Abstract
In a previous immunophenotypic molecular-based analysis it was shown that bcl2 over-expression characterizes the SS gene profile in addition to the non-random translocations. Here we show that the over-expression of an additional potentially antiapoptotic gene, the c-KIT gene, is associated with this tumour. Interestingly, whereas bcl2 over-expression appears to be restricted to the spindle cell tumoral component, c-kit mainly involves the epithelial component of biphasic SS. Twenty-three primary and metastatic samples from 21 patients were analysed by immunophenotyping (23/23), immunoprecipitations and Western blotting (3/23), and RT-PCR (23/23). Ten cases were biphasic and 13 monophasic in sub-type. Twelve, 10 and 1 case carried the SYT-SSX1, SYT-SSX2 and SYT-SSX4 fusion transcript, respectively. Co-presence of both c-Kit and SCF mRNA was observed in almost all cases (20/23), suggesting the occurrence of an autocrine loop. Immunophenotyping, confirmed by biochemical analyses, showed a modulation of c-Kit expression which was faint in the spindle and strong in the epithelial component, respectively. The study was complemented by c-Met/HGF receptor/ligand expression and c-Met protein analysis with results superimposable to those already reported. Since in each tumour, epithelial and spindle cell components harbour the same type of translocation t(X;18) the present findings suggest a shifting of the anti-apoptotic role from BCL2 to c-KIT gene during the transition from the uncommitted spindle to the differentiated epithelial cells. © 2001 Cancer Research Campaign
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References
Adams V, Kempf W, Hassam S and Briner J (1995) Determination of Hexokinase isoenzyme I and II composition by RT-PCR: increased hexokinase isoenzyme II in human renal cell carcinoma. Biochem Mol Med 54: 53–58
Anderson DM, Lyman SD, Baird A, Wignall JM, Eisenman J, Rauch C, March CJ, Boswell HS, Gimpel SD, Cosman D and Wiliams DE (1990) Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms. Cell 63: 235
Besmer P, Murphy JE, George PC, Qui F, Bergold PJ, Lederman L, Snyder, Jr. HW, Brodeur D, Zuckerman EE and Hardy WD (1986) A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family. Nature 320: 415–421
Brizzi MF, Zini MG, Aronica MG, Blechman JM, Yarden Y and Pegoraro L (1994) Convergence of Signaling by Interleukin-3, granulocyte-macrophage-colony-stimulating factor, and mast cell growth factor on JAK2 Tyrosine Kinase. JBC 269: 31680–31684
Clark J, Rocques PJ, Crew AJ, Gill S, Shipley J, Chan AM, Gusterson BA and Cooper CS (1994) Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Nat Genet 7: 502–508
Cooper CS, Park M, Blair D, Tainsky MA, Heubner K, Croce CM and Vande Woude GF (1984) Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 311: 29–33
Copeland NG, Gilbert DJ, Cho BC, Donovan PJ, Jenkins NA, Cosman D, Anderson D, Lyman SD and Williams DE (1990) Mast cell growth factor maps near the steel locus on mouse chromosome 10 and is deleted in a number of steel alleles. Cell 63: 175–183
Dei Tos AP, Wadden C, Calonie E, Sciot R, Pauwels P, Knight JC, Dal Cin P and Fletcher CDM (1995) Immunohistochemical demonstration of glycoprotein p30/32 MIC2 (CD99) in synovial sarcoma. A potential cause of diagnostic confusion. Applied Immunohist 3: 168–174
