Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2016

Open Access 01-12-2016 | Research

The TGFβ-SMAD3 pathway inhibits IL-1α induced interactions between human pancreatic stellate cells and pancreatic carcinoma cells and restricts cancer cell migration

Authors: Vegard Tjomsland, Dagny Sandnes, Ewa Pomianowska, Smiljana Torbica Cizmovic, Monica Aasrum, Ingvild Johnsen Brusevold, Thoralf Christoffersen, Ivar P. Gladhaug

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2016

Login to get access

Abstract

Background

The most abundant cells in the extensive desmoplastic stroma of pancreatic adenocarcinomas are the pancreatic stellate cells, which interact with the carcinoma cells and strongly influence the progression of the cancer. Tumor stroma interactions induced by IL-1α/IL-1R1 signaling have been shown to be involved in pancreatic cancer cell migration. TGFβ and its receptors are overexpressed in pancreatic adenocarcinomas. We aimed at exploring TGFβ and IL-1α signaling and cross-talk in the stellate cell cancer cell interactions regulating pancreatic adenocarcinoma cell migration.

Methods

Human pancreatic stellate cells were isolated from surgically resected pancreatic adenocarcinomas and cultured in the presence of TGFβ or pancreatic adenocarcinoma cell lines. The effects of TGFβ were blocked by inhibitors or amplified by silencing the endogenous inhibitor of SMAD signaling, SMAD7. Pancreatic stellate cell responses to IL-1α or to IL-1α-expressing pancreatic adenocarcinoma cells (BxPC-3) were characterized by their ability to stimulate migration of cancer cells in a 2D migration model.

Results

In pancreatic stellate cells, IL-1R1 expression was found to be down-regulated by TGFβ and blocking of TGFβ signaling re-established the expression. Endogenous inhibition of TGFβ signaling by SMAD7 was found to correlate with the levels of IL-1R1, indicating a regulatory role of SMAD7 in IL-1R1 expression. Pancreatic stellate cells cultured in the presence of IL-1α or in co-cultures with BxPC-3 cells enhanced the migration of cancer cells. This effect was blocked after treatment of the pancreatic stellate cells with TGFβ. Silencing of stellate cell expression of SMAD7 was found to suppress the levels of IL-1R1 and reduce the stimulatory effects of IL-1α, thus inhibiting the capacity of pancreatic stellate cells to induce cancer cell migration.

