Top

Published in:

01-03-2005

Abrogation of Transforming Growth Factor-β Signaling in Pancreatic Cancer

Authors: Xia Lin, Ph.D., Xin-Hua Feng, Ph.D.

Published in: World Journal of Surgery | Issue 3/2005

Abstract

Transforming growth factor-β (TGFβ) functions as a growth inhibitor for many cell types by inhibiting cell cycle progression. Loss of TGFβ responsiveness can lead to deregulated cell proliferation and ultimately tumor progression. For example, the TGFβ signaling pathway is a frequent target for inactivation in pancreatic cancer. Functional connection between the potent growth inhibitory activity of TGFβ and the tumor suppressor activity of Smads has been well documented. Smads directly modulate transcription of the genes involved in cell cycle progression in response to TGFβ, and that abrogation of this regulation leads to tumor progression. In this review, we summarize recent research progress on TGFβ signaling and pancreatic cancer.

Hanahan, D, Weinberg, RA 2000The hallmarks of cancerCell1005770PubMed

Hoeijmakers, J 2001Genome maintenance mechanisms for preventing cancerNature411366374CrossRefPubMed

Balmain, A, Gray, J, Ponder, B 2003The genetics and genomics of cancerNat. Genet.33 238244CrossRefPubMed

Evan, G, Vousden, K 2001Proliferation, cell cycle and apoptosis in cancerNature411342348PubMed

Brume-Jensen, P, Hunter, T 2001Oncogenic kinase signalingNature411355365CrossRefPubMed

Druker, BJ, Tamura, S, Buchdunger, E, et al. 1996Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cellsNat. Med.2561566CrossRefPubMed

McNeil, C 1998Heceptin raises its sights beyond advanced breast cancerJ. Natl. Cancer Inst.90882883CrossRefPubMed

Tamrakar, S, Rubin, E, Ludlow, JW 2000Role of pRB dephosphorylation in cell cycle regulationFront Biosci.5D121D137PubMed

Sherr, CJ, Roberts, JM 1999CDK inhibitors: positive and negative regulators of G₁-phase progressionGenes Dev.1315011512PubMed

10.

Derynck, R, Choy, L 1998Transforming growth factor-β, its receptorsIn The Cytokine Handbook3AcademicSan Diego593636

11.

Roberts, AB, Sporn, MB 1990The transforming growth factor-βRoberts, ABSporn, MB eds. Peptide Growth Factors and Their ReceptorsSpringer-VerlagBerlin

12.

Derynck, R, Feng, XH 1997TGF-β receptor signalingBiochim. Biophys. Acta1333F105F150PubMed

13.

Heldin, CH, Miyazono, K, ten Dijke, P 1997TGF-β signaling from cell membrane to nucleus through SMAD proteinsNature390465471CrossRefPubMed

14.

Derynck, R, Zhang, Y, Feng, XH 1998Smads: transcriptional activators of TGF-β responsesCell95737740CrossRefPubMed

15.

Shi, Y, Massague, J 2003Mechanisms of TGF-β signaling from cell membrane to the nucleusCell113685700CrossRefPubMed

16.

Ten Dijke, P, Miyazono, K, Heldin, CH 2000Signaling inputs converge on nuclear effectors in TGF-β signalingTrends Biochem. Sci.256470CrossRefPubMed

17.

Massagué, J, Blain, S, Lo, R 2000TGFβ signaling in growth control, cancer, and heritable disordersCell103295309CrossRefPubMed

18.

Reynisdottir, I, Massague, J 1997The subcellular locations of p15(Ink4b) and p27(Kipl) coordinate their inhibitory interactions with cdk4 and cdk2Genes Dev.11492503PubMed

19.

Laiho, M, DeCaprio, JA, Ludlow, JW, et al. 1990Growth inhibition by TGFβ linked to suppression of retinoblastoma protein phosphorylationCell62175185CrossRefPubMed

20.

Herrera, RE, Makela, TP, Weinberg, RA 1996TGFβ-induced growth inhibition in primary fibroblasts requires the retinoblastoma proteinMol Biol Cell713351342PubMed

21.

Feng, XH, Lin, X, Derynck, R 2000Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15^Ink4B transcription in response to TGF-βEMBO J.1951785193PubMed

22.

Iavarone, A, Massague, J 1997Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-β in cells lacking the CDK inhibitor p15Nature387417422CrossRefPubMed

23.

Iavarone, A, Massague, J 1999E2F and histone deacetylase mediate transforming growth factor beta repression of cdc25A during keratinocyte cell cycle arrestMol. Cell. Biol.19916922PubMed

24.

Landesman, Y, Pagano, M, Draetta, G, et al. 1992Modifications of cell cycle controlling nuclear proteins by transforming growth factor beta in the HaCaT keratinocyte cell lineOncogene716611665PubMed

25.

Geng, Y, Weinberg, RA 1993Transforming growth factor beta effects on expression of G1 cyclins and cyclin-dependent protein kinasesProc. Natl. Acad. Sci. U.S.A.901031510319PubMed

26.

Reddy, KB, Hocevar, BA, Howe, PH 1994Inhibition of G₁ phase cyclin dependent kinases by transforming growth factor β1 JCell. Biochem.56418425

27.

Barlat, I, Fesquet, D, Brechot, C, et al. 1993Loss of the G₁-S control of cyclin A expression during tumoral progression of Chinese hamster lung fibroblastsCell Growth Differ.4105113PubMed

28.

Ralph, D, McClelland, M, Welsh, J 1993RNA fingerprinting using arbitrarily primed PCR identifies differentially regulated RNAs in mink lung (My1Lu) cells growth arrested by transforming growth factor β1 ProcNatl. Acad. Sci. U.S.A.901071010714

29.

Satterwhite, DJ, Aakre, ME, Gorska, AE, et al. 1994Inhibition of cell growth by TGFβ₁ is associated with inhibition of B-myb and cyclin A in both BALB/MK and Mv1Lu cellsCell Growth Differ.5789799PubMed

30.

Feng, XH, Filvaroff, EH, Derynck, R 1995Transforming growth factor-beta (TGF-beta)-induced down-regulation of cyclin A expression requires a functional TGF-beta receptor complex: characterization of chimeric and truncated type I and type II receptorsJ Biol. Chem.2702423724245PubMed

31.

Eblen, ST, Fautsch, MP, Burnette, RJ, et al. 1994Cell cycle-dependent inhibition of p34^cdc2 synthesis by transforming growth factor β1, in cycling epithelial cellsCell Growth Differ5109116PubMed

32.

Ewen, ME, Sluss, HK, Whitehouse, LL, et al. 1993TGF-β inhibition of Cdk4 synthesis is linked to cell cycle arrestCell7410091020PubMed

33.

Koff, A, Ohtsuki, M, Polyak, K, et al. 1993Negative regulation of G₁ in mammalian cells: inhibition of cyclin E-dependent kinase by TGF-betaScience260536539PubMed

34.

Zentella, A, Weis, FM, Ralph, DA, et al. 1991Early gene responses to transforming growth factor-beta in cells lacking growth-suppressive RB functionMol. Cell. Biol.1149524958PubMed

35.

Alexandrow, MG, Kawabata, M, Aakre, M, et al. 1995Overexpression of the c-Myc oncoprotein blocks the growth-inhibitory response but is required for the mitogenic effects of transforming growth factor beta 1Proc Natl. Acad. Sci. U.S.A.9232393243PubMed

36.

Warner, BJ, Blain, SW, Seoane, J, et al. 1999Myc downregulation by transforming growth factor beta required for activation of the p15(Ink4b) G(1) arrest pathwayMol. Cell Biol.1959135922PubMed

37.

