset. This difference was not strictly dependent on endogenous NRG1 expression; however, the growth-inhibiting effect of the pan-ErbB tyrosine kinase inhibitor CI-1033 or PD158780 clearly correlated with NRG1 expression indicating an autocrine growth stimulation loop which may constitute an interesting target of new therapeutic strategies in this tumor entity.

Clear-Cell Sarcoma (CCS) is a rare malignant soft tissue tumor of young adults that often metastasizes to the lymph nodes. The fine needle aspirate cytology (FNAC) findings of CCS have been described previously and it is included in the cytological category of polygonal soft tissue tumors. We describe the cytology of a case of CCS, with emphasis on the so called "tigroid background." Though this tigroid background is a nonspecific feature and has been described in various other tumors, to the best of our knowledge, it has not been described in CCS. This feature may be useful in the recognition of CCS.

Clear cell sarcoma is a high-grade sarcoma with morphological features resembling those of malignant melanoma. An osteoclast-rich tumor of the gastrointestinal tract with features resembling those of clear cell sarcomas of soft parts is very rare. Herein, we report an unusual stomach tumor with microscopic and immunohistochemical characteristics of an osteoclast-rich tumor of the gastrointestinal tract with features resembling those of clear cell sarcomas of soft parts. The tumor cells were predominantly oval, admixed with some round and spindle elements arranged in nests and fascicles, and admixed with scattered osteoclast-like multinucleated giant cells. Neoplastic cells were positive for S-100 protein, and osteoclast-like multinucleated giant cells were immunoreactive to CD68. The unusual morphology of the tumor caused significant diagnostic difficulties. The differential diagnosis included gastrointestinal stromal tumor, primary or metastatic melanoma, and epithelioid malignant peripheral nerve sheath tumor. To the best of our knowledge, this is possibly the second description of an osteoclast-rich tumor of the gastrointestinal tract with features resembling those of clear cell sarcomas of soft parts.

Clear cell sarcoma of soft tissue (CCS-ST) is a rare malignant neoplasm characterized by a tumor-defining translocation [t(12;22) (q13;q12)], resulting in the EWS-ATF1 gene fusion. An extremely limited number of visceral CCS-ST cases have been reported in the literature. Here the authors report a visceral CCS-ST in a Hispanic adolescent male with a large infiltrative mass involving the small bowel. The tumor was evaluated by light microscopy, immunocytochemistry, electron microscopy, cytogenetics, and molecular genetics. The tumor cells were strongly positive for S-100 protein, but negative for HMB-45. Rare premelanosomes were identified only after an extensive search with electron microscopy. Cytogenetics showed a characteristic t(12;22)(q13;q12) for CCS-ST with isochromosome 18q and trisomy 22. An EWS exon 8 sense primer and an antisense ATF1 primer were employed for detection of the CCS-ST tumor-defining EWS-ATF1 translocation, using reverse transcriptase-polymerase chain reaction techniques (RT-PCR), and the fusion gene breakpoint underwent DNA sequencing. This tumor is exceptional, because it is the first visceral CCS-ST that has been confirmed by RT-PCR and DNA sequencing. This case also illustrates the necessity of a multimodal approach to tumor diagnosis, and the utility of cytogenetics and molecular pathology in confirming the diagnosis of CCS-ST and eliminating conventional metastatic or primary visceral malignant melanoma as a consideration.

Clear cell sarcoma of soft tissue (CCSST), also known as malignant melanoma of soft parts, represents a rare lesion of the musculoskeletal system usually affecting adolescents and young adults. CCSST is typified by a chromosomal t(12;22)(q13;q12) translocation resulting in a fusion between the Ewing sarcoma gene (EWSR1) and activating transcription factor 1 (ATF1), of which the activity in nontransformed cells is regulated by cyclic AMP. Our aim was to identify critical differentially expressed genes in CCSST tumor cells in comparison with other solid tumors affecting children and young adults to better understand signaling pathways regulating specific features of the development and progression of this tumor entity. We applied Affymetrix Human Genome U95Av2 oligonucleotide microarrays representing approximately 12,000 genes to generate the expression profiles of the CCSST cell lines GG-62, DTC-1, KAO, MST2, MST3, and Su-CC-S1 in comparison with 8 neuroblastoma, 7 Ewing tumor, and 6 osteosarcoma cell lines. Subsequent hierarchical clustering of microarray data clearly separated all four of the tumor types from each other and identified differentially expressed transcripts, which are characteristically up-regulated in CCSST. Statistical analysis revealed a group of 331 probe sets, representing approximately 300 significant (P < 0.001) differentially regulated genes, which clearly discriminated between the CCSST and other tumor samples. Besides genes that were already known to be highly expressed in CCSST, like S100A11 (S100 protein) or MITF (microphthalmia-associated transcription factor), this group shows an obvious portion of genes that are involved in cyclic AMP response or regulation, in pigmentation processes, or in neuronal structure and signaling. Comparison with other expression profile analyses on neuroectodermal childhood tumors confirms the high robustness of this strategy to characterize tumor entities based on their gene expression. We found the avian erythroblastic leukemia viral oncogene homologue 3 (ERBB3) to be one of the most dramatically up-regulated genes in CCSST. Quantitative real-time PCR and Northern blot analysis verified the mRNA abundance and confirmed the absence of the inhibitory transcript variant of this gene. The protein product of the member of the epidermal growth factor receptor family ERBB3 could be shown to be highly present in all of the CCSST cell lines investigated, as well as in 18 of 20 primary tumor biopsies. In conclusion, our data demonstrate new aspects of the phenotype and the biological behavior of CCSST and reveal ERBB3 to be a useful diagnostic marker.

