the role of the polyomavirus, jc virus, in the …...the role of the polyomavirus, jc virus, in the...
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The Role of the Polyomavirus, JC Virus, in the Pathogenesis
of Colorectal CancerII Falk Gastro-Conference
Dresden, GermanyOctober 12, 2007
C. Richard Boland, M.D.Baylor University Medical Center
Dallas, Texas
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Normal
5q (APC)alterations*
Adenoma
Colonic epithelium
Benignneoplasia
Advancedadenoma
Ras mutation
17p (p53)alterations*
Carcinoma
Malignantneoplasia
Larger
Fearon and Vogelstein, 1990
(* “alterations” imply both mutations and allelic losses, or CIN)
18q loss
Multistep Colorectal Carcinogenesis (1990)
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Multiple Pathways to CRC (2007)
CIN TSG’s lost by LOH: APC, p53, 18q genes
LynchSyndrome
CIMP
MSILose DNA MMR gene
methylate hMLH1
Mutations at target genes:R2, Bax, etc.
TSG’s lost by methylation:APC, PTEN, HIC-1, p16, MGMT, etc. Cancer
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Hypothesis (1994)
• Polyomaviruses encode a transforming gene (T-antigen)
• When cells are transformed (in the laboratory) with SV40 (a polyomavirus), they develop CIN and become aneuploid
• Perhaps a polyomavirus is in CRCs
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Are Viruses Involved in the Pathogenesis of Any Cancers?
• Rous sarcoma virus (chickens)• Avian leukosis virus, etc (retroviruses)• Murine leukemia viruses, etc.• Oncogenes in NIH 3T3 cells (Bishop and
Varmus)• SV40 caused cancers in rodents (1960’s)
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Are viruses involved in any human cancers?
• HPV and genital tract cancers – (possibly esophagus, nasopharyngeal, and other cancers)
• EBV and lymphomas (also gastric cancer?)• Kaposi’s sarcoma and herpes virus (HHV8)• HTLV-1 and lymphomas• Hepatitis B & C and hepatocellular carcinoma• Polyomaviruses
– SV40 and mesothelioma or lymphomas– JCV and CNS tumors
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Polyomaviruses
• All encode a potent oncogene (T antigen)• All potentially potent oncogenic viruses
– Polyomavirus (mouse)– SV40 (monkeys)– JCV (human)– BKV (human)
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Polyomavirus Structure
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JC Virus (Mad1, complete genome)
5 kbp DNA virusClosed circular genomeSupercoiledEncodes 5 genes
T Antigen3 viral capsids
VP1, VP2, VP3Agnoprotein
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Why JCV?
• Nearly all humans have antibody titers to JCV– every population studied (including Yanomami)– remains latent in most of us
• causes PML in immunosuppressed patients
• JCV has encodes a potent oncogene– T antigen
• JCV causes tumors when injected into the CNS of rodents or monkeys
• JCV is associated with “rogue” (aneuploid) lymphocytes in humans (James Neel)
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T-Antigen Has Multiple FunctionalDomains
J.S. Butel, Baylor College of Medicine
Takes out the RB protein
Takes out p53
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JCV DNA in Colorectal Tissues
Initial PCRn = 46 samples12/46 positive (26%)
With topoisomerase (TISPA)n = 54 samples48/54 positive (89%)
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JCV in CRC: Confirmatory Studies
• *Laghi et al. PNAS, 1999 (89% CRCs)• *Ricciardiello et al., Gastro, 2000 (81%, nl colon)• *Ricciardiello et al., J. Virology, 2001
(promoters)• Enam et al., Cancer Res, 2002 (83%)• Theodoropoulis et al. Dis Col Rectum, 2005
(quantitated copy number)• Hori et al., Virchows Arch, 2005 (viral proteins)• Weinreb, Virchows Arch, 2006• *Jung et al, Cancer, 2007 (adenomatous polyps)
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How Many Copies of JCV in Human Colorectal Neoplasms?
100-250147 (+50)6Normal
9-20 X 10314.0 (+3.1) x 103
15Adenomas
50-450242 (+127)35Adjacent normal
9-20 X 10314.3 (+4.2) X103
49Cancer
RANGEMEAN (SD)NTISSUE
Thoedoropoulos et al, Dis Colon & Rectum 2005
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JCV in the GI Tract (I)Upper GI Tract (71%)
• esophagus: 10/15 (67%)• gastric corpus: 9/17 (53%)• gastric antrum: 8/17 (47%)• duodenum: 10/17 (59%)
Lower GI Tract (81%)• cecum: 10/15 (67%)• transverse colon: 11/16 (69%)• sigmoid colon: 8/16 (50%)• rectum: 10/16 (63%)
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Interpretation
The GI tract is a reservoir for JCV
Suggests fecal-oral transmissionof the virus
Ricciardiello L at al. JC virus DNA sequences are frequently present in the human upper and lower gastrointestinal tract. Gastroenterology 119:1228-
1235, 2000.
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JCV and other GI Cancers
• JCV is also present in cancers of the:
– Esophagus (DelValle et al. Cancer, 2005)– Stomach (Shin et al. Cancer, 2006)– Pancreas (Fuerst et al. Gastro, 2005 (abstr.)– Lung (Zheng et al. J Pathol, 2007)
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MODEL 1: JCV T Ag in HCT116 cells
• HCT116 cells– diploid, MSI, no CIN– does not support JCV infection
• T Ag/GFP construct inserted into plasmid
• Plasmid transfected into HCT116
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JCV T Ag in HCT116 Cells
• JCV T Ag protein localizes in the nucleus
• Transfected cells develop CIN
• Control constructs (GFP only): – no CIN
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JCV TJCV T--Antigen Transfection Causes Antigen Transfection Causes CIN in HCT116 CellsCIN in HCT116 Cells
Dicentrics: A, C, F, G
Breaks: A, B, E
Fused: D, F, I
Rings: H
A B C
D E F
G H I
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CIN IN HCT116/T Ag: CIN IN HCT116/T Ag: 90 Population Doublings90 Population Doublings
Clones ChromÕs Breaks Dicentric Rings Others
C1 409 0 0 0 0
C2 401 2 1 0 0
C3 457 1 0 0 FUSION
T Ag-1 332 10 11 17 0
T Ag-2 398 14 7 17 TRICEN-TRIC (2)
T Ag-3 402 17 3 3 FUSION
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Model 2:Induction of CIN in RKO cells
A full JCV genome induces CIN in the diploid colon cell line:
RKO
Ricciardiello et al. Cancer Res 63:7256-62, 2003
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Transfection of JCV Genome into Diploid CRC cells
• Model: RKO cells– diploid, microsatellite instability (MSI)
• hypermethylated hMLH1– wild type p53, APC, β-catenin– a CIMP model
• JCV cloned into pBR322 plasmid– full length, Mad-1 inserted into plasmid– transfected into RKO
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Results: RKO transfected with JCV
• JCV integrates into RKO• T antigen expressed within 7 days
– nuclear localization of T Ag protein• VP1 expressed (late gene; viral capsid)
– low level expression• suggests viral replication
• T Ag and β-catenin interaction• p53 stabilized• CIN induced
Ricciardiello et al, Cancer Res 63:7256-62, 2003
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JCV INDUCES CIN
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Model 3:Making NMC460 cells tumorigenic
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Normal Colonic Cells:NCM460 cells
• Normal, non-transformed colonic epithelial cell lines
• Derived from the normal colon mucosa of a 68-year-old Hispanic male and selected for in vitro growth.
• Cells were not infected or transfected with any exogenous genetic information.
• Expression of colonic epithelial cell-associated antigens, such as cytokeratins and villin.
• Normal colonic physiology (Gastroenterol.1997, Am J Physiol. 1998; 2000, JBC 1997, J Clin Invest 1997)
• Wild type p53 (Cancer Gene Therapy. 2000, Gastroenterol. 2005).
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T antigen expression vector:CMV-JCV TAg
5019 of JCVRemoved TAg intronnt 4772/4426
nt 2473of JCV
20 bp AvaII-EcoRIadapter sequence
XbaI site of pVL1392 and pCR3
pCR3 pCR3
Authentic TAg polyA site
ATG5013
TAA2603
m 4274
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Stable Transfected NCM460 with T-Ag
T-Ag
p53
- + + T-Ag Transfection
Clon
e_1_
8 wk
sCl
one_
2_8
wks
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JCV T-Ag results in tumor formation in nude mice at 3 weeks
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JCV Transformed NMC460 Cells in Nude Mouse
(No tumors from cells transfected with control vector)
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JCV T Ag and β-Catenin• JCV DNA found in 83% of CRCs
– 22/27 tumors
• T Ag and agnoprotein expressed by IHC in >50% of CRCs (not viral capsid proteins)– β-catenin expression in nucleus of T Ag+ cells– T Ag not expressed in the normal colon
• T Ag and β-catenin co-immunoprecipitated
Enam et al Cancer Res 62:7093, 2002 (Khalili lab)
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β-catenin regulates proliferation
nucleus
Tcf-4
β-catTarget genes
β-cat
Wnt-1
Frizzled(Receptor)
Cell membrane
APC
GSK3β
DSH
axin
C-myc, PPARδ, cyclin D, etcExpressed (proliferation program)
β-cat
β-cat
Wnt binds receptor
β-cat
APC inhibited
increasedβ-catenin
Proliferating cells:-nuclear β-catenin-no APC
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APC regulates β-catenin
nucleus
Tcf-4 Target genes
cell-cell adhesion inhibitedWnt-1
Frizzled(Receptor)
Cell membrane
β-catAPC
GSK3β
DSH
β-cat
degradedaxin
genes repressed
α-cat
no ligand bound
x
x
Differentiated cells- APC expressed
- β-catenin degraded
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0102030405060708090
100
Normal (150) Cancer (100) Adenoma (80) Ad/Ca withLOH of APC
(30)
APC +
beta-catnuc
APC and β-catenin IHC in Normal, Sporadic/FAP Adenomas and Cancers
Nuclear stabilization of β-catenin precedes loss of APC
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Normal
5q (APC)alterations*
Adenoma
Colonic epithelium
Benignneoplasia
Advancedadenoma
Ras mutation
17p (p53)alterations*
Carcinoma
Malignantneoplasia
Larger
Fearon and Vogelstein, 1990
(* “alterations” imply both mutations and allelic losses, or CIN)
18q loss
Multistep Colorectal Carcinogenesis
β-catenin chaperoned to the nucleus by
JCV T-Ag
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JCV T antigen expression may “chaperone” β-catenin, and initiate the neoplastic phenotype
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JCV and Genomic/EpigeneticInstability in CRC
• JCV T Antigen expression occurs in about half of all CRCs with JCV DNA– CIN and CIMP inversely associated with each
other• CRCs develop as a consequence of JCV
– some permit expression of JCV genes, and develop CIN (most tumors)
– some respond to JCV with promoter methylation (CIMP)
Goel et al, Gastroenterology, 2007
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CIMP: Summary of Results
• Expression of JCV T antigen in CRC cell lines induces promoter methylation and CIMP (in vitro)
Goel, unpublished data
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SUMMARY
• Most people are infected with JCV• JCV is present in most GI cancers
– CRC, gastric, esophageal, pancreatic• T Ag can initiate a neoplastic phenotype
prior to any mutations via β-catenin • T Ag can induce CIN• JCV transfection can cause CIN• T Ag expression may induce CIMP
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Conclusions (2007)• JCV is a plausible explanation for:
– CIN– CIMP– MSI (which is caused by either CIMP or CIN)
• This is the best available explanation for how GI cancers begin in humans
• This raises the hypothesis that if one could prevent infection, one might greatly reduce the incidence of GI cancers
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Luigi Laghi, MDMilan, Italy
Initially optimizedJCV PCR, quant-itative JCV assays,etc.
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KEY RESEARCH COLLABORATORS
Luigi Ricciardiello, MDAjay Goel, PhD
Found JCV throughout gutInduced CIN in RKO cellsRearrangements in promoter
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KEY RESEARCH COLLABORATORS
Luigi Ricciardiello, MDAjay Goel, PhD
Association between JCV and CINAssociation between JCV and CIMPJCV in gastric cancerJCV in polypsMechanisms of genetic/epigenetic instability