Folpe AW, Schmid RA, Champman D and Gown AM (1998) Poorly differentiated Synovial sarcoma. Immunoistochemical distinction from primitive neuroectodermal tumors and high grade malignant peripheral nerve sheath tumors. Am J Sur Pathol 22: 673–680
Fukuda T, Ichimura E, Shinozaki T, Sano T, Kashiwabara K, Oyama T, Nakajiama T and Nakamura T (1998) Coexpression of HGF and c-Met receptor in human bone and soft tissue tumors. Path Int 48: 757–762
Galli SJ, Tsai M and Wershil BK (1993) The c-Kit receptor, stem cell factor and mast cells. What each is teaching us about the others. Am J Pathol 142: 965–974
Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Tunio GM, Matsuzawa Y, Kanakura H, Shinomura Y and Kiramura Y (1998) Gain-of-function of c-Kit in human gastrointestinal stromal tumors. Science 279: 577–580
Hirota S, Okazaki T, Kitamura Y, O'Brien P, Kapusta L and Dardick I (2000) Cause of familial and multiple gastrointestinal autonomic nerve tumors with hyperplasia of interstitial cells of Cajal is germeline mutation of the c-Kit gene. Am J Surg Pathol 24: 326–327
Kawai A, Woodruff J, Healey JH, Brennan MF, Antonescu CR and Ladanyi M (1998) SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med 338: 153–160
Kindblom LG, Remotti HE, Aldenborg F and Meis-Kindblom JM (1998) Gastrointestinal pacemaker cell tumor (GIPACT). Gastrointestinal strom tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 152: 1259–1269
Kuhnen C, Tolnay E, Steinau HU, Voss B and Muller KM (1998) Expression of c-met receptor and hepatocyte growth factor/scatter factor in Synovial sarcoma and epithelioid sarcoma. Virch Arch 432: 337–342
Lasota J, Jasinski M, Darlomo-Rikala M and Miettinen M (1999) Mutation in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. Am J Pathol 154: 53–60
Leader M, Patel J, Collins M and Kristin H (1987) Synovial sarcomas. True carcinosarcomas?. Cancer 59: 2096–2098
Mancuso T, Mezzelani A, Riva C, Fabbri A, Dal Bo L, Sampietro G, Perego P, Casali P, Zunino F, Sozzi G, Pierotti MA and Pilotti S (2000) Analysis of SYT-SSX fusion trascript and bcl2 expression and phosphorylation status in synovial sarcoma. Lab Invest 80: 805–813
Mezzelani A, Sozzi G, Pierotti MA and Pilotti S (1998) Morpho-Immunophenotypic-Genotypic infidelity in synovial sarcoma. Diagn Mol Pathol 7: 232–233
Miettinen M and Virtanen I (1984) Synovial Sarcoma: a misnomer. Am J Pathol 117: 18–25
Moryama T, Kataoka H, Tsubouchi H and Koono M (1995) Concomitant expression of hepatocyte growth factor (HGF), HGF activator and c-met genes in human glioma cells in vitro. FEBS 372: 78–82
Moskaluk CA, Tian Q, Marshall CR, Rumpel CA, Franquemont DW and Frierson HF (1999) Mutations of c-Kit JM domain are found in a minority of human gastrointestinal stromal tumors. Oncogene 18: 1897–1902
Motoi T, Ishida T, Kuroda M, Horiuchi H, Oka T, Matsumoto K, Nakamura T and Machinami R (1998) Co-expression of hepatocyte growth factor and c-Met proto-oncogene product in Synovial Sarcoma. Path Int 48: 769–775
Nishida T, Hirota S, Taniguchi M, Hashimoto K, Isozaki K, Nakamura H, Kanakura H, Tanaka T, Takabayashi A, Matsuda H and Kiramura Y (1998) Familial gastrointestinal stromal tumors with germline mutations of the c-Kit gene. Nature Genetics 19: 323–324
Nocka K, Buck J, Levi E and Besmer P (1990) Candidate ligand for the c-Kit transmembrane kinase receptor. KL, a fibroblast derived growth factor stimulates mast cells and erythroid progenitors. EMBO J 9: 3287–3294
