Pancreatic Cancer Cells Invasiveness is Mainly Affected by Interleukin-1β not by Transforming Growth Factor-β1

Abstract

Background

We investigated in vitro whether IL-1β and TGF-β1 affect pancreatic cancer cell growth, adhesion to the extracellular matrix and Matrigel invasion.

Materials and methods

Adhesion to fibronectin, laminin and type I collagen, and Matrigel invasion after stimulation with saline, IL-1β and TGF-β1 were evaluated using three primary and three metastatic pancreatic cancer cell lines.

Results

Extracellular matrix adhesion of control cells varied independently of the metastatic characteristics of the studied cell lines, whereas Matrigel invasion of control cells was partly correlated with the in vivo metastatic potential. IL-1β did not influence extracellular matrix adhesion, whereas it significantly enhanced the invasiveness of three of the six cell lines. TGF-β1 affected the adhesion of one cell line, and exerted contrasting effects on Matrigel invasion of different cell lines.

Conclusions

IL-1β enhances the invasive capacity of pancreatic cancer cells, whereas TGF-β1 has paradoxical effects on pancreatic cancer cells; this makes it difficult to interfere with TGF-β1 signaling in pancreatic cancer treatment.

Keywords

Interleukin-1β Transforming growth factor-β1 Pancreatic cancer Metastasis Matrigel Extracellular matrix

References

Wells

. Tumor invasion: role of growth factor-induced cell motility. Adv Cancer Res 2000; 78: 31–101.

Keleg

, Büchler

, Ludwig

, Büchler

M.W.

, Friess

. Invasion and metastasis in pancreatic cancer. Mol Cancer 2003; 2: 14–20.

Dejana

, Bertocchi

, Bortolami

M.C.

. Interleukin 1 promotes tumor cell adhesion to cultured human endothelial cells. J Clin Invest 1988; 82: 1466–70.

Albo

, Berger

D.H.

, Tuszynski

G.P.

. The effect of thrombospondin-1 and TGF-β1 on pancreatic cancer cell invasion. J Surg Res 1998; 76: 86–90.

Stefani

A.L.

, Basso

, Panozzo

M.P.

. Cytokines modulate MIA PaCa 2 and CAPAN-1 adhesion to extracellular matrix proteins. Pancreas 1999; 19: 362–9.

Sawai

, Takeyama

, Yamamoto

. Enhancement of integrins by interleukin-1a, and their relationship with metastatic and invasive behavior of human pancreatic ductal adenocarcinoma cells. J Surg Oncol 2003; 82: 51–6.

Müerköster

, Wegehenkel

, Arlt

. Tumor stroma interactions induce chemoresistance in pancreatic ductal carcinoma cells involving increased secretion and paracrine effects of nitric oxide and interleukin-1beta. Cancer Res 2004; 64: 1331–7.

Baldwin

R.L.

, Korc

. Growth inhibition of human pancreatic carcinoma cells by transforming growth factor beta-1. Growth Factors 1993; 8: 23–34.

Friess

, Yamanaka

, Büchler

M.W.

. Enhanced expression of transforming growth factor β isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 1993; 105: 1846–56.

10.

Vidal-Vanaclocha

, Amèzaga

, Asumendi

, Kaplanski

, Dinarello

C.A.

. Interleukin-1 receptor blockade reduces the number and the size of murine B16 melanoma hepatic metastases. Cancer Res 1994; 4: 2667–72.

11.

Derynck

, Akhurst

R.J.

, Balmain

. TGF-β1 signaling in tumor suppression and cancer progression. Nature Genet 2001; 29: 117–29.

12.

Ellenrieder

, Hendler

S.F.

, Ruhland

, Boeck

, Adler

, Gress

T.M.

. TGF-β1 induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system. Int J Cancer 2001; 93: 204–11.

13.

Teraoka

, Sawada

, Yamashiti

. TGF-β1 promotes liver metastasis of pancreatic cancer by modulating the capacity of cellular invasion. Int J Oncol 2001; 19: 709–15.

14.

Wakefield

L.M.

, Roberts

A.B.

. TGF-β1 signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Develop 2002; 12: 22–9.

15.

Voronov

, Shouval

D.S.

, Krelin

. IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci USA 2003; 100: 2645–50.

16.