Objective: There has been no report on useful immunohistological markers for epithelioid sarcoma (ES) so far. The purpose of this study is to evaluate the positivity and specificity of CA125 as a marker for the correct diagnosis of ES., Methods: This study was performed in 11 patients with ES (nine men and two women; distal type: 10 cases; proximal type: one case), 78 patients with other soft tissue tumors and nine with benign granulomas. The other soft tissue tumors consisted of six synovial sarcomas, six clear cell sarcomas, eight leiomyosarcomas, six rhabdomyosarcomas, five malignant peripheral nerve sheath tumors, ten malignant fibrous histiocytomas, 17 desmoid tumors, 14 liposarcomas, six squamous cell carcinomas (cutaneous SCC of the distal extremities), two rheumatoid nodules and seven foreign body granulomas. Immunohistochemical analysis for CA125 was performed for these 89 soft tissue tumors and nine granulomas using a labeled streptavidin biotin method. Immunohistochemical analysis of epithelial membrane antigen, cytokeratin, carcinoembrionic antigen, vimentin and CD34 was performed only for the 11 ES patients., Results: CA125 was strongly expressed in 10 out of the 11 ES patients. EMA, cytokeratin and vimentin were also positive in all the cases. CEA was positive in two of the 11 patients. Immunohistochemical study in six ES patients showed expression of CD 34. The other 78 soft tissue tumors and nine granulomas did not express CA125., Conclusion: This study clearly revealed the specificity and positivity of CA125 in ES. These data indicate that CA125 may be a useful tumor marker for diagnosing ES.

Clear cell sarcoma is a rare malignant soft tissue neoplasm that usually arises adjacent to tendons or aponeuroses. The clinical course is rather slow, with repeated local recurrences followed by late metastases and eventual death. The principal sites of this neoplasm are the extremities, but tumors do occur in the trunk on rare occasions. We report a case of clear cell sarcoma arising from the chest wall. The patient, a 20-year-old woman, had noticed a chest wall mass and pain for 2 years. Biopsy of the mass showed abundant nests of round cells with clear cytoplasm. On immunohistochemical examination, tumor cells were strongly immunoreactive for S-100 and HMB-45. A diagnosis of clear cell sarcoma was confirmed. There was no other lesion found in the patient through routine imaging studies. She was treated with two courses of chemotherapy using ifosfamide, carboplatin, and etoposide. Subsequently, the tumor, including adjacent tissue, the chest wall, and sternum, was resected with a wide margin; and the defect of the chest wall was covered with Marlex mesh fabric, regin, and a musculocutaneous flap. She has shown no symptoms or signs of recurrence during 2 years of follow-up.

