Skip to main content
NCBI home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2001 Mar;92(3):269–278. doi: 10.1111/j.1349-7006.2001.tb01091.x

The Autocrine Loop of Epidermal Growth Factor Receptor‐Epidermal Growth Factor/Transforming Growth Factor‐α in Malignant Rhabdoid Tumor Cell Lines: Heterogeneity of Autocrine Mechanism in TTC549

Tsutomu Narita 1, Takashi Taga 1, Kanji Sugita 2, Shinpei Nakazawa 2, Shigeru Ohta 1,✉
PMCID: PMC5926717  PMID: 11267936

Abstract

To investigate the effects of the autocrine loop of epidermal growth factor receptor (EGFR)‐epidermal growth factor (EGF)/transforming growth factor‐α (TGF‐α) on the proliferation and differentiation of malignant rhabdoid tumor (MRT), we used five MRT cell lines, TM87‐16, STM91‐01, TTC549, TTC642, and YAM‐RTK1. RT‐PCR analyses revealed expression of EGFR mRNA in all MRT cell lines. In contrast, the expression of either EGF or TGF‐α mRNA was detected in all MRT cell lines. Expression of EGF, TGF‐α, and EGFR as determined by immunocytochemical staining and in situ hybridization, correlated with the results of RT‐PCR. Upon differentiation‐induction with 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA), in TTC549, showing an expression of TGF‐α but not EGF initially, de novo expression of EGF mRNA appeared abruptly on day 2 of TPA treatment. To confirm the EGFR‐EGF/TGF‐α autocrine loop, we used TGF‐α, EGF, and their antibodies in the cultures. Monoclonal antibody (mAb) to EGFR alone significantly inhibited the growth of cell line TTC549. However, mAb to EGF or TGF‐α could inhibit proliferation of this cell line only when administrated together. Our findings would suggest that growth of the TTC549 cell line is constitutionally regulated by TGF‐α/EGFR, but that inhibition of this autocrine mechanism results in transient activation of an autocrine loop involving EGF/EGFR. Our results may indicate the presence of two different autocrine loops of EGFR‐EGF and/or EGFR‐TGF‐α in MRT cell lines. The heterogeneity of autocrine mechanisms found in MRT cell lines would be consistent with the multiphenotypic diversity and aggressive characteristics of this enigmatic tumor.

Keywords: EGF, TGF‐a, Autocrine loop, Malignant rhabdoid tumor, Apoptosis

Full Text

The Full Text of this article is available as a PDF (3.5 MB).

