title: Notch and TGF-β/Smad3 pathways are involved in the interaction between cancer cells and cancer-associated fibroblasts in papillary thyroid carcinoma.
abstract: Accumulating evidence suggests that cancer-associated stromal fibroblasts (CAFs) contribute to tumor growth by actively communicating with cancer cells. Our aim was to identify the signaling pathways that are involved in tumor-stromal cell interactions in human papillary thyroid carcinoma (PTC). Immunohistochemical analyses were performed with 127 archived formalin-fixed and paraffin-embedded thyroid tissue samples that included 70 cases of PTC, 35 cases of nodular goiter (NG), and 22 cases of normal thyroid tissues. The results showed that the expression levels of Notch1, transforming growth factor β (TGF-β1), and p-Smad3 in PTC cells and α-smooth muscle actin (α-SMA) in the stroma of PTC were all significantly higher than in NG and normal thyroid tissues. Further analysis showed that in PTC, higher expression levels of Notch1 and TGF-β1 were closely related with lymph node metastasis (P < 0.05), whereas for α-SMA and p-Smad3, the percent expression increased significantly with advanced tumor stages (P < 0.05). Correlation analysis revealed that TGF-β1 expression increased with increased Notch1 and p-Smad3 levels in PTC cells (P < 0.05). Moreover, a significant correlation was found between higher TGF-β1 expression in PTC cells and increased α-SMA levels in the fibroblasts surrounding the cancer cells (P < 0.05). We identified TGF-β1 as an important factor from PTC cells that act in a paracrine manner to influence the activation of stromal fibroblasts. These data suggest that the activation of Notch and TGF-β/Smad3 pathways in cancer cells influence tumor growth. Moreover, cancer cell-derived-TGF-β ligands also affect stromal cells in a paracrine fashion and enhance tumor growth.
authors.affiliation: Department of Head and Neck Surgery, Fourth Hospital, Hebei Medical University, No 12, Jiankang Rd, Shijiazhuang, Hebei, 050011, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Shanghua
authors.initials: S
authors.lastname: Jing
mesh_terms: D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology*; D002291:Carcinoma, Papillary; D002450:Cell Communication; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D051881:Receptor, Notch1 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D051881:Receptor, Notch1; D051880:Receptors, Notch; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1
references.citation: Endocr Pathol. 2002 Fall;13(3):219-25
references.pmid: 12446921
references.citation: Cancer Microenviron. 2010 Jan 26;3(1):127-35
references.pmid: 21209779
references.citation: Curr Opin Genet Dev. 2008 Feb;18(1):27-34
references.pmid: 18282701
references.citation: Virchows Arch. 2012 Jun;460(6):587-600
references.pmid: 22527019
references.citation: J Immunol. 2008 Mar 1;180(5):2796-804
references.pmid: 18292500
references.citation: Stem Cells. 2012 Dec;30(12):2810-9
references.pmid: 23034983
references.citation: J Biol Chem. 2009 Jul 17;284(29):19452-62
references.pmid: 19473993
references.citation: Oncogene. 2008 Oct 6;27(45):5913-9
references.pmid: 18836472
references.citation: Br J Cancer. 2004 Feb 23;90(4):822-32
references.pmid: 14970860
references.citation: Cancer Lett. 2011 Apr 1;303(1):47-55
references.pmid: 21310528
references.citation: Gastroenterology. 2013 Jun;144(7):1530-1542.e12
references.pmid: 23419361
references.citation: Am J Pathol. 2000 May;156(5):1701-10
references.pmid: 10793081
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2803-8
references.pmid: 17296934
references.citation: Genes Dev. 2005 Dec 1;19(23):2783-810
references.pmid: 16322555
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Arch Pathol Lab Med. 1993 Jun;117(6):645-6