Claassen, GF, Hann, SR 2000A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor beta-induced cell-cycle arrestProc. Natl. Acad. Sci. U.S.A.9794989503PubMed

38.

Sun, P, Dong, P, Dai, K, et al. 1998p53-independent role of MDM2 in TGF-β1 resistanceScience28222702272PubMed

39.

Feng, XH, Liang, YY, Liang, M, et al. 2002Direct interaction of oncogenic c-Myc with tumor suppressors Smad2 and Smad3 to inhibit TGF-β-mediated induction of the CDK inhibitor p15^INK4BMol. Cell9133143PubMed

40.

Wang, J, Sun, L, Meyeroff, L, et al. 1995Demonstration that mutation of the type II TGF-β receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cellsJ. Biol. Chem.2702204422049PubMed

41.

Markowitz, S, Wang, J, Myeroff, L, et al. 1995Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instabilityScience26813361338PubMed

42.

Myeroff, L, Parsons, R, Kim, SJ, et al. 1995A TGF-β receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instabilityCancer Res.5555455547PubMed

43.

Sun, L, Wu, G, Willson, JKV, et al. 1994Expression of transforming growth factor b type II receptor leads to reduced malignancy in human breast. cancer MCF-7 cellsJ. Biol. Chem.2692644926455PubMed

44.

Venkatasubbara, K, Ammanamanchi, S, Brattain, MG, et al. 2001Reversion of transcriptional repression of Sp1 by 5 aza-2′ deoxycytidine restores TGF-beta type II receptor expression in the pancreatic cancer cell line MIA PaCa-2Cancer Res.6162396247PubMed

45.

Hansel, DE, Kern, SE, Hruban, RH 2003Molecular pathogenesis of pancreatic cancerAnnu. Rev. Genomics Hum. Genet.4237256PubMed

46.

Sun, L, Wu, G, Willson, JKV, et al. 1994Expression of transforming growth factor b type II receptor leads to reduced malignancy in human breast cancer MCF-7 cells,J. Biol. Chem.2692644926455PubMed

47.

Su, GH, Bansal, R, Murphy, KM, et al. 2001ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinomaProc. Natl. Acad. Sci. U.S.A.9832543257PubMed

48.

Hahn, SA, Hoque, AT, Moskaluk, CA, et al. 1996Homozygous deletion map at 18q21.1 in pancreatic cancerCancer Res.56490494PubMed

49.

Hahn, SA, Schutte, M, Hoque, AT, et al. 1996DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1Science271350353PubMed

50.

Riggins, GJ, Thiagalingam, S, Rozenblum, E, et al. 1996Mad-related genes in the humanNat. Genet.13347349CrossRefPubMed

51.

Schutte, M, Hruban, RH, Hedrick, L, et al. 1996DPC4 gene in various tumor typesCancer Res.5625272530PubMed

52.

Riggins, GJ, Kinzler, KW, Vogelstein, B, et al. 1997Frequency of Smad gene mutations in human cancersCancer Res.5725782580PubMed

53.

Thiagalingam, S, Lengauer, C, Leach, FS, et al. 1996Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancersNat. Genet.13343346CrossRefPubMed

54.

Hoque, AT, Hahn, SA, Schutte, M, et al. 1997DPC4 gene mutation in colitis associated neoplasiaGut40120122PubMed

55.

Kim, SK, Fan, Y, Papadimitrakopulou, V, et al. 1996DPC4, a candidate tumor suppressor gene, is altered infrequently in head and neck squamous carcinomaCancer Res.5625192521PubMed

56.

Nagatake, M, Takagi, Y, Osada, H, et al. 1996Somatic in vivo alterations of the DPC4 gene at 18q21 in human lung cancersCancer Res.5627182720PubMed

57.

Takakura, S, Okamoto, A, Saito, M, et al. 1999Allelic imbalance in chromosome band 18q21 and SMAD4 mutations in ovarian cancersGenes Chromosomes Cancer24264271PubMed

58.