Noguera R, Navarro S, Cremades A, Rosello'-Sastre E, Pellin A, Peydro'-Olaya A and Llombardt-Bosch A (1998) Translocation (X;18) in a biphasic Synovial Sarcoma with morphologic features of neural differentiation. Diag Mol Patol 7: 16–23
Oda Y, Sakamoto A, Saito T, Kinukawa N, Iwamoto Y and Tsuneyoshi M (2000) Expression of Hepathocyte Growth factor (HGF)/scatter factor and its receptor c-Met correlates with poor prognosis in Synovial Sarcoma. Hum Pathol 31: 185–192
Qui FH, Ray P and Brown K (1987) Primary structure of c-Kit: relationship with the CSF-1/PDGF receptor kinase family-oncogenic activation v-kit involves deletion of extracellular domain and C terminus. EMBO J 7: 1003–1011
Ricotti E, Fagioli F, Garelli E, Linari C, Crescenzio N, Horenstein AL, Pistamiglio P, Vai S, Berger M, Cordero di Montezemolo L, Madon E and Basso G (1998) c-Kit is expressed in soft tissue sarcoma of neuroectodermic origin and its ligand prevents apoptosis of neoplastic cells. Blood 91: 2397–2405
Shi ZR, Itzkowitz SH and Kim YS (1988) A comparison of three immunoperoxidase techniques for antigen detection in colorectal carcinoma tissues. J Histochem Cytochem 36: 317–322
Timeus F, Crescenzio N, Valle P, Pistamiglio P, Piglione M, Garelli E, Ricotti E, Rocchi P, Strippoli PL, Cordero di Montezemolo L, Madon E, Ramenghi U and Basso G (1997) Stem cell factor suppresses apoptosis in neuroblastoma cell line. Exp Hematol 25: 1253–1260
Torihashi S, Nishi K, Tokutomi Y, Nishi T, Ward S and Sanders KM (1999) Blockade of kit signaling induces transdifferentiation of interstitial cells of Cajal to a smooth muscle phenotype. Gastroenterology 117: 140–148
Toskoz D, Zsebo KM, Smith KA, Brankow D, Suggs SV, Martin FH and Williams DA (1992) Support of human hematopoiesis in long term bone marrow cultures by murine stromal cells selectively expressing the membrane bound and secreted forms of the human homolog of the steel gene product, stem cell factor. PNAS 89: 7350
Ueda T, Aozasa K, Tsujimoto M, Yoshikawa H, Kato T, Ono K and Matsumoto K (1988) Prognostic significance of Mast cells in soft tissue sarcoma. Cancer 62: 2416–2419
van de Rijn M, Barr FG, Xiong QB, Hedges M, Shipley J and Fisher C (1999) Poorly differentiated Synovial sarcoma. An analysis of clinical, pathologic and molecular genetic features. Am J Sur Pathol 23: 106–112
Williams DE, Eisenman J, Baird A, Rauch C, Ness VK, March CJ, Park LS, Martin U, Mochizuki DY and Boswell HS (1990) Identification of a ligand for the c-Kit proto-oncogene. Cell 63: 167–174
Xie Y, Skytting B, Nilsson G, Brodin B and Larsson O (1999) Expression of insulin like growth factor 1 receptor in Synovial Sarcoma: association with an aggressive phenotype. Cancer Res 59: 3588–3591
Yarden Y, Kuang WJ and Yang-Feng T (1987) Human proto-oncogene c-Kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J 6: 3341–3351
Zhang S, Anderson DF, Bradding P, Coward WR, Baddeley SM, MacLeod JDA, McJill JI, Church MK, Holgate ST and Roche WR (1998) Human mast cells express stem cell factor. J Pathol 186: 59–66
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Tamborini, E., Papini, D., Mezzelani, A. et al. c-KIT and c-KIT ligand (SCF) in synovial sarcoma (SS): an mRNA expression analysis in 23 cases. Br J Cancer 85, 405–411 (2001). https://doi.org/10.1054/bjoc.2001.1935
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DOI: https://doi.org/10.1054/bjoc.2001.1935
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