references.pmid: 8503738
references.citation: PLoS One. 2011;6(8):e23057
references.pmid: 21826227
references.citation: EMBO J. 1997 May 15;16(10):2621-33
references.pmid: 9184209
references.citation: Gastroenterology. 2008 Jun;134(7):1981-93
references.pmid: 18439605
references.citation: Am J Pathol. 2009 May;174(5):1745-55
references.pmid: 19349363
references.citation: Semin Cell Dev Biol. 2010 Feb;21(1):19-25
references.pmid: 19857592
references.citation: Genes Dev. 2004 Jan 1;18(1):99-115
references.pmid: 14701881
references.citation: FASEB J. 2004 Jun;18(9):1016-8
references.pmid: 15059978
references.citation: Blood. 2006 Mar 15;107(6):2223-33
references.pmid: 16291593
references.citation: J Cell Biol. 2003 Nov 24;163(4):723-8
references.pmid: 14638857
references.citation: Clin Cancer Res. 2011 Sep 1;17(17):5686-94
references.pmid: 21771876
references.citation: Cancer. 2001 Mar 1;91(5):964-71
references.pmid: 11251948
references.citation: Cancer Res. 2010 Dec 1;70(23):9621-30
references.pmid: 21098712
references.citation: Nature. 2004 Nov 18;432(7015):332-7
references.pmid: 15549095
references.citation: Oncol Rep. 2012 Nov;28(5):1838-44
references.pmid: 22923201
references.citation: Oncogene. 2004 Sep 23;23(44):7436-40
references.pmid: 15273715
references.citation: Breast Cancer Res Treat. 2008 Jul;110(1):39-49
references.pmid: 17674196
references.citation: Cancer Res. 1999 Oct 1;59(19):5002-11
references.pmid: 10519415
references.citation: J Biol Chem. 2008 Jul 11;283(28):19864-71
references.pmid: 18495668
references.citation: Mod Pathol. 2009 Jun;22(6):776-85
references.pmid: 19329939
references.citation: J Clin Endocrinol Metab. 2008 Oct;93(10):4080-7
references.pmid: 18664540
references.citation: Cell Oncol (Dordr). 2012 Dec;35(6):435-42
references.pmid: 23008060
references.citation: J Clin Oncol. 2004 Sep 1;22(17):3531-9
references.pmid: 15337802
references.citation: Clin Cancer Res. 2007 Apr 1;13(7):2082-90
references.pmid: 17404090
references.citation: J Clin Invest. 2005 Apr;115(4):1068-81
references.pmid: 15761501
references.citation: Clin Cancer Res. 2004 Mar 15;10(6):2035-43
references.pmid: 15041723
references.citation: Am J Surg Pathol. 2011 Nov;35(11):1615-25
references.pmid: 21997683
references.citation: Korean J Pathol. 2013 Apr;47(2):167-71
references.pmid: 23667377
references.citation: Thyroid. 2011 Dec;21(12):1323-30
references.pmid: 22066479
references.citation: J Biol Chem. 2008 Jan 18;283(3):1324-1333
references.pmid: 17981798
references.citation: Science. 1999 Apr 30;284(5415):770-6
references.pmid: 10221902
references.citation: Oncogene. 2005 Oct 6;24(44):6646-56
references.pmid: 16007166
references.citation: Am J Respir Cell Mol Biol. 2011 Jul;45(1):136-44
references.pmid: 21749980
references.citation: Nat Rev Mol Cell Biol. 2002 May;3(5):349-63
references.pmid: 11988769
references.citation: Anticancer Res. 2007 Jul-Aug;27(4C):2613-20
references.pmid: 17695423
references.citation: Br J Cancer. 2009 Oct 20;101(8):1365-73
references.pmid: 19773759
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8430-5
references.pmid: 12808151
references.citation: Cancer Res. 2005 Feb 15;65(4):1587-97
references.pmid: 15735049
references.citation: Circ Res. 2006 Jun 23;98(12):1468-70
references.pmid: 16741155
references.citation: J Biol Chem. 1997 Oct 31;272(44):27678-85
references.pmid: 9346908
references.citation: J Biol Chem. 2006 Sep 29;281(39):28555-64
references.pmid: 16867989
references.citation: Development. 2007 Aug;134(15):2709-18
references.pmid: 17611219
references.citation: World J Gastroenterol. 2009 Mar 28;15(12):1431-42
references.pmid: 19322915
references.citation: Ann Dermatol. 2013 May;25(2):135-44
references.pmid: 23717002
references.citation: Exp Mol Pathol. 2009 Dec;87(3):189-94
references.pmid: 19747910