References

  • 1.Beckwith , J. B. and Palmer , N. F . Histopathology and prognosis of Wilm's tumor: results from the first National Wilms' Tumor study . Cancer , 41 , 1937 – 1948 ( 1978. ). [DOI] [PubMed] [Google Scholar]
  • 2.Biggs , P. J. , Garen , P. D. , Powers , J. M . and Garvin , A. J . Malignant rhabdoid tumor of the central nervous system . Hum. Pathol. , 18 , 332 – 337 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 3.Jakate , S. M. , Marsden , H. B . and Ingram , L . Primary rhabdoid tumor of brain . Virchows Arch. A Pathol. Anat. Histopathol , 412 , 393 – 397 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 4.Blatt , J. , Russo , P . and Taylor , S . Extrarenal rhabdoid sarcoma . Med. Pediatr. Oncol. , 14 , 221 – 226 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 5.Frierson , H. F. , Mills , S. E . and Inners , D. J . Malignant rhabdoid tumor of the pelvis . Cancer , 52 , 290 – 296 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 6.Schmidt , D. , Leuschner , L , Harms , D. , Sprenger , E. and Schafer , H. J . Malignant rhabdoid tumor: a morphological and flow cytometric study . Pathol. Res. Pract. , 184 , 202 – 210 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 7.Lynch , H. T. , Shurin , S. B. , Dahms , B. B. , Izant , R. J. , Lynch , J. and Danes , B. S . Paravertebral malignant rhabdoid tumor in infancy . Cancer , 52 , 290 – 296 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 8.Haas , J. E. , Palmer , N. F. , Weinberg , A. G. and Beckwith , J. B . infrastructure of malignant rhabdoid tumor of the kidney: a distinctive renal tumor of children . Hum. Pathol. , 12 , 646 – 657 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 9.Giangaspero , F. , Zanetti G. and Mancini , A . Sarcomatous variant of Wilm's tumor: a light and immunohistochemical study of four cases . Tumori , 63 , 367 – 373 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 10.Tsokos , M. , Kouraklis , G. , Chandra , R. S. , Bhagavan , B. S . and Triche , T. J . Malignant rhabdoid tumor of the kidney and soft tissues: evidence for a diverse morphological and immunocytochemical phenotype . Arch. Pathol. Lab. Med. , 113 , 115 – 120 ( 1989. ). [PubMed] [Google Scholar]
  • 11.Gonzalez‐Crussi , F. , Goldschmidt , R. A. , Hsueh , W . and Trujillo , Y. P . Infantile sarcoma with intracytoplasmic filamentous inclusions: distinctive tumor of possible histiocytic origin . Cancer , 492365 – 2375 ( 1982. ). [DOI] [PubMed] [Google Scholar]
  • 12.Bonnin , J. M. , Rubinstein , L. J. , Palmer , N. F. and Beckwith , J. B . The association of embryonal tumors originating in the kidney and in the brain: a report of seven cases . Cancer , 54 , 2137 – 2146 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 13.Parham , D. M. , Peiper , S. C . and Robicheaux , G . Malignant rhabdoid tumor of the liver: evidence for epithelial differentiation . Arch. Pathol. Lab. Med. , 112 , 61 – 64 ( 1988. ). [PubMed] [Google Scholar]
  • 14.Handgretinger , R. , Kimmig , A. , Koscielank , E. , Schmidt , D. , Rudolpha , G. , Wolburg , H. , Paulus , W. , Schilbach‐Stueckle , K. , Ottenlinger , C. , Menrad , A. , Sproll , M. , Bruchelt , G. , Dopfer , R. , Treuner , J. . and Niethammer , D.Establishment and characterization of a cell line (Wa‐2) derived from an extrarenal rhabdoid tumor . Cancer Res. , 50 , 2177 – 2182 ( 1990. ). [PubMed] [Google Scholar]
  • 15.Gansler , T. , Gerald , W. , Anderson , G. , Gramling , T. S. , Williams , C. H. , Sens , D. and Garvin , A. J . Characterization of a cell line derived from rhabdoid tumor of kidney . Hum. Pathol. , 22 , 259 – 266 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 16.Ota , S. , Crabbe , D. C. , Tran , T. N. , Triche , T. J. and Shimada , H . Malignant rhabdoid tumor: a study with two established cell lines . Cancer , 71 , 2862 – 2872 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 17.Suzuki , A. , Ohta , S. and Shimada , M . Gene expression of malignant tumor cell lines by reverse transcriptase‐poly‐merase chain reaction . Diagn. Mol. Pathol , 6326 – 332 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 18.Suardet , L. , Gross , N. , Gaide , A. C. , Beck , D . and Eliason , F . Epidermal growth factor responsiveness of a human neuroblastoma cell line . Int. J. Cancer , 44661 – 668 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 19.Hollenberg , M. D. and Cuatrecasas , P . Epidermal growth factor: receptors in human fibroblasts and modulation of action by cholera toxin . Proc. Natl. Acad. Sci. USA , 70 , 2964 – 2968 ( 1973. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Blanc , P. , Etienne , H. , Daujut , M. , Fabre , L. , Zindy , F. , Domergue , J. , Astre , C. , Aubert , B. S. , Michel , H . and Maurel , P . Mitotic responsiveness of cultured adult human hepatocytes to epidermal growth factor, transforming growth factor a, and human serum . Gastroenterology , 102 , 1340 – 1350 ( 1992. ). [PubMed] [Google Scholar]