Clear cell sarcoma (CCS) is a rare malignant soft tissue tumor particularly associated with tendons and aponeuroses. The cytogenetic hallmark is the translocation t(12;22)(q13;q12) resulting in a chimeric EWS/ATF1 gene in which the 3'-terminal part of EWS at 22q is replaced by the 3'-terminal part of ATF1 at 12q. To date, only 13 cases of CCS have been analyzed for fusion genes at the transcription level, and there is no information about the breakpoints at the genomic level. In the present study, we describe the molecular genetic characteristics of CCS from 10 patients. Karyotypes were obtained from 10 cases, 7 of which showed the characteristic t(12;22). As an initial step in the characterization of the EWS/ATF1 and ATF1/EWS chimeras, we constructed an exon/intron map of the ATF1 gene. The entire ATF1 gene spanned >40 kb and was composed of 7 exons. Intron 3, in which most of the genomic breakpoints occurred, was to a large extent (83%) composed of repetitive elements. RT-PCR amplified EWS/ATF1 cDNA fragments in all patients and ATF1/EWS cDNA fragments in 6 of 10 patients. Four types of EWS/ATF1 chimeric transcript, designated types 1-4, were identified. The most frequent chimeric transcript (type 1) was an in-frame fusion of exon 8 of EWS with exon 4 of ATF1. This was the only chimeric transcript in 5 patients but found together with other variants in 3 tumors. The type 2 transcript of EWS/ATF1, an in-frame fusion of exon 7 of EWS with exon 5 of ATF1, was detected in 4 patients, as the only transcript in 1 case and together with other variants in 3 cases. An in-frame fusion of exon 10 of EWS with exon 5 of ATF1 (type 3) was found in 1 patient as the only transcript, and an out-of-frame fusion of EWS exon 7 with ATF1 exon 7 (type 4) was detected in 1 patient together with type 1 and type 2 transcripts. Sequencing of the amplified ATF1/EWS cDNA fragments showed in 5 patients that ATF1 exon 3 was fused with EWS exon 10, resulting in an out-of-frame chimeric transcript. In 1 case, nt 428 of ATF1 (exon 4) was fused with EWS exon 8; at the junction, there was an insertion of 4 nucleotides, also resulting in an out-of-frame transcript. Genomic extra long PCR and sequence analysis mapped the genomic breakpoints to introns 7, 8 and 9 of EWS and intron 3 and exon 4 of ATF1. While a simple end-to-end fusion was observed in 2 cases, additional nucleotides were found at the junctions in 2 other cases. In addition, topoisomerase I consensus sequences were found close to the junctions, suggesting that this enzyme may participate in the genesis of the EWS/ATF1 fusion., (Copyright 2002 Wiley-Liss, Inc.)

Clear cell sarcoma (CCS), malignant melanoma of soft parts, is a rare malignant tumor with a poor prognosis. In this study, a CCS cell line, designated MP-CCS-SY, was established from a metastatic tumor of a 17-year-old Japanese girl that originated in the left Achilles tendon. A small number of melanosomes were detected in the cytoplasm by electron microscopy. The melanosomes immunoreacted with two melanoma-associated antibodies, HMB45 and Melan-A. A Western blot demonstrated the existence of a Melan-A antigen in this cell line. Although a t(12;22)(q13;q12), which is characteristic of CCS, was not identified by a chromosomal analysis with conventional banding techniques, fluorescence in situ hybridization analysis with painting probes of chromosomes 12 and 22 revealed the insertion of a chromosome 12 fragment into one of the long arms of chromosome 22. The chimeric EWS/ATF1 transcript was detected by the reverse transcriptase polymerase chain reaction. Extra copies and structural abnormalities of chromosome 8 were observed. Overexpression of c-myc mRNA was detected by Northern blot analysis and may have a role in malignant progression of CCS. The availability of this MP-CCS-SY cell line will help to understand the molecular biology of this malignancy and should be useful as a tool for developing an immunotherapy.

We describe the cytologic features of clear cell sarcoma of soft tissue (CCS) in 11 fine-needle aspiration biopsy (FNAB) specimens and 6 exfoliative specimens from 11 patients. In 3 patients, FNAB was the initial method of tumor evaluation. In 6 of 11 cases, immunostaining with S-100 or HMB-45 was evaluated. Electron microscopic evaluation was performed in 1 case. Both the FNAB and exfoliative specimens varied in overall cellularity, although reproducible cytologic features were identified. A significant diagnostic pitfall, namely the potential of CCS to form microacinar structures mimicking adenocarcinoma, is described with particular reference to CCS metastatic to regional lymph nodes. A rare case of the granular cell variant of CCS is illustrated as well. Owing to the rarity of CCS, the diagnosis on cytologic smears is extremely difficult and is aided substantially by pertinent clinical data. The diagnosis can be made conclusively by

The recurrent t(12;22) (q13;q12) chromosomal translocation associated with soft tissue clear cell sarcoma results in a chimeric protein EWS-ATF-1 that acts as a constitutive transcriptional activator. The CBP/p300 transcriptional coactivator, which links various transcriptional factors to basal transcription apparatus, participates in transcriptional activation, growth and cell cycle control and differentiation. In this study, we show that EWS-ATF-1 associates constitutively with CBP both in vitro and in vivo. Both EWS and ATF-1 fusion domains are needed for this interaction. Here, we demonstrate that EWS-ATF-1 represses p53/CBP-mediated trans-activation function. Overexpression of CBP can counteract this repressive effect of EWS-ATF-1. Taken together, these findings suggest that one of the mechanisms by which EWS-ATF-1 may cause tumors is through targeting CBP/p300 resulting in the loss of function of p53. This novel mechanism may be responsible for the development of these and other related solid tumors.

Microphthalmia transcription factor, a melanocytic nuclear protein critical for the embryonic development and postnatal viability of melanocytes, is a master regulator in modulating extracellular signals. Recently, microphthalmia transcription factor expression was shown to be both a sensitive and specific marker of epithelioid melanoma. We investigated the sensitivity of D5, an anti-microphthalmia transcription factor antibody, for diagnosis of clear cell sarcoma (also known as malignant melanoma of soft parts). Immunoreactivity in a nuclear pattern for D5 was present in 8 of 12 (75%) tumors. D5 staining was strong in three tumors, moderate in two, and weak in three. S-100 protein expression was seen in all 12 cases that had clear cell sarcoma examined. HMB-45 staining was seen in 11 of 12 (92%) tumors. Focal Melan-A positivity was seen in 3 of 7 (43%) tumors. Although D5 was shown in a previous study to be a highly sensitive and specific marker for epithelioid melanomas, the results of this study expand the spectrum of tumors showing immunoreactivity for D5. D5 immunoreactivity in clear cell sarcoma provides further evidence for melanocytic differentiation in this unusual tumor.

The embryologic histogenesis of cartilage is not well characterized. While cranial cartilage is believed to be derived from pluripotential precursor cells of the neural crest, chondrocytes found elsewhere in the body are thought to be derived from mesoderm. As such, soft tissue tumors with cartilaginous differentiation may be related to neural crest or mesoderm. Peripherin is an intermediate filament encoded on chromosome 12, involved in growth and development of the peripheral nervous system. Peripherin is apparently expressed exclusively in cells derived from the neural crest and neural tube. A group of six soft tissue tumor types was selected because they are either of controversial differentiation or cytogenetically related to chromosome 12. A total of 41 cases was evaluated with antibodies against the intermediate filament peripherin. A panel of neural and neuroendocrine differentiation markers was used in selected cases. Three of five extraskeletal myxoid chondrosarcomas showed strong cytoplasmic reactivity with anti-peripherin. No peripherin expression was noted in any of eleven epithelioid sarcomas, eight liposarcomas, seven conventional chondrosarcomas, four neurothekeomas, three alveolar soft part sarcomas, or three clear cell sarcomas. The finding of peripherin expression in some extraskeletal myxoid chondrosarcomas may suggest the ability of some tumors to demonstrate both neural and chondroid differentiation.

Enhanced hepatocyte growth factor (HGF) receptor (Met) signaling has been suggested to play an important role in the development and progression of various epithelial and nonepithelial tumors. N-terminally truncated forms of the HGF receptor have been shown to be constitutively activated and tumorigenic in animal experiments. In the present study, 102 benign and malignant human musculoskeletal tumors were examined for expression of the HGF receptor by Western blotting and/or immunohistochemistry. A clear predominance of HGF receptor expression was seen in malignant as compared to benign tumors (Western blotting, P < 0.001; immunohistochemistry, P < 0.02). For the first time we show HGF receptor expression in the following four tumor types: dermatofibrosarcoma protuberans, clear cell sarcoma of tendons, malignant primitive neuroectodermal tumor, and benign fibrous histiocytoma. In three cases of sarcoma with high HGF receptor expression by Western blotting, we found indications of a short 85-kd N-terminally truncated HGF receptor that was tyrosine phosphorylated and located in the cytoplasm. Although fragments of this length were seen in 18 of 65 tumors, most were not tyrosine-phosphorylated. Northern blotting revealed only the 7.5-kb full-length HGF receptor transcript, suggesting that the 85-kd fragment is generated by an alternative initiation of translation or by proteolytic cleavage. Southern blotting detected no amplification of the Hgfr/Met gene in the 35 tumors examined, in contrast to our recent report of Hgfr/Met gene amplification in 7, 12-dimethylbenz(a)anthracene (DMBA)-induced rat sarcomas. The present data suggest that the locally aggressive and malignant properties of human mesenchymal tumors maybe related, in part, to high levels of full-length HGF receptors, and in some cases to the occurrence of N-terminally truncated HGF receptors, activated independently of HGF.