The Race from Chronic Pancreatitis to Pancreatic

Giulia Martina Cavestro1, Giuseppe Comparato1, Antonio Nouvenne1, Mario Sianesi2,
Francesco Di Mario1
1Department of Clinical Science, Chair of Gastroenterology; 2Department of Surgical Science,
General Surgery and Organ Transplantation; University of Parma. Parma, Italy
The latest data on pancreatic cancer
epidemiology were published in 2002 by the
American National Cancer Institute. It was
confirmed as the 5th leading cause of death
from cancer, causing more than 24,000 deaths
each year. The fact that nearly all patients die
from the disease within one year from the
diagnosis was also confirmed, similarly to 15
years ago [1, 2].
A number of studies focused on risk factors;
the incidence seems to be higher among men
than among women. It also seems higher in
the black population rather than in the white
population. Furthermore, environmental
factors are also associated with the disease:
cigarette smoking, meat consumption and low
consumption of vegetables. Moreover, the
relationship between chronic pancreatitis and
genetics in the development of pancreatic
cancer was analyzed [3, 4, 5, 6, 7].
Two main studies focused on the association
of chronic pancreatitis with pancreatic cancer.
The first one, from the International
Pancreatitis Study Group, was a large
multicenter historical cohort study which
assessed the significantly increased risk of
pancreatic cancer in subjects with chronic
pancreatitis; the association appeared to be
independent of sex, nationality and type of
pancreatitis [8]. Two years later, Bansal and
Sonnenberg confirmed these findings in a
retrospective study of data taken from the
records of the American Department of
Veterans Affairs from 1970 to 1994 regarding
diagnoses at discharge [9].
A number of studies also confirmed the
association of chronic pancreatitis with
pancreatic cancer [10, 11, 12, 13, 14, 15];
moreover, genetic changes in the
development of pancreatic cancer were also
analyzed [16, 17, 18, 19, 20, 21] even if only
a few studies focused on the role of
inflammation “per se”, despite genetic
mutations [22, 23].
The way human cancers result from a
multistep pathogenesis associated with the
progressive accumulation of mutations in
proto-oncogenes and tumor-suppressor genes
is well-known. This mechanism accounts for
the occurrence of dysplastic lesions before
cancer development. Types of genetic
aberration include mutations in coding or
regulatory sequences, changes in ploidy and
in genome copy number, amplification,
structural rearrangement, homozygous
deletion as well as loss of heterozygosity.
This mechanism is also thought to be
applicable to pancreatic cancer development.
K-ras mutations are found in a majority of
pancreatic carcinomas such as loss of
DPC4/Smad and p53 [16, 17, 18, 19, 20, 21].
What appears to be largely unclear at present
is the relationship between the early and the
late stages of tumor development as well as
the role of genetic instability in cancer
progression. Indeed, the same genetic
alterations can be detected in tissue from both
chronic pancreatitis and pancreatic cancer
[18, 19]. This common finding uncovered a
possible role for cellular environment that

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JOP. Journal of the Pancreas – – Vol. 4, No. 5 – September 2003
restrains or promotes the emergence of
pancreatic cancer is a neoplasia described as a
pathological imbalance of tissue-cell
interactions. As a matter of fact, changes in
the behavior of stromal cells from individuals
with cancer and epithelial/stromal interactions
have been shown to influence tumor
progression [22].
Chronic pancreatitis is characterized by
irreversible morphological and functional
alterations: inflammation and healing occur
simultaneously producing fibrosis.
Cross-talk between mesenchyme and
epithelium has been described as a known
driver of differentiation and development
[24]. The pathogenesis and the progression of
chronic pancreatitis are determined from the
profile of cytokines persisting in pancreatic
tissue: TNF-alpha, IL-6, IL-8, PDGF, TGF-
beta. Interestingly, the same pattern of
chemokines is found to be increased in
pancreatic cancer [23]. Monocytes, which
differentiate into macrophages in tissue,
represent one of the first recruited effectors of
the acute inflammatory response. Once
activated, macrophages are claimed to be the
main source of growth factors and cytokines,
which deeply affect endothelial, epithelial and
mesenchymal cells in the local
microenvironment [25]. Of note, pancreatic
cancer is usually characterized by a
macrophages being widely represented on
histological specimens from pancreatic cancer
A cascade of chemokines is largely secreted
from inflammatory cells, representing being
one of the ways in which inflammation acts as
a tumor promoter [26].
Chronic pancreatitis is characterized by over-
production of IL-1, IL-8, EGF, IGF-1, TGF-
β1 leading to a stimulatory effect on both
angiogenesis and cellular proliferation.
Moreover, chronic inflammation of the
pancreas is also characterized by production
of both IL-6, which shifts myeloid precursors
towards a macrophage-like phenotype and
TGF-alpha which promotes progressive
fibrosis [23]. TNF-alpha is secreted from
macrophages and, despite the name, plays an
important role in early events in chronic
inflammation and cancer. Furthermore, it
upregulates both PDGF causing a worsening
of pancreatic fibrogenesis and IL-8 enhancing
tumorigenic and metastatic effects of human
pancreatic cancer cells. One of the biological
effects of TNF-