Sporadic vs. Colitis Sporadic vs. Colitis - - Associated Colon Associated Colon Cancer: Vive la difference! Cancer: Vive la difference! Steven H. Itzkowitz, M.D. Steven H. Itzkowitz, M.D. The Dr. The Dr. Burrill Burrill B. B. Crohn Crohn Professor of Medicine Professor of Medicine Mount Sinai School of Medicine Mount Sinai School of Medicine New York City, N.Y. New York City, N.Y.
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Sporadic vs. Colitis-Associated Colon Cancer: Vive la ... · Sporadic vs. Colitis-Associated Colon Cancer: ... Control UC CD Ca Ca distant mucosa ... in Crohn's disease and colon
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Sporadic vs. ColitisSporadic vs. Colitis--Associated Colon Associated Colon Cancer: Vive la difference!Cancer: Vive la difference!
Steven H. Itzkowitz, M.D.Steven H. Itzkowitz, M.D.The Dr. The Dr. BurrillBurrill B. B. CrohnCrohn Professor of MedicineProfessor of Medicine
Mount Sinai School of MedicineMount Sinai School of MedicineNew York City, N.Y.New York City, N.Y.
ConclusionConclusionThere There mustmust be a difference between SCC and be a difference between SCC and CAC. CAC. Otherwise, many of us would not get research Otherwise, many of us would not get research funding!funding!
Risk of Developing Colorectal CancerRisk of Developing Colorectal Cancer
0 20 40 60 80 100
General General poppop’’nn
Personal Personal hxhx of of adenoma/CRCadenoma/CRC
•• Arises directly from LGD.Arises directly from LGD.•• Accounts for 11% of IBDAccounts for 11% of IBD--associated CRC.associated CRC.•• WellWell--differentiated differentiated adenocarcinomaadenocarcinoma with with
Levi and Levi and HarpazHarpaz, , Am J Am J Surg PatholSurg Pathol 2006, in press2006, in press
Does Inflammation Cause CRC in IBD?Does Inflammation Cause CRC in IBD?Evidence Evidence ““ForFor””
CRC risk is increased with:CRC risk is increased with:•• longer duration of colitis (>7 yrs)longer duration of colitis (>7 yrs)•• greater extent of colitis greater extent of colitis
CpGCpG Island Island MethylationMethylation (CIMP)(CIMP)••Suppression of gene expression by promoter Suppression of gene expression by promoter hypermethylationhypermethylation••Target genes: hMLH1, MGMT, othersTarget genes: hMLH1, MGMT, others
2525--30%30%
Ahnen 2000
Although the biology of UC-associated dysplasia (p53 lesions early, APC late)and sporadic adenomas differ, the biology of UC-associated cancer and sporadic cancer are remarkably similar
COLITISCOLITIS--ASSOCIATED COLON CANCERASSOCIATED COLON CANCER
APCp53 mut.
DCC/DPC4DCC/DPC4
DCC/DPC4DCC/DPC4
Itzkowitz and Yio, Am J Physiol. 287:G7-17, 2004
p53p53 p53p53DiagnosisDiagnosis No.No. MutatedMutated** AneuploidAneuploid LOHLOHCancerCancer 66 83%83% 83%83% 83%83%DysplasiaDysplasia 5656 48%48% 46%46% 44%44%IndefiniteIndefinite 9696 3%3% 15%15% 00NegativeNegative 5757 29%29% 5%5% 00------------------------------------------------------------------------------------------------------------------------------------------------------*based on *based on colectomycolectomy material from 2 patients with mutations of material from 2 patients with mutations of p53 p53
RedstonRedston et al. et al. GastroenterologyGastroenterology 108:383, 1995108:383, 1995Meltzer et al. Meltzer et al. Cancer ResCancer Res. 50:3627, 1990. 50:3627, 1990BurmerBurmer et al. et al. GastroenterologyGastroenterology 99:416, 199099:416, 1990Chen et al. Chen et al. GastroenterologyGastroenterology 102:1983, 1992102:1983, 1992Bell et al. Bell et al. Br J CancerBr J Cancer 64:174, 199164:174, 1991
KK--rasras mutations occurmutations occur late in UC late in UC neoplasmsneoplasms
Genetic/epigenetic changes:• p53 mutation/activation• damage/mutation of DNA MMR system• methylation of regulatory genes• telomere shortening
Itzkowitz and Yio, Am J Physiol. 287:G7-17, 2004
•• 50% of 50% of bxbx’’eses from inflamed UC tissues exhibited:from inflamed UC tissues exhibited:•• GG--toto--A transition at A transition at codoncodon 248 (C248 (CGGGG-->C>CAAG)G)•• CC--toto--T transition at T transition at codoncodon 247 (AA247 (AACC-->AA>AATT))
•• Only found in UC tissues, not normal controlsOnly found in UC tissues, not normal controls•• In UC tissues, only in In UC tissues, only in ““lesionallesional”” biopsiesbiopsies•• Correlated with NOS2 activity Correlated with NOS2 activity
Chronic inflammation can induce p53 mutationsChronic inflammation can induce p53 mutations
p53 Mutations in Nonp53 Mutations in Non--NeoplasticNeoplastic UC UC TissuesTissues
HussainHussain et al. et al. Cancer Res.Cancer Res. 60:333360:3333--7, 20007, 2000
MSH6MSH6
basebase--basebasemismatchmismatch
DNA Mismatch RepairDNA Mismatch Repair
1 base 1 base insertion/deletioninsertion/deletionlooploop
22--8 base 8 base insertion/deletion insertion/deletion looploop
MSH2MSH2MSH3MSH3
MSH2MSH2
MLH1MLH1 PMS2PMS2 MLH1MLH1 PMS2PMS2
MLH1MLH1 MLH3MLH3
MLH1MLH1 PMS1PMS1
MSH6MSH6
basebase--basebasemismatchmismatch
DNA Mismatch RepairDNA Mismatch Repair
1 base 1 base insertion/deletioninsertion/deletionlooploop
22--8 base 8 base insertion/deletion insertion/deletion looploop
MSH2MSH2MSH3MSH3
MSH2MSH2
MLH1MLH1 PMS2PMS2 MLH1MLH1 PMS2PMS2
MLH1MLH1 MLH3MLH3
MLH1MLH1 PMS1PMS1HH22OO22
HH22OO22
Inflammation Predisposes to Colon Cancer:Inflammation Predisposes to Colon Cancer:In VivoIn Vivo Evidence from Animal ModelsEvidence from Animal Models
Three main approaches:Three main approaches:1. 1. Normal miceNormal mice: :
Induce colitis with noxious agent and monitor for Induce colitis with noxious agent and monitor for development of development of neoplasianeoplasia..
2. 2. Cancer prone mice:Cancer prone mice:–– Induce colitis and monitor for higher rates of Induce colitis and monitor for higher rates of neoplasianeoplasia
--oror--–– Reduce colitis and monitor for lower rates of Reduce colitis and monitor for lower rates of neoplasianeoplasia
•• DysplasiaDysplasia and cancer can be induced after repeated cycles and cancer can be induced after repeated cycles of of dextrandextran sulfate sodium (DSS)sulfate sodium (DSS)
•• Longer disease duration Longer disease duration ----> increased rate of > increased rate of neoplasianeoplasia, , even in the setting clinical remissioneven in the setting clinical remission
•• NeoplasiaNeoplasia associated with more severe degrees of associated with more severe degrees of inflammation, especially in the distal colon.inflammation, especially in the distal colon.
•• Treatment with antioxidant (NTreatment with antioxidant (N--acetylcysteineacetylcysteine) reduced both ) reduced both inflammation and tumor incidenceinflammation and tumor incidence
Cooper et al. Carcinogenesis 21:757, 2000Seril et al. Carcinogenesis 23:993, 2002
Culture of mucosa-associated bacteria in IBD and colon cancer
Martin et al, Gastroenterology 2004 127(1):80-93
0
10
20
30
40
50
60
% h
aem
aggl
utin
atio
n
Control UC CD Ca Cadistant mucosa
NS <0.02 <0.0001
<0.01
Increased haemagglutinating activity by mucosa-associated E. coliin Crohn's disease and colon cancer correlates with their ability to adhere to and invade intestinal epithelial cells
Martin et al Gastroenterology 2004;127:80-930
200000
400000
600000
800000
1000000
1200000
Attachment Invasion
num
ber o
f bac
teria
per
wel
l Agglutinating E. coliNon-agglutinating E. coli
Inflammation
Unesterified arachidonicacid
Mucosal apoptosisCancer
Common mechanisms for IBD-associated and sporadic colon cancer
Adapted from Rhodes & Campbell Trends Molecular Med 2002
SummarySummary•• There are more There are more clinicopathologicclinicopathologic and molecular and molecular
differences between SCC and CAC than there differences between SCC and CAC than there are similaritiesare similarities
•• This appears to be due to chronic inflammationThis appears to be due to chronic inflammation•• Whether bacteria play a role in Whether bacteria play a role in humanhuman colitiscolitis--
associated associated neoplasianeoplasia (or perhaps even sporadic (or perhaps even sporadic CRC) requires further investigation. CRC) requires further investigation.
SummarySummary--Human Observations Human Observations •• IBD patients are at increased risk for CRC.IBD patients are at increased risk for CRC.•• The risk of CRC rises with increased duration, The risk of CRC rises with increased duration,
extent, and severity of inflammation, and with extent, and severity of inflammation, and with associated PSC.associated PSC.
•• Use of certain antiUse of certain anti--inflammatory medications inflammatory medications (5(5--ASA, steroids) may reduce the ASA, steroids) may reduce the development of CRC in IBD.development of CRC in IBD.
•• Oxidative stress causes genomic instability Oxidative stress causes genomic instability leadingleading to the development of to the development of dysplasiadysplasia. .
•• Molecular markers may help to identify Molecular markers may help to identify patients at increased risk of CRC.patients at increased risk of CRC.