Xu, J, Attisano, L 2000Mutations in the tumor suppressors Smad2, Smad4 inactivate transforming growth factor beta signaling by targeting Smads to the ubiquitin-proteasome pathwayProc. Natl. Acad. Sci. U.S.A.9748204825PubMed

59.

Lin, X, Liang, M, Liang, YY, et al. 2003SUMO/Ubc9 promotes nuclear accumulation and metabolic stability of tumor suppressor Smad4J. Biol. Chem.2783104331048PubMed

60.

Jen, J, Harper, J, Bigner, S, et al. 1994Deletion of p16 and p15 genes in brain tumorsCancer Res.5463536358PubMed

61.

Nobori, T, Miura, K, Wu, DJ, et al. 1994Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancersNature368753756PubMed

62.

Herman, JG, Jen, J, Merlo, A, et al. 1996Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4BCancer Res.56722727PubMed

63.

Goretzki, PE, Gorelov, V, Dotzenrath, C, et al. 1996A frequent mutation/polymorphism in tumor suppressor gene INK4B (MTS-2) in papillary and medullary thyroid cancerSurgery12010811088PubMed

64.

Suzuki, H, Zhou, X, Yin, J, et al. 1995Intragenic mutations of CDKN2B and CDKN2A in preprimary human esophageal cancersHum. Mol. Genet.418831887PubMed

65.

Naumann, M, Savitskaia, N, Eilert, C, et al. 1996Frequent codeletion of p16/MTS1 and p15/MTS2 and genetic alterations in p16/MTS1 in pancreatic tumorsGastroenterology1012151224

66.

Villanueva, A, Garcia, C, Paules, AB, et al. 1998Disruption of the antiproliferative TGF-β signaling pathways in human pancreatic cancer cellsOncogene1719691978PubMed

67.

Washimi, O, Nagatake, M, Osada, H, et al. 1995In vivo occurrence of p16 (MTS1) and p15 (MTS2) alterations preferentially in non-small cell lung cancersCancer Res.55514517PubMed

68.

Batova, A, Diccianni, MB, Yu, JC, et al. 1997Frequent and selective methylation of p15 and deletion of both p15 and p16 in T-cell acute lymphoblastic leukemiaCancer Res.57832836PubMed

69.

Nakashima, R, Fujita, M, Enomoto, T, et al. 1999Alteration of p16 and p15 genes in human uterine tumoursBr. J. Cancer80458467PubMed

70.

Xing, EP, Nie, Y, Song, Y, et al. 1999Mechanisms of inactivation of p14ARF, p15INK4b, and p16INK4a genes in human esophageal squamous cell carcinomaClin. Cancer Res.527042713PubMed

Title: Abrogation of Transforming Growth Factor-β Signaling in Pancreatic Cancer
Authors: Xia Lin, Ph.D.
Xin-Hua Feng, Ph.D.
Publication date: 01-03-2005
Publisher: Springer-Verlag
Published in: World Journal of Surgery / Issue 3/2005
Print ISSN: 0364-2313
Electronic ISSN: 1432-2323
DOI: https://doi.org/10.1007/s00268-004-7824-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abrogation of Transforming Growth Factor-β Signaling in Pancreatic Cancer

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2005

Second Molecular Surgeon Symposium on Pancreatic Cancer and Other Cancers: An Introduction

Tissue MicroArray Analyses of Pancreatic Duodenal Homeobox-1 in Human Cancers

Intraoperative Ultrasound-Guided Excision of Nonpalpable Breast Lesions

Role of Gastrointestinal Hormones in Neuroblastoma

Repeat Pulmonary Resection for Isolated Recurrent Lung Metastases Yields Results Comparable to Those after First Pulmonary Resection in Colorectal Cancer

Evaluation of Blood Flow by Color Doppler Sonography in Free Jejunal Interposition Grafts for Cervical Esophageal Reconstruction