nach oben

Erschienen in:

01.07.2010 | Original Article—Liver, Pancreas, and Biliary Tract

Expression of MSX2 predicts malignancy of branch duct intraductal papillary mucinous neoplasm of the pancreas

verfasst von: Kennichi Satoh, Shin Hamada, Atsushi Kanno, Morihisa Hirota, Jun Umino, Hiromichi Ito, Atsushi Masamune, Shinichi Egawa, Michiaki Unno, Tooru Shimosegawa

Erschienen in: Journal of Gastroenterology | Ausgabe 7/2010

Einloggen, um Zugang zu erhalten

Abstract

Background

To distinguish malignant from benign branch duct (BD)-intraductal papillary mucinous neoplasm (IPMN) still remains difficult. Recently, we revealed that MSX2 was frequently expressed in pancreatic cancer and its expression was correlated with aggressive behavior of the cancer. The aim of this study was to assess the involvement of MSX2 in IPMN development and whether its expression would differentiate malignant from benign IPMN.

Methods

Seventeen microdissected lesions and 45 IPMN tissues were used for quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. The role of MSX2 in the pancreatic duct cell was assessed by the induced expression of MSX2 in a normal human pancreatic duct epithelial cell line (HPDE).

Results

Malignant IPMN expressed significantly higher levels of MSX2 mRNA than benign IPMN lesions. MSX2 protein expression was frequently found in borderline and malignant lesions (20/29, 68.9%), while its expression was seen in only one of 16 benign IPMN tissues. Univariate analysis showed that nodules of 6 mm or more and MSX2 expression were significantly correlated with the malignancy of BD-IPMN (P = 0.022 and 0.0026, respectively), and multivariate analysis revealed that only MSX2 expression was identified as an independent factor to predict malignant BD-IPMN. HPDE cells expressing MSX2 showed increased cellular proliferation compared to control cells.

Conclusions

Based on our results, MSX2 plays a pivotal role in the development of IPMN through growth stimulation of tumor cells, and its expression was identified as an independent predictive factor for malignancy of BD-IPMN.

Loftus JEV, Olivares-Pakzad BA, Batts KP, Adkins MC, Stephens DH, Sarr MG, et al. Intraductal papillary-mucinous tumors of the pancreas: clinicopathologic features, outcome, and nomenclature. Gastroenterology. 1996;110:1909–18.CrossRefPubMed

Terris B, Ponsot P, Paye F, Hammel P, Sauvanet A, Molas G, et al. Intraductal papillary mucinous tumors of the pancreas confined to secondary ducts show less aggressive pathologic features as compared with those involving the main pancreatic duct. Am J Surg Pathol. 2000;24:1372–7.CrossRefPubMed

Hara T, Yamaguchi T, Ishihara T, Tsuyuguchi T, Kondo F, Kato K, et al. Diagnosis and patient management of intraductal papillary-mucinous tumor of the pancreas by using peroral pancreatoscopy and intraductal ultrasonography. Gastroenterology. 2002;122:34–43.CrossRefPubMed

Kobari M, Egawa S, Shibuya K, Shimamura H, Sunamura M, Takeda K, et al. Intraductal papillary mucinous tumors of the pancreas comprise 2 clinical subtypes: differences in clinical characteristics and surgical management. Arch Surg. 1999;134:1131–6.CrossRefPubMed

Doi R, Fujimoto K, Wada M, Imamura M. Surgical management of intraductal papillary mucinous tumor of the pancreas. Surgery. 2002;132:80–5.CrossRefPubMed

Matsumoto T, Aramaki M, Yada K, Hirano S, Himeno Y, Shibata K, et al. Optimal management of the branch duct type intraductal papillary mucinous neoplasms of the pancreas. J Clin Gastroenterol. 2003;36:261–5.CrossRefPubMed

Kitagawa Y, Unger TA, Taylor S, Kozarek RA, Traverso LW. Mucus is a predictor of better prognosis and survival in patients with intraductal papillary mucinous tumor of the pancreas. J Gastrointest Surg. 2003;7:12–8. discussion 18–19.CrossRefPubMed

Sugiyama M, Izumisato Y, Abe N, Masaki T, Mori T, Atomi Y. Predictive factors for malignancy in intraductal papillary-mucinous tumours of the pancreas. Br J Surg. 2003;90:1244–9.CrossRefPubMed

Satoh K, Sawai T, Shimosegawa T, Koizumi M, Yamazaki T, Mochizuki F, et al. The point mutation of c-Ki-ras at codon 12 in carcinoma of the pancreatic head region and in intraductal mucin-hypersecreting neoplasm of the pancreas. Int J Pancreatol. 1993;14:135–43.PubMed

10.

Satoh K, Shimosegawa T, Moriizumi S, Koizumi M, Toyota T. K-ras mutation and p53 protein accumulation in intraductal mucin-hypersecreting neoplasms of the pancreas. Pancreas. 1996;12:362–8.CrossRefPubMed

11.

Satoh K, Kanno A, Hamada S, Hirota M, Umino J, Masamune A, et al. Expression of Sonic hedgehog signaling pathway correlates with the tumorigenesis of intraductal papillary mucinous neoplasm of the pancreas. Oncol Rep. 2008;19:1185–90.PubMed

12.

Satoh K, Sasano H, Shimosegawa T, Koizumi M, Yamazaki T, Mochizuki F, et al. An immunohistochemical study of the c-erbB-2 oncogene product in intraductal mucin-hypersecreting neoplasms and in ductal cell carcinomas of the pancreas. Cancer. 1993;72:51–6.CrossRefPubMed

13.

Satoh K, Kaneko K, Hirota M, Masamune A, Satoh A, Shimosegawa T. Expression of survivin is correlated with cancer cell apoptosis and is involved in the development of human pancreatic duct cell tumors. Cancer. 2001;92:271–8.CrossRefPubMed

14.

Fukushige S, Furukawa T, Satoh K, Sunamura M, Kobari M, Koizumi M, et al. Loss of chromosome 18q is an early event in pancreatic ductal tumorigenesis. Cancer Res. 1998;58:4222–6.PubMed

15.

Sugiyama M, Atomi Y, Saito M. Intraductal papillary tumors of the pancreas: evaluation with endoscopic ultrasonography. Gastrointest Endosc. 1998;48:164–71.CrossRefPubMed

16.

Yasuda H, Takada T, Amano H, Yoshida M. Surgery for mucin-producing pancreatic tumor. Hepatogastroenterology. 1998;45:2009–15.PubMed

17.

Lee SY, Lee KT, Lee JK, Jeon YH, Choi D, Lim JH, et al. Long-term follow up results of intraductal papillary mucinous tumors of pancreas. J Gastroenterol Hepatol. 2005;20:1379–84.CrossRefPubMed

18.

Traverso LW. Surgical treatment of intraductal papillary mucinous neoplasms of the pancreas: the aggressive approach. J Gastrointest Surg. 2002;6:662–3.CrossRefPubMed

19.

Bernard P, Scoazec JY, Joubert M, Kahn X, Le Borgne J, Berger F, et al. Intraductal papillary-mucinous tumors of the pancreas: predictive criteria of malignancy according to pathological examination of 53 cases. Arch Surg. 2002;137:1274–8.CrossRefPubMed

20.

Irie H, Yoshimitsu K, Aibe H, Tajima T, Nishie A, Nakayama T, et al. Natural history of pancreatic intraductal papillary mucinous tumor of branch duct type: follow-up study by magnetic resonance cholangiopancreatography. J Comput Assist Tomogr. 2004;28:117–22.CrossRefPubMed

21.

Kobayashi G, Fujita N, Noda Y, Ito K, Horaguchi J, Takasawa O, et al. Mode of progression of intraductal papillary-mucinous tumor of the pancreas: analysis of patients with follow-up by EUS. J Gastroenterol. 2005;40:744–51.CrossRefPubMed

22.

Tanaka M. International consensus guidelines for the management of IPMN and MCN of the pancreas. Nippon Shokakibyo Gakkai Zasshi. 2007;104:1338–43.PubMed

23.

Pelaez-Luna M, Chari ST, Smyrk TC, Takahashi N, Clain JE, Levy MJ, et al. Do consensus indications for resection in branch duct intraductal papillary mucinous neoplasm predict malignancy? A study of 147 patients. Am J Gastroenterol. 2007;102:1759–64.CrossRefPubMed

24.

Takahashi Y, Le Douarin N. cDNA cloning of a quail homeobox gene and its expression in neural crest-derived mesenchyme and lateral plate mesoderm. Proc Natl Acad Sci USA. 1990;87:7482–6.CrossRefPubMed

25.