  • 21.Stoker , M. G. P. , Pigott , D . and Taylor‐Papadimimitriou , J.Response to epidermal growth factors of cultured human mammary epithelial cells from benign tumors . Nature , 264 , 764 – 767 ( 1976. ). [DOI] [PubMed] [Google Scholar]
  • 22.Gill , G. N . and Lazar , C. S . Increased phosphotyrosine content and inhibition of proliferation in EGF‐treated A431 cells . Nature , 293 , 305 – 307 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 23.Smith , J. J. , Derynck , R. and Korc , M . Production of transforming growth factor α in human pancreatic cancer cells: evidence for a superagonist autocrine cycle . Proc. Natl. Acad. Sci. USA , 84 , 7567 – 7570 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Liu , C. , Tsao , M. . and Grisham , J. W.Transforming growth factors produced by normal and neoplastically transformed rat liver epithelial cells in culture . Cancer Res. , 48 , 850 – 855 ( 1988. ). [PubMed] [Google Scholar]
  • 25.Massgue , J . Epidermal growth factor‐like transforming growth factor. II. Interaction with epidermal growth factor receptors in human placenta membranes and A431 cells . J. Biol. Chem. , 258 , 13614 – 13620 ( 1983. ). [PubMed] [Google Scholar]
  • 26.Meyer , M. B. , Violet Shen , W. P. , Spengler , B. A. , Ciccarone , V. , O'Brain , J. P. , Donner , D. B. , Furth , M. E. and Biedler , J. L . Increased epidermal growth factor receptor in multidrug‐resistant human neuroblastoma cells . J. Cell. Biochem. , 38 , 87 – 97 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 27.Ohta , H. , Sweeney , E. A. , Masamune , A. , Yatomi , Y. , Hakomori , S . and Igarashi , Y . Induction of apoptosis by sphingosine in human leukemic HL‐60 cells: a possible endogenous modulator of apoptotic DNA fragmentation occurring during phorbol ester‐induced differentiation . Cancer Res. , 55 , 691 – 697 ( 1995. ). [PubMed] [Google Scholar]
  • 28.Zhu , W. H . and Loh , T. T . Differential effects of phorbol ester on apoptosis in HL‐60 promyelocytic leukemia cells . Biochem. Pharmacol , 51 , 1229 – 1236 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 29.Bell , L. L. , Fong , N. M. , Stempien , M. M. , Wormsted , M. A. , Caput , D. , Ku , L. L. , Urdea , M. S. , Rail , L. B . and Sanchez‐Pescador , R . Human epidermal growth factor precursor: cDNA sequence, expression in vitro and gene organization . Nucleic Acids Res. , 14 , 8427 – 8446 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Xu , Y. H. , Ishii , S. , Clark , A. J. , Sullivan , M. , Wilson , R. K. , Ma , D. P. , Roe , B. A. , Merlino , G. T . and Pastan , I.Human epidermal growth factor receptor cDNA is homologous to a variety of RNAs overproduced in A431 carcinoma cells . Nature , 309 , 806 – 810 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 31.Tokunaga , K. , Nakamura , Y. , Sakata , K. , Fujimori , K. , Ohkubo , M. , Sawada , K . and Sakiyama , S.Enhanced expression of a glyceraldehyde‐3‐phosphate dehydrogenase gene in human lung cancers . Cancer Res. , 47 , 5616 – 5619 ( 1987. ). [PubMed] [Google Scholar]
  • 32.Mahieu‐Caputo , D. , Dommergues , M. , Delezoide , A. L. , Lacoste , M. , Cai , Y. , Narcy , F. , Jolly , D. , Gonzales , M. , Dumez , Y. . and Gubler , M. C.Twin‐to‐twin transfusion syndrome. Role of the fetal renin‐angiotensin system . Am. J. PathoL , 156 , 629 – 636 ( 2000. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Fantl , W. J. , Johnson , D. E . and Williams , L. T . Signaling by receptor tyrosine kinase . Annu. Rev. Biochem. , 62 , 453 – 481 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 34.Sporn , M. B. and Roberts , A. B . Autocrine growth factors and cancer . Nature , 313 , 745 – 747 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 35.Morishige , K. , Kurachi , H. , Amemiya , K. , Adachi , H. , Inoue , M. , Miyake , A. , Tanizawa , O. and Sakoyama , Y . Involvement of transforming growth factor α/epidermal growth factor receptor autocrine growth mechanism in an ovarian cancer cell line in vitro . Cancer Res. , 51 , 5951 – 5955 ( 1991. ). [PubMed] [Google Scholar]
  • 36.Tang , P. , Steck , P. A. and Yung , W. K . The autocrine loop of TGF‐α/EGFR and brain tumors . J. Neurooncol. , 35 , 303 – 314 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 37.Takeuchi , T. , Misaki , A. , Liang , S. , Tachibana , A. , Hayashi , N. , Sonobe , H . and Ohtsuki , Y . Expression of T‐cadherin (CDH13, H‐cadherin) in human brain and its characteristics as a negative growth regulator of epidermal growth factor in neuroblastoma cells . J. Neurochem. , 74 , 1489 – 1497 ( 2000. ). [DOI] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES