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Journal of Gastrointestinal Cancer

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01-06-2019 | Pancreatic Cancer | Review Article

TGF-β Inhibitors in Metastatic Pancreatic Ductal Adenocarcinoma

Authors: Marcus A. Alvarez, Júlia Pedó Freitas, S. Mazher Hussain, Evan S. Glazer

Published in: Journal of Gastrointestinal Cancer | Issue 2/2019

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancerrelated mortality in the USA, and the overall incidence of the disease is increasing such that it is expected to be the third leading cause of cancer-related deaths in the next decade. Minimal improvements in therapy have not changed the overall mortality rate over the past decade for patients with PDAC. The purpose of this review is to identify new data regardign the role of Transforming growth factor beta (TGF-β) based therapeuics in patients with PDAC.

Methods

The literature was searched for peer reviewed manuscripts regarding the use of TGF-β inhibitors in PDAC therapy and the mechanism in which TGF-β intracellular signaling effects patient survival.

Results

TGF-β plays a vital, context-dependent role as both a tumor suppressor and promoter of PDAC. The downstream effects of this duality play a significant role in the immunologic response of the tumor microenvironment (TME), epithelial-mesenchymal transformation (EMT), and the development of metastatic disease. Immunologic pathways have been shown to be successful targets in the treatment of other diseases, though they have not been shown efficacious in PDAC. TGF-β-mediated EMT does play a critical role in PDAC progression in the development of metastases. The use of anti-TGF-β-based therapies in phase I and II clinical trials for metastatic PDAC demonstrate the importance of understanding the role of TGF-β in PDAC progression.

Conclusion

This review clarifies the recent literature investigating the role of anti-TGF-β-based therapy in PDAC and areas ripe for targeted investigations and therapies.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.CrossRef

Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66(4):271–89.CrossRef

Luberice K, Downs D, Sadowitz B, Ross S, Rosemurgy A. Has survival improved following resection for pancreatic adenocarcinoma? Am J Surg. 2017;214(2):341–6.CrossRef

Huttner FJ, Fitzmaurice C, Schwarzer G, et al. Pylorus-preserving pancreaticoduodenectomy (pp Whipple) versus pancreaticoduodenectomy (classic Whipple) for surgical treatment of periampullary and pancreatic carcinoma. The Cochrane database of systematic reviews. 2016;2:Cd006053.

Gao J, Wu Y, Su Z, Amoah Barnie P, Jiao Z, Bie Q, et al. Infiltration of alternatively activated macrophages in cancer tissue is associated with MDSC and Th2 polarization in patients with esophageal cancer. PLoS One. 2014;9(8):e104453.CrossRef

Kerkar SP, Leonardi AJ, van Panhuys N, Zhang L, Yu Z, Crompton JG, et al. Collapse of the tumor stroma is triggered by IL-12 induction of Fas. Mol Ther. 2013;21(7):1369–77.CrossRef

Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211(5):781–90.CrossRef

Qi W, Huang X, Wang J. Correlation between Th17 cells and tumor microenvironment. Cell Immunol. 2013;285(1–2):18–22.CrossRef

Takeuchi Y, Nishikawa H. Roles of regulatory T cells in cancer immunity. Int Immunol. 2016;28(8):401–9.CrossRef

10.

Seo YD, Pillarisetty VG. T-cell programming in pancreatic adenocarcinoma: a review. Cancer Gene Ther. 2017;24(3):106–13.CrossRef

11.

Glazer ES, Rashid OM, Pimiento JM, Hodul PJ, Malafa MP. Increased neutrophil-to-lymphocyte ratio after neoadjuvant therapy is associated with worse survival after resection of borderline resectable pancreatic ductal adenocarcinoma. Surgery. 2016;160(5):1288–93.CrossRef

12.

Hao NB, Lu MH, Fan YH, Cao YL, Zhang ZR, Yang SM. Macrophages in tumor microenvironments and the progression of tumors. Clin Dev Immunol. 2012;2012:948098.CrossRef

13.

Pickup M, Novitskiy S, Moses HL. The roles of TGF beta in the tumour microenvironment. Nat Rev Cancer. 2013;13(11):788–99.CrossRef

14.

Hussain SM, Reed LF, Krasnick BA, Miranda-Carboni G, Fields RC, Bi Y, et al. IL23 and TGF-ss diminish macrophage associated metastasis in pancreatic carcinoma. Sci Rep. 2018;8(1):5808.CrossRef

15.

Principe DR, DeCant B, Mascarinas E, Wayne EA, Diaz AM, Akagi N, et al. TGFbeta signaling in the pancreatic tumor microenvironment promotes fibrosis and immune evasion to facilitate tumorigenesis. Cancer Res. 2016;76(9):2525–39.CrossRef

16.

Stylianou A, Gkretsi V, Stylianopoulos T. Transforming growth factor-beta modulates pancreatic cancer associated fibroblasts cell shape, stiffness and invasion. Biochim Biophys Acta. 2018;1862:1537–46.CrossRef

17.

Moir JA, Mann J, White SA. The role of pancreatic stellate cells in pancreatic cancer. Surg Oncol. 2015;24(3):232–8.CrossRef

18.

Lohr M, Schmidt C, Ringel J, et al. Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res. 2001;61(2):550–5.PubMed

19.

Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2006;20(10):1218–49.CrossRef

20.

David CJ, Huang YH, Chen M, Su J, Zou Y, Bardeesy N, et al. TGF-beta tumor suppression through a lethal EMT. Cell. 2016;164(5):1015–30.CrossRef

21.

Glazer ES, Welsh E, Pimiento JM, Teer JK, Malafa MP. TGFbeta1 overexpression is associated with improved survival and low tumor cell proliferation in patients with early-stage pancreatic ductal adenocarcinoma. Oncotarget. 2017;8(1):999–1006.CrossRef

22.

Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.CrossRef

23.

Pickup M, Novitskiy S, Moses HL. The roles of TGFbeta in the tumour microenvironment. Nat Rev Cancer. 2013;13(11):788–99.CrossRef

24.

Kubiczkova L, Sedlarikova L, Hajek R, Sevcikova S. TGF-beta - an excellent servant but a bad master. J Transl Med. 2012;10:183.CrossRef

25.

Lebrun JJ. The dual role of TGFbeta in human cancer: from tumor suppression to cancer metastasis. ISRN molecular biology. 2012;2012:381428.PubMedPubMedCentral

26.

Heldin CH, Landstrom M, Moustakas A. Mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition. Curr Opin Cell Biol. 2009;21(2):166–76.CrossRef

27.

Truty MJ, Urrutia R. Basics of TGF-beta and pancreatic cancer. Pancreatology. 2007;7(5–6):423–35.CrossRef

28.

Ikushima HM, K. TGFβ signalling: a complex web in cancer progression. Nat Rev Cancer. 2010;10:415–24.CrossRef

29.

Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113(6):685–700.CrossRef

30.

Massague J. TGF beta signalling in context. Nat Rev Mol Cell Biol. 2012;13(10):616–30.CrossRef

31.

Heldin C-H, Moustakas A. Role of Smads in TGF beta signaling. Cell Tissue Res. 2012;347(1):21–36.CrossRef

32.

Singh P, Srinivasan R, Wig JD, Radotra BD. A study of Smad4, Smad6 and Smad7 in surgically resected samples of pancreatic ductal adenocarcinoma and their correlation with clinicopathological parameters and patient survival. BMC Res Notes. 2011;4:560.CrossRef

33.

Yamada S, Fujii T, Shimoyama Y, Kanda M, Nakayama G, Sugimoto H, et al. SMAD4 expression predicts local spread and treatment failure in resected pancreatic cancer. Pancreas. 2015;44(4):660–4.CrossRef

34.

Zhao M, Mishra L, Deng CX. The role of TGF-beta/SMAD4 signaling in cancer. Int J Biol Sci. 2018;14(2):111–23.CrossRef

35.

Xia X, Wu W, Huang C, Cen G, Jiang T, Cao J, et al. SMAD4 and its role in pancreatic cancer. Tumor Biol. 2015;36:111–9.CrossRef

36.

Tanaka S. Molecular pathogenesis and targeted therapy of pancreatic cancer. Ann Surg Oncol. 2016;23(Suppl 2):S197–205.CrossRef

37.

Makohon-Moore A, Iacobuzio-Donahue CA. Pancreatic cancer biology and genetics from an evolutionary perspective. Nat Rev Cancer. 2016;16(9):553–65.CrossRef

38.

Giovannetti E, van der Borden CL, Frampton AE, Ali A, Firuzi O, Peters GJ. Never let it go: stopping key mechanisms underlying metastasis to fight pancreatic cancer. Semin Cancer Biol. 2017;44:43–59.CrossRef

39.

Ferguson MD, Dong L, Wan J, Deneve JL, Dickson PV, Behrman SW, et al. Molecular alterations associated with DNA repair in pancreatic adenocarcinoma are associated with sites of recurrence. J Gastrointest Cancer. 2018.

40.

Shugang X, Hongfa Y, Jianpeng L, Xu Z, Jingqi F, Xiangxiang L, et al. Prognostic value of SMAD4 in pancreatic cancer: A meta-analysis. Transl Oncol. 2016;9(1):1–7.CrossRef

41.

Wang G, Yu Y, Sun C, Liu T, Liang T, Zhan L, et al. STAT3 selectively interacts with Smad3 to antagonize TGF-beta. Oncogene. 2016;35(33):4388–98.CrossRef

42.

Principe DR, Doll JA, Bauer J, et al. TGF-beta: duality of function between tumor prevention and carcinogenesis. J Natl Cancer Inst. 2014;106(2):djt369.

43.

Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science. 2005;307(5715):1603–9.CrossRef

44.

Vogelmann R, Nguyen-Tat MD, Giehl K, Adler G, Wedlich D, Menke A. TGFbeta-induced downregulation of E-cadherin-based cell-cell adhesion depends on PI3-kinase and PTEN. J Cell Sci. 2005;118(20):4901–12.CrossRef

45.

Adorno M, Cordenonsi M, Montagner M, Dupont S, Wong C, Hann B, et al. A mutant p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis. Cell. 2009;137(1):87–98.CrossRef

46.

Craven KE, Gore J, Wilson JL, Korc M. Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes. Oncotarget. 2016;7(1):323–41.CrossRef

47.

Shields MA, Ebine K, Sahai V, Kumar K, Siddiqui K, Hwang RF, et al. Snail cooperates with KrasG12D to promote pancreatic fibrosis. Mol Cancer Res. 2013;11(9):1078–87.CrossRef

48.

Kim H, Choi JA, Kim JH. Ras promotes transforming growth factor-beta (TGF-beta)-induced epithelial-mesenchymal transition via a leukotriene B4 receptor-2-linked cascade in mammary epithelial cells. J Biol Chem. 2014;289(32):22151–60.CrossRef

49.

Kwak HJ, Park DW, Seo JY, Moon JY, Kim TH, Sohn JW, et al. The Wnt/beta-catenin signaling pathway regulates the development of airway remodeling in patients with asthma. Exp Mol Med. 2015;47:e198.CrossRef

50.

Chen S, Huang J, Liu Z, Liang Q, Zhang N, Jin Y. FAM83A is amplified and promotes cancer stem cell-like traits and chemoresistance in pancreatic cancer. Oncogene. 2017;6(3):e300.CrossRef

51.

Sannino G, Armbruster N, Bodenhofer M, et al. Role of BCL9L in transforming growth factor-beta (TGF-beta)-induced epithelial-to-mesenchymal-transition (EMT) and metastasis of pancreatic cancer. Oncotarget. 2016;7(45):73725–38.CrossRef

52.

Akhmetshina AP, K.; Dees, C.; Bergmann, C.; Venalis, P.; Zerr, P.; Horn, A.; Kireva, T.; Beyer, C.; Zwerina, J.; Schneider, H.; Sadowski, A.; Riener, M.; MacDougald, O. A.; Distler, O.; Schett, G.; Distler, J. H. W. Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis. Nat Commun 2012;3:1–12.

53.

Zhou BL, Y.; Kahn, M.; Ann, D. K.; Han, A.; Wang, H.; Nguyen, C.; Flodby, P.; Zhong, Q.; Krishnaveni, M. S.; Liebler, J. M.; Minoo, P.; Crandalll, E.D.; Borok, Z. Interactions between β-catenin and transforming growth factor-β signalling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP). J Biol Chem 2012;287(10):7026–7038.

54.

Shang S, Hua F, Hu ZW. The regulation of beta-catenin activity and function in cancer: therapeutic opportunities. Oncotarget. 2017;8(20):33972–89.CrossRef

55.

Valenta T, Hausmann G, Basler K. The many faces and functions of beta-catenin. EMBO J. 2012;31(12):2714–36.CrossRef

56.

Javle M, Li Y, Tan D, Dong X, Chang P, Kar S, et al. Biomarkers of TGF-beta signaling pathway and prognosis of pancreatic cancer. PLoS One. 2014;9(1):e85942.CrossRef

57.

Ikeda M, Takahashi H, Kondo S, Lahn MMF, Ogasawara K, Benhadji KA, et al. Phase 1b study of galunisertib in combination with gemcitabine in Japanese patients with metastatic or locally advanced pancreatic cancer. Cancer Chemother Pharmacol. 2017;79(6):1169–77.CrossRef

58.

Fujiwara Y, Nokihara H, Yamada Y, Yamamoto N, Sunami K, Utsumi H, et al. Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2015;76(6):1143–52.CrossRef

59.

de Gramont A, Faivre S, Raymond E. Novel TGF-beta inhibitors ready for prime time in onco-immunology. Oncoimmunology. 2017;6(1):e1257453.CrossRef

Title: TGF-β Inhibitors in Metastatic Pancreatic Ductal Adenocarcinoma
Authors: Marcus A. Alvarez
Júlia Pedó Freitas
S. Mazher Hussain
Evan S. Glazer
Publication date: 01-06-2019
Publisher: Springer US
Keywords: Pancreatic Cancer
Pancreatic Cancer
Published in: Journal of Gastrointestinal Cancer / Issue 2/2019
Print ISSN: 1941-6628
Electronic ISSN: 1941-6636
DOI: https://doi.org/10.1007/s12029-018-00195-5

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