Davidson DR, Crawley A, Hill RE, Tickle C. Position-dependent expression of two related homeobox genes in developing vertebrate limbs. Nature. 1991;352:429–31.CrossRefPubMed

26.

Jowett AK, Vainio S, Ferguson MW, Sharpe PT, Thesleff I. Epithelial-mesenchymal interactions are required for msx 1 and msx 2 gene expression in the developing murine molar tooth. Development. 1993;117:461–70.PubMed

27.

Phippard DJ, Weber-Hall SJ, Sharpe PT, Naylor MS, Jayatalake H, Maas R, et al. Regulation of Msx-1, Msx-2, Bmp-2 and Bmp-4 during foetal and postnatal mammary gland development. Development. 1996;122:2729–37.PubMed

28.

Suzuki M, Tanaka M, Iwase T, Naito Y, Sugimura H, Kino I. Over-expression of HOX-8, the human homologue of the mouse Hox-8 homeobox gene, in human tumors. Biochem Biophys Res Commun. 1993;194:187–93.CrossRefPubMed

29.

Hamada S, Satoh K, Hirota M, Kimura K, Kanno A, Masamune A, et al. Bone morphogenetic protein 4 induces epithelial–mesenchymal transition through MSX2 induction on pancreatic cancer cell line. J Cell Physiol. 2007;213:768–74.CrossRefPubMed

30.

Satoh K, Hamada S, Kimura K, Kanno A, Hirota M, Umino J, et al. Up-regulation of MSX2 enhances the malignant phenotype and is associated with twist 1 expression in human pancreatic cancer cells. Am J Pathol. 2008;172:926–39.CrossRefPubMed

31.

Longnecker DS, Adler G, Hruban RH, Kloppel G. Intraductal papillary mucinous neoplasms of the pancreas. In: Hamilton SR, Aaltonen LA, editors. Pathology and genetics. Tumours of the digestive system. WHO classification of tumours. Lyon: IARC Press; 2000. p. 237–40.

32.

Furukawa T, Duguid WP, Rosenberg L, Viallet J, Galloway DA, Tsao MS. Long-term culture and immortalization of epithelial cells from normal adult human pancreatic ducts transfected by the E6E7 gene of human papilloma virus 16. Am J Pathol. 1996;148:1763–70.PubMed

33.

Specht K, Richter T, Muller U, Walch A, Werner M, Hofler H. Quantitative gene expression analysis in microdissected archival formalin-fixed and paraffin-embedded tumor tissue. Am J Pathol. 2001;158:419–29.PubMed

34.

Kim J, Reber HA, Hines OJ, Kazanjian KK, Tran A, Ye X, et al. The clinical significance of MAGEA3 expression in pancreatic cancer. Int J Cancer. 2006;118:2269–75.CrossRefPubMed

35.

Ohuchida K, Mizumoto K, Fujita H, Yamaguchi H, Konomi H, Nagai E, et al. Sonic hedgehog is an early developmental marker of intraductal papillary mucinous neoplasms: clinical implications of mRNA levels in pancreatic juice. J Pathol. 2006;210:42–8.CrossRefPubMed

36.

Takahashi C, Akiyama N, Matsuzaki T, Takai S, Kitayama H, Noda M. Characterization of a human MSX-2 cDNA and its fragment isolated as a transformation suppressor gene against v-Ki-ras oncogene. Oncogene. 1996;12:2137–46.PubMed

37.

Dodig M, Tadic T, Kronenberg MS, Dacic S, Liu YH, Maxson R, et al. Ectopic Msx2 overexpression inhibits and Msx2 antisense stimulates calvarial osteoblast differentiation. Dev Biol. 1999;209:298–307.CrossRefPubMed

38.

Liu YH, Tang Z, Kundu RK, Wu L, Luo W, Zhu D, et al. Msx2 gene dosage influences the number of proliferative osteogenic cells in growth centers of the developing murine skull: a possible mechanism for MSX2-mediated craniosynostosis in humans. Dev Biol. 1999;205:260–74.CrossRefPubMed

39.

Satoh K, Ginsburg E, Vonderhaar BK. Msx-1 and Msx-2 in mammary gland development. J Mammary Gland Biol Neoplasia. 2004;9:195–205.CrossRefPubMed

40.

Satoh K, Hovey RC, Malewski T, Warri A, Goldhar AS, Ginsburg E, et al. Progesterone enhances branching morphogenesis in the mouse mammary gland by increased expression of Msx2. Oncogene. 2007;26:7526–34.CrossRefPubMed

41.

Brody JR, Witkiewicz A, Williams TK, Kadkol SS, Cozzitorto J, Durkan B, et al. Reduction of pp32 expression in poorly differentiated pancreatic ductal adenocarcinomas and intraductal papillary mucinous neoplasms with moderate dysplasia. Mod Pathol. 2007;20:1238–44.CrossRefPubMed

42.

Bai J, Brody JR, Kadkol SS, Pasternack GR. Tumor suppression and potentiation by manipulation of pp32 expression. Oncogene. 2001;20:2153–60.CrossRefPubMed

43.

Biankin AV, Biankin SA, Kench JG, Morey AL, Lee CS, Head DR, et al. Aberrant p16 (INK4A) and DPC4/Smad4 expression in intraductal papillary mucinous tumours of the pancreas is associated with invasive ductal adenocarcinoma. Gut. 2002;50:861–8.CrossRefPubMed

44.

Hirooka Y, Goto H, Itoh A, Hashimoto S, Niwa K, Ishikawa H. Case of intraductal papillary mucinous tumor in which endosonography-guided fine-needle aspiration biopsy caused dissemination. J Gastroenterol Hepatol. 2003;18:1323–4.CrossRefPubMed

Titel: Expression of MSX2 predicts malignancy of branch duct intraductal papillary mucinous neoplasm of the pancreas
verfasst von: Kennichi Satoh
Shin Hamada
Atsushi Kanno
Morihisa Hirota
Jun Umino
Hiromichi Ito
Atsushi Masamune
Shinichi Egawa
Michiaki Unno
Tooru Shimosegawa
Publikationsdatum: 01.07.2010
Verlag: Springer Japan
Erschienen in: Journal of Gastroenterology / Ausgabe 7/2010
Print ISSN: 0944-1174
Elektronische ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-010-0200-1

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Echinokokkose medikamentös behandeln oder operieren?

06.05.2024 DCK 2024 Kongressbericht

Die Therapie von Echinokokkosen sollte immer in spezialisierten Zentren erfolgen. Eine symptomlose Echinokokkose kann – egal ob von Hunde- oder Fuchsbandwurm ausgelöst – konservativ erfolgen. Wenn eine Op. nötig ist, kann es sinnvoll sein, vorher Zysten zu leeren und zu desinfizieren.

Wo hapert es noch bei der Umsetzung der POMGAT-Leitlinie?

03.05.2024 DCK 2024 Kongressbericht

Seit November 2023 gibt es evidenzbasierte Empfehlungen zum perioperativen Management bei gastrointestinalen Tumoren (POMGAT) auf S3-Niveau. Vieles wird schon entsprechend der Empfehlungen durchgeführt. Wo es im Alltag noch hapert, zeigt eine Umfrage in einem Klinikverbund.

Das Risiko für Vorhofflimmern in der Bevölkerung steigt

02.05.2024 Vorhofflimmern Nachrichten

Das Risiko, im Lauf des Lebens an Vorhofflimmern zu erkranken, ist in den vergangenen 20 Jahren gestiegen: Laut dänischen Zahlen wird es drei von zehn Personen treffen. Das hat Folgen weit über die Schlaganfallgefährdung hinaus.

VHF-Ablation nützt wohl nur bei reduzierter Auswurfleistung

02.05.2024 Ablationstherapie Nachrichten

Ob die Katheterablation von Vorhofflimmern bei Patienten mit Herzinsuffizienz die Komplikationsraten senkt, scheint davon abzuhängen, ob die Auswurfleistung erhalten ist oder nicht. Das legen die Ergebnisse einer Metaanalyse nahe.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Chronische Unterbauch- und Viszeralschmerzen in der Praxis managen"

Springer Medizin

Abstract

Background

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 7/2010

Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH

Clinical usefulness of AGEs as a biomarker for the attenuation of NASH

Analysis of regulatory T cells and IgG4-positive plasma cells among patients of IgG4-related sclerosing cholangitis and autoimmune liver diseases

Reply to the letter by I. Tasci regarding ‘Clinical usefulness of AGEs as a biomarker for the attenuation of NASH’

K-ras mutation in the major duodenal papilla and gastric and colonic mucosa in patients with autoimmune pancreatitis