Conclusions

TGFβ signaling suppressed IL-1α mediated pancreatic stellate cell induced carcinoma cell migration. Depletion of SMAD7 upregulated the effects of TGFβ and reduced the expression of IL-1R1, leading to inhibition of IL-1α induced stellate cell enhancement of carcinoma cell migration. SMAD7 might represent a target for inhibition of IL-1α induced tumor stroma interactions.
Literature
1.
2.
Bliss LA, Witkowski ER, Yang CJ, Tseng JF. Outcomes in Operative Management of Pancreatic Cancer. J Surg Oncol. 2014;110:592–8.CrossRefPubMed
3.
Wang Z, Li Y, Ahmad A, Banerjee S, Azmi AS, Kong D, Sarkar FH. Pancreatic cancer: understanding and overcoming chemoresistance. Nat Rev Gastroenterol Hepatol. 2011;8:27–33.CrossRefPubMed
4.
Carrato A, Falcone A, Ducreux M, Valle JW, Parnaby A, Djazouli K, Alnwick-Allu K, Hutchings A, Palaska C, Parthenaki I. A Systematic Review of the Burden of Pancreatic Cancer in Europe: Real-World Impact on Survival, Quality of Life and Costs. J Gastrointest Cancer. 2015;46:201–11.CrossRefPubMedPubMedCentral
5.
6.
Albini A, Sporn MB. The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer. 2007;7:139–47.CrossRefPubMed
7.
Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–22.CrossRefPubMed
8.
9.
Neesse A, Algul H, Tuveson DA, Gress TM. Stromal biology and therapy in pancreatic cancer: a changing paradigm. Gut 2015;64:1476–84.
10.
11.
Apte MV, Park S, Phillips PA, Santucci N, Goldstein D, Kumar RK, Ramm GA, Buchler M, Friess H, McCarroll JA, et al. Desmoplastic reaction in pancreatic cancer - Role of pancreatic stellate cells. Pancreas. 2004;29:179–87.CrossRefPubMed
12.
13.
Tang D, Wang DR, Yuan ZX, Xue XF, Zhang Y, An Y, Chen JM, Tu M, Lu ZP, Wei JS, et al. Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma. Int J Cancer. 2013;132:993–1003.CrossRefPubMed
14.
Haqq J, Howells LM, Garcea G, Metcalfe MS, Steward WP, Dennison AR. Pancreatic stellate cells and pancreas cancer: current perspectives and future strategies. Eur J Cancer. 2014;50:2570–82.CrossRefPubMed
15.
Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25:719–34.CrossRefPubMedPubMedCentral
16.
Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, Dekleva EN, Saunders T, Becerra CP, Tattersall IW, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014;25:735–47.CrossRefPubMedPubMedCentral
17.
18.
Apte RN, Dotan S, Elkabets M, White MR, Reich E, Carmi Y, Song XP, Dvozkin T, Krelin Y, Voronov E. The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions. Cancer Metastasis Rev. 2006;25:387–408.CrossRefPubMed
19.
O’Neill LAJ. The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunol Rev. 2008;226:10–8.CrossRefPubMed
20.
Xu D, Matsuo Y, Ma J, Koide S, Ochi N, Yasuda A, Funahashi H, Okada Y, Takeyama H. Cancer cell-derived IL-1alpha promotes HGF secretion by stromal cells and enhances metastatic potential in pancreatic cancer cells. J Surg Oncol. 2010;102:469–77.CrossRefPubMed
21.
Tjomsland V, Spangeus A, Valila J, Sandstrom P, Borch K, Druid H, Falkmer S, Falkmer U, Messmer D, Larsson M. Interleukin 1alpha sustains the expression of inflammatory factors in human pancreatic cancer microenvironment by targeting cancer-associated fibroblasts. Neoplasia. 2011;13:664–75.CrossRefPubMedPubMedCentral
22.
23.
Ling J, Kang Y, Zhao R, Xia Q, Lee DF, Chang Z, Li J, Peng B, Fleming JB, Wang H, et al. KrasG12D-induced IKK2/beta/NF-kappaB activation by IL-1alpha and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21:105–20.CrossRefPubMedPubMedCentral
24.
25.
Wu MY, Hill CS. Tgf-beta superfamily signaling in embryonic development and homeostasis. Dev Cell. 2009;16:329–43.CrossRefPubMed
26.
27.
Wahl SM, Wen J, Moutsopoulos N. TGF-beta: a mobile purveyor of immune privilege. Immunol Rev. 2006;213:213–27.CrossRefPubMed
28.
29.
Bierie B, Moses HL. TGF beta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006;6:506–20.CrossRefPubMed
30.
Neuzillet C, de Gramont A, Tijeras-Raballand A, de Mestier L, Cros J, Faivre S, Raymond E. Perspectives of TGF-beta inhibition in pancreatic and hepatocellular carcinomas. Oncotarget. 2014;5:78–94.PubMed
31.
Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, Siech M, Beger H, Grunert A, Adler G. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998;115:421–32.CrossRefPubMed
32.
Pomianowska E, Sandnes D, Grzyb K, Schjolberg AR, Aasrum M, Tveteraas IH, Tjomsland V, Christoffersen T, Gladhaug IP. Inhibitory effects of prostaglandin E2 on collagen synthesis and cell proliferation in human stellate cells from pancreatic head adenocarcinoma. BMC Cancer. 2014;14:413.CrossRefPubMedPubMedCentral
33.
Ye J, Coulouris G, Zaretskaya I, Cutcutache I, Rozen S, Madden TL. Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics. 2012;13:134.CrossRefPubMedPubMedCentral
34.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(T) (−Delta Delta C) method. Methods. 2001;25:402–8.CrossRefPubMed
35.
Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9:676–82.CrossRefPubMed
36.
Liang CC, Park AY, Guan JL. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc. 2007;2:329–33.CrossRefPubMed
37.
38.
Curtis BM, Gallis B, Overell RW, McMahan CJ, DeRoos P, Ireland R, Eisenman J, Dower SK, Sims JE. T-cell interleukin 1 receptor cDNA expressed in Chinese hamster ovary cells regulates functional responses to interleukin 1. Proc Natl Acad Sci U S A. 1989;86:3045–9.CrossRefPubMedPubMedCentral
39.
Matsumura T, Hayashi H, Takii T, Thorn CF, Whitehead AS, Inoue J, Onozaki K. TGF-beta down-regulates IL-1alpha-induced TLR2 expression in murine hepatocytes. J Leukoc Biol. 2004;75:1056–61.CrossRefPubMed
40.
Barnes PJ, Chung KF, Page CP. Inflammatory mediators of asthma: an update. Pharmacol Rev. 1998;50:515–96.PubMed
41.
Matsuo Y, Sawai H, Ochi N, Yasuda A, Takahashi H, Funahashi H, Takeyama H, Guha S. Interleukin-1alpha secreted by pancreatic cancer cells promotes angiogenesis and its therapeutic implications. J Surg Res. 2009;153:274–81.CrossRefPubMed
42.
Neesse A, Michl P, Frese KK, Feig C, Cook N, Jacobetz MA, Lolkema MP, Buchholz M, Olive KP, Gress TM, Tuveson DA. Stromal biology and therapy in pancreatic cancer. Gut. 2011;60:861–8.CrossRefPubMed
43.
Hezel AF, Deshpande V, Zimmerman SM, Contino G, Alagesan B, O’Dell MR, Rivera LB, Harper J, Lonning S, Brekken RA, Bardeesy N. TGF-beta and alpha v beta 6 Integrin Act in a Common Pathway to Suppress Pancreatic Cancer Progression. Cancer Res. 2012;72:4840–5.CrossRefPubMedPubMedCentral
44.
Melisi D, Ishiyama S, Sclabas GM, Fleming JB, Xia Q, Tortora G, Abbruzzese JL, Chiao PJ. LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther. 2008;7:829–40.CrossRefPubMedPubMedCentral
45.
Friess H, Yamanaka Y, Buchler M, Ebert M, Beger HG, Gold LI, Korc M. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology. 1993;105:1846–56.CrossRefPubMed
46.
Lohr M, Schmidt C, Ringel J, Kluth M, Muller P, Nizze H, Jesnowski R. Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res. 2001;61:550–5.PubMed
47.
Satoh K, Shimosegawa T, Hirota M, Koizumi M, Toyota T. Expression of transforming growth factor beta1 (TGFbeta1) and its receptors in pancreatic duct cell carcinoma and in chronic pancreatitis. Pancreas. 1998;16:468–74.CrossRefPubMed
48.
Tjomsland V, Bojmar L, Sandstrom P, Bratthall C, Messmer D, Spangeus A, Larsson M. IL-1alpha expression in pancreatic ductal adenocarcinoma affects the tumor cell migration and is regulated by the p38MAPK signaling pathway. PLoS One. 2013;8:e70874.CrossRefPubMedPubMedCentral
49.
Melisi D, Niu J, Chang Z, Xia Q, Peng B, Ishiyama S, Evans DB, Chiao PJ. Secreted interleukin-1alpha induces a metastatic phenotype in pancreatic cancer by sustaining a constitutive activation of nuclear factor-kappaB. Mol Cancer Res. 2009;7:624–33.CrossRefPubMedPubMedCentral
50.
Niu J, Li Z, Peng B, Chiao PJ. Identification of an autoregulatory feedback pathway involving interleukin-1alpha in induction of constitutive NF-kappaB activation in pancreatic cancer cells. J Biol Chem. 2004;279:16452–62.CrossRefPubMed
51.
Dubois CM, Ruscetti FW, Palaszynski EW, Falk LA, Oppenheim JJ, Keller JR. Transforming growth factor beta is a potent inhibitor of interleukin 1 (IL-1) receptor expression: proposed mechanism of inhibition of IL-1 action. J Exp Med. 1990;172:737–44.CrossRefPubMed
52.
Kleeff J, Ishiwata T, Maruyama H, Friess H, Truong P, Buchler MW, Falb D, Korc M. The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene. 1999;18:5363–72.CrossRefPubMed
53.
Monteleone G, Kumberova A, Croft NM, McKenzie C, Steer HW, MacDonald TT. Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J Clin Invest. 2001;108:601–9.CrossRefPubMedPubMedCentral
54.
Monteleone G, Neurath MF, Ardizzone S, Di Sabatino A, Fantini MC, Castiglione F, et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease. The New England journal of medicine. 2015;372(12):1104–13.CrossRefPubMed
55.
Lee YS, Kim JH, Kim ST, Kwon JY, Hong S, Kim SJ, et al. Smad7 and Smad6 bind to discrete regions of Pellino-1 via their MH2 domains to mediate TGF-beta 1-induced negative regulation of IL-1R/TLR signaling. Biochemical and biophysical research communications. 2010;393(4):836–43.CrossRefPubMed
56.
Moynagh PN. The roles of Pellino E3 ubiquitin ligases in immunity. Nature Reviews Immunology. 2014;14(2):122–31.CrossRefPubMed
57.
Erez N, Truitt M, Olson P, Arron ST, Hanahan D. Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-kappaB-Dependent Manner. Cancer Cell. 2010;17:135–47.CrossRefPubMed
58.
Oyanagi J, Kojima N, Sato H, Higashi S, Kikuchi K, Sakai, K et al. Inhibition of transforming growth factor-beta signaling potentiates tumor cell invasion into collagen matrix induced by fibroblast-derived hepatocyte growth factor. Exp Cell Res. 2014;326(2):267–79.CrossRefPubMed
59.
60.
Metadata
Title
The TGFβ-SMAD3 pathway inhibits IL-1α induced interactions between human pancreatic stellate cells and pancreatic carcinoma cells and restricts cancer cell migration
Authors
Vegard Tjomsland
Dagny Sandnes
Ewa Pomianowska
Smiljana Torbica Cizmovic
Monica Aasrum
Ingvild Johnsen Brusevold
Thoralf Christoffersen
Ivar P. Gladhaug
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2016
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-016-0400-5

Other articles of this Issue 1/2016

Journal of Experimental & Clinical Cancer Research 1/2016 Go to the issue

Research

MicroRNA-138 functions as a tumor suppressor in osteosarcoma by targeting differentiated embryonic chondrocyte gene 2

Research

Spheres derived from the human SN12C renal cell carcinoma cell line are enriched in tumor initiating cells

Research

Hepatitis B virus X protein promotes interleukin-7 receptor expression via NF-κB and Notch1 pathway to facilitate proliferation and migration of hepatitis B virus-related hepatoma cells

Research

Interleukin-9 promotes cell survival and drug resistance in diffuse large B-cell lymphoma

Research

Topographic expression of the Hippo transducers TAZ and YAP in triple-negative breast cancer treated with neoadjuvant chemotherapy

Research

Epitelial-to-mesenchimal transition and invasion are upmodulated by tumor-expressed granzyme B and inhibited by docosahexaenoic acid in human colorectal cancer cells
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits