title: TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: a retrospective study.
abstract: BACKGROUND
  Histological phenotype and clinical behaviour of malignant tumours are not only dependent on alterations in the epithelial cell compartment, but are affected by their interaction with inflammatory cells and tumour-associated stroma. Studies in animal models have shown influence of tumour-associated macrophages (TAM) on histological grade of differentiation in colon carcinoma. Disruption of transforming growth factor beta (TGF-beta) signalling in tumour cells is related to more aggressive clinical behaviour. Expression data of components of this pathway in tumour-associated stroma is limited.
  
  
  METHODS
  Tissue micro arrays of 310 colon carcinomas from curatively resected patients in UICC stage II and III were established. In a first step we quantified amount of CD68 positive TAMs and expression of components of TGF-beta signalling (TGF-beta1, TGF-beta receptors type 1 and 2, Smad 3 and 4) in tumour and associated stroma. Further we analyzed correlation to histological and clinical parameters (histological grade of differentiation (low-grade (i.e. grade 1 and 2) vs. high-grade (i.e. grade 3 and 4)), lymph node metastasis, distant metastasis, 5 year cancer related survival) using Chi-square or Fisher's exact test, when appropriate, to compare frequencies, Kaplan-Meier method to calculate 5-year rates of distant metastases and cancer-related survival and log rank test to compare the rates of distant metastases and survival. To identify independent prognostic factors Cox regression analysis including lymph node status and grading was performed.
  
  
  RESULTS
  High-grade tumours and those with lymph node metastases showed higher rates of TAMs and lower expression of TGF-beta1. Loss of nuclear Smad4 expression in tumor was associated with presence of lymph node metastasis, but no influence on prognosis could be demonstrated. Decrease of both TGF-beta receptors in tumour-associated stroma was associated with increased lymph node metastasis and shorter survival. Stromal TGF-beta receptor 2 expression was an independent prognostic factor for cancer related survival.
  
  
  CONCLUSIONS
  Histological phenotype and clinical behaviour of colon cancer is not only influenced by mutational incidents in tumour cells but also affected by interaction of tumour tissue with inflammatory cells like macrophages and associated stroma and TGF-beta signalling is one important part of this crosstalk. Further studies are needed to elucidate the exact mechanisms.
authors: Institute of Pathology, St, Vincentius hospital, Karlsruhe, Germany. david_bacman2@yahoo.de
authors: David
authors: D
authors: Bacman
authors: Susanne
authors: S
authors: Merkel
authors: Roland
authors: R
authors: Croner
authors: Thomas
authors: T
authors: Papadopoulos
authors: Wolfgang
authors: W
authors: Brueckl
authors: Arno
authors: A
authors: Dimmler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D012189:Retrospective Studies; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D015996:Survival Rate; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; D051901:Smad4 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II
references: Int J Gastrointest Cancer. 2002;31(1-3):47-59
references: 12622415
references: Anticancer Res. 2002 Nov-Dec;22(6C):4291-6
references: 12553072
references: Cancer J. 2003 Jul-Aug;9(4):302-12
references: 12967141
references: Nat Rev Cancer. 2004 Jan;4(1):71-8
references: 14708027
references: Dig Dis Sci. 2003 Dec;48(12):2284-9
references: 14714614
references: Anticancer Res. 2003 Nov-Dec;23(6D):5015-22
references: 14981961
references: Strahlenther Onkol. 2004 Apr;180(4):201-8
references: 15057430
references: Nat Cell Biol. 2004 Apr;6(4):366-72
references: 15104092
references: Proc Natl Acad Sci U S A. 1985 Jan;82(1):119-23
references: 3871521
references: Immunol Today. 1992 Jul;13(7):265-70
references: 1388654
references: Am J Surg. 1994 Jan;167(1):14-9; discussion 19-20
references: 8311125
references: Oncogene. 1995 Jan 5;10(1):177-84
references: 7824270
references: Cancer Epidemiol Biomarkers Prev. 1995 Jul-Aug;4(5):549-54
references: 7549813
references: Nat Genet. 1996 Jul;13(3):343-6
references: 8673134
references: Nat Genet. 1996 Jul;13(3):347-9
references: 8673135
references: J Exp Med. 1996 Apr 1;183(4):1323-9
references: 8666890
references: J Biol Chem. 1996 Jul 19;271(29):17366-71
references: 8663343
references: Cell. 1996 Aug 23;86(4):543-52
references: 8752209
references: Br J Cancer. 1996 Sep;74(5):753-8
references: 8795578
references: Cancer Res. 1996 Oct 15;56(20):4625-9
references: 8840975
references: Gastroenterology. 1996 Nov;111(5):1369-72
references: 8898652
references: Oncogene. 1997 Aug 28;15(9):1111-4
references: 9285566
references: Biochim Biophys Acta. 1997 Oct 24;1333(2):F105-50
references: 9395284
references: Annu Rev Biochem. 1998;67:753-91
references: 9759503
references: Br J Cancer. 1999 Apr;80(1-2):194-205
references: 10389996
references: Cancer Res. 2004 Nov 1;64(21):7690-6
references: 15520171
references: World J Gastroenterol. 2005 Feb 28;11(8):1193-5
references: 15754403
references: Clin Cancer Res. 2005 Apr 1;11(7):2606-11
references: 15814640
references: Cancer Res. 2005 May 15;65(10):4228-37
references: 15899814
references: J Pathol. 2005 Oct;207(2):147-55
references: 16104052
references: Curr Pharm Des. 2006;12(3):261-71
references: 16454743
references: Anticancer Res. 2006 Jan-Feb;26(1B):507-10
references: 16739311
references: Anticancer Res. 2006 Jul-Aug;26(4B):2901-7
references: 16886611
references: Am J Pathol. 2000 Oct;157(4):1105-11
references: 11021814
references: Eur J Cancer. 2001 Jan;37(2):224-33
references: 11166150
references: Lancet. 2001 Feb 17;357(9255):539-45
references: 11229684
references: J Exp Med. 2001 Mar 19;193(6):F23-6
references: 11257144
references: J Immunol. 2001 Jun 1;166(11):6483-90
references: 11359798
references: Nat Genet. 2001 Oct;29(2):117-29
references: 11586292
references: J Leukoc Biol. 2001 Oct;70(4):478-90
references: 11590184
references: Trends Cell Biol. 2001 Nov;11(11):S44-51
references: 11684442
references: J Pathol. 2002 Mar;196(3):254-65
references: 11857487
references: Trends Immunol. 2002 Nov;23(11):549-55
references: 12401408
references: J Lab Clin Med. 2002 Nov;140(5):320-8
references: 12434133
references: Nature. 2002 Dec 19-26;420(6917):860-7
references: 12490959
references: Nat Rev Immunol. 2003 Jan;3(1):23-35
references: 12511873
references: J Pathol. 2003 Jul;200(4):429-47
references: 12845611