Genetic Deletion of the Desmosomal Component Promotes Tumor Microinvasion in a Mouse Model of Pancreatic Neuroendocrine Carcinogenesis

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We used the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis to profile the transcriptome of pancreatic neuroendocrine tumors (PNET) that were either non-invasive or highly invasive, seeking to identify pro- and anti-invasive molecules. Expression of multiple components of desmosomes, structures that help maintain cellular adhesion, was significantly reduced in invasive carcinomas. Genetic deletion of one of these desmosomal components, desmoplakin, resulted in increased local tumor invasion without affecting tumor growth parameters in RT2 PNETs. Expression of cadherin 1, a component of the adherens junction adhesion complex, was maintained in these tumors despite the genetic deletion of desmoplakin. Our results demonstrate that loss of desmoplakin expression and resultant disruption of desmosomal adhesion can promote increased local tumor invasion independent of adherens junction status.

Vyšlo v časopise: Genetic Deletion of the Desmosomal Component Promotes Tumor Microinvasion in a Mouse Model of Pancreatic Neuroendocrine Carcinogenesis. PLoS Genet 6(9): e32767. doi:10.1371/journal.pgen.1001120
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001120

Souhrn

Zdroje

1. HanahanD

WeinbergRA

2000 The hallmarks of cancer. Cell 100 57 70

2. ChristoforiG

2006 New signals from the invasive front. Nature 441 444 450

3. HirohashiS

1998 Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol 153 333 339

4. HirakiA

ShinoharaM

IkebeT

NakamuraS

KuraharaS

1996 Immunohistochemical staining of desmosomal components in oral squamous cell carcinomas and its association with tumour behaviour. Br J Cancer 73 1491 1497

5. ShinoharaM

HirakiA

IkebeT

NakamuraS

KuraharaS

1998 Immunohistochemical study of desmosomes in oral squamous cell carcinoma: correlation with cytokeratin and E-cadherin staining, and with tumour behaviour. J Pathol 184 369 381

6. GarrodD

ChidgeyM

2008 Desmosome structure, composition and function. Biochim Biophys Acta 1778 572 587

7. HartsockA

NelsonWJ

2008 Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta 1778 660 669

8. PerlAK

WilgenbusP

DahlU

SembH

ChristoforiG

1998 A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392 190 193

9. VleminckxK

VakaetLJr

MareelM

FiersW

van RoyF

1991 Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66 107 119

10. HanahanD

1985 Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315 115 122

11. ChristoforiG

NaikP

HanahanD

1994 A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature 369 414 418

12. InoueM

HagerJH

FerraraN

GerberHP

HanahanD

2002 VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 1 193 202

13. OlsonP

LuJ

ZhangH

ShaiA

ChunMG

2009 MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer. Genes Dev 23 2152 2165

14. GallicanoGI

KouklisP

BauerC

YinM

VasioukhinV

1998 Desmoplakin is required early in development for assembly of desmosomes and cytoskeletal linkage. J Cell Biol 143 2009 2022

15. LopezT

HanahanD

2002 Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 1 339 353

16. JeanesA

GottardiCJ

YapAS

2008 Cadherins and cancer: how does cadherin dysfunction promote tumor progression? Oncogene 27 6920 6929

17. HerzigM

SavareseF

NovatchkovaM

SembH

ChristoforiG

2007 Tumor progression induced by the loss of E-cadherin independent of beta-catenin/Tcf-mediated Wnt signaling. Oncogene 26 2290 2298

18. VasioukhinV

BowersE

BauerC

DegensteinL

FuchsE

2001 Desmoplakin is essential in epidermal sheet formation. Nat Cell Biol 3 1076 1085

19. GuG

DubauskaiteJ

MeltonDA

2002 Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129 2447 2457

20. OffieldMF

JettonTL

LaboskyPA

RayM

SteinRW

1996 PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122 983 995

21. Gidekel FriedlanderSY

ChuGC

SnyderEL

GirniusN

DibeliusG

2009 Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16 379 389

22. BergersG

JavaherianK

LoKM

FolkmanJ

HanahanD

1999 Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284 808 812

23. BazziH

ChristianoAM

2007 Broken hearts, woolly hair, and tattered skin: when desmosomal adhesion goes awry. Curr Opin Cell Biol 19 515 520

24. ChidgeyM

DawsonC

2007 Desmosomes: a role in cancer? Br J Cancer 96 1783 1787

25. RunswickSK

O'HareMJ

JonesL

StreuliCH

GarrodDR

2001 Desmosomal adhesion regulates epithelial morphogenesis and cell positioning. Nat Cell Biol 3 823 830

26. TselepisC

ChidgeyM

NorthA

GarrodD

1998 Desmosomal adhesion inhibits invasive behavior. Proc Natl Acad Sci U S A 95 8064 8069

27. PapagerakisS

ShabanaAH

PollockBH

PapagerakisP

DepondtJ

2009 Altered desmoplakin expression at transcriptional and protein levels provides prognostic information in human oropharyngeal cancer. Hum Pathol 40 1320 1329

28. PeinadoH

OlmedaD

CanoA

2007 Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7 415 428

29. HalbleibJM

NelsonWJ

2006 Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. Genes Dev 20 3199 3214

30. LewisJE

JensenPJ

WheelockMJ

1994 Cadherin function is required for human keratinocytes to assemble desmosomes and stratify in response to calcium. J Invest Dermatol 102 870 877

31. LewisJE

WahlJKIII

SassKM

JensenPJ

JohnsonKR

1997 Cross-talk between adherens junctions and desmosomes depends on plakoglobin. J Cell Biol 136 919 934

32. NavaP

LaukoetterMG

HopkinsAM

LaurO

Gerner-SmidtK

2007 Desmoglein-2: a novel regulator of apoptosis in the intestinal epithelium. Mol Biol Cell 18 4565 4578

33. WanH

SouthAP

HartIR

2007 Increased keratinocyte proliferation initiated through downregulation of desmoplakin by RNA interference. Exp Cell Res 313 2336 2344

34. VasioukhinV

BauerC

DegensteinL

WiseB

FuchsE

2001 Hyperproliferation and defects in epithelial polarity upon conditional ablation of alpha-catenin in skin. Cell 104 605 617

35. GochevaV

ZengW

KeD

KlimstraD

ReinheckelT

2006 Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes Dev 20 543 556

36. JoyceJA

FreemanC

Meyer-MorseN

ParishCR

HanahanD

2005 A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer. Oncogene 24 4037 4051

37. GochevaV

WangHW

GadeaBB

ShreeT

HunterKE

2010 IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev 24 241 255

38. LawlorER

SoucekL

Brown-SwigartL

ShchorsK

BialuchaCU

2006 Reversible kinetic analysis of Myc targets in vivo provides novel insights into Myc-mediated tumorigenesis. Cancer Res 66 4591 4601

39. ParangiS

DietrichW

ChristoforiG

LanderES

HanahanD

1995 Tumor suppressor loci on mouse chromosomes 9 and 16 are lost at distinct stages of tumorigenesis in a transgenic model of islet cell carcinoma. Cancer Res 55 6071 6076