Matsuo

, Sawai

, Funahashi

. Enhanced angiogenesis due to inflammatory cytokines from pancreatic cancer cell lines and relation to metastatic potential. Pancreas 2004; 28: 344–52.

17.

Pepper

M.S.

. Transforming growth factor-beta: vasculogenesis, angiogenesis and vessel wall integrity. Cytokine Growth Factor Rev 1997; 8: 21–43.

18.

Massaguè

. How cells read TGF-β1 signals. Nature Rev Mol Cell Biol 2000; 1: 169–78.

19.

Simeone

D.M.

, Zhang

, Graziano

. Smad4 mediates activation of mitogen-activated protein kinase by TGF-β in pancreatic acinar cells. Am J Physiol Cell Physiol 2001; 281: C311–9.

20.

Goggins

, Shekher

, Turnacioglu

, Yeo

C.J.

, Hruban

R.H.

, Kern

S.E.

. Genetic alterations of the transforming growth factor β receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res 1998; 58: 5329–32.

21.

Schwarte-Waldhoff

, Volpert

O.V.

, Bouck

N.P.

. Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc Natl Acad Sci USA 2000; 97: 9624–9.

22.

Jonson

, Albrechtsson

, Axelson

. Altered expression of TGFB receptor and mitogenic effects of TGFB in pancreatic carcinomas. Int J Oncol 2001; 19: 71–81.

23.

Liu

. SMAD/DPC4 and pancreatic cancer survival. Clin Cancer Res 2001; 7: 3853–6.

24.

Maurice

, Pierreux

C.E.

, Howell

, Wilentz

R.E.

, Owen

M.J.

, Hill

C.S.

. Loss of smad4 function in pancreatic tumors. J Biol Chem 2001; 276: 43175–81.

25.

Jonson

, Heidenblad

, Håkansson

. Pancreatic carcinoma cell lines with SMAD4 inactivation show distinct expression responses to TGFB1. Genes Chromosomes Cancer 2003; 36: 340–52.

26.

Brooks

J.W.

, Mizel

S.B.

. Interleukin-1 signal transduction. Eur Cytokine Net 1994; 5: 547–61.

27.

Dinarello

C.A.

. The biological properties of interleukin-1. Eur Cytokine Net 1994; 5: 517–31.

28.

Sawai

, Funahashi

, Yamamoto

. Interleukin-1a enhances integrin a6β1 expression and metastatic capability of human pancreatic cancer. Oncology 2003; 65: 167–73.

29.

Zambon

C-F

, Basso

, Navaglia

. Helicobacter pylori virulence genes and host IL-1RN and IL-1β genes interplay in favouring the development of peptic ulcer and intestinal metaplasia. Cytokine 2002; 18: 242–51.

30.

Barber

M.D.

, Powell

J.J.

, Lynch

S.F.

, Fearon

K.C.

, Ross

J.A.

. A polymorphism of the interleukin-1 beta gene influences survival in pancreatic cancer. Br J Cancer 2000; 83: 1443–7.

31.

Hwang

I-R

, Kodama

, Kikuchi

. Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1β production in Helicobacter pylori infection. Gastroenterology 2002; 123: 1793–803.

32.

Albini

, Iwamoto

, Kleinman

H.K.

. A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res 1987; 47: 3239–45.

33.

Fogar

, Greco

, Basso

. Suicide gene therapy with HSV-TK in pancreatic cancer has no effect in vivo in a mouse model. Eur J Surg Oncol 2003; 29: 721–30.

34.

Sipos

, Moser

, Kalthoff

, Torok

, Lohr

, Kloppel

. A comprehensive characterization of pancreatic ductal carcinoma cell lines: towards the establishment of an in vitro research platform. Virchows Arch 2003; 442: 444–52.

35.

Fralix

K.D.

, Zhao

, Venkatasubbarao

, Freeman

J.W.

. Rap1 reverses transcriptional repression of TGF-β type II receptor by a mechanism involving AP-1 in the human pancreatic cancer cell line, UK Pan-1. J Cell Physiol 2002; 194: 88–99.

36.

Basso

, Plebani

, Fogar

. Insulin-like growth factor-I, interleukin-1 alpha and beta in pancreatic cancer: role in tumor invasiveness and associated diabetes. Int J Clin Lab Res 1995; 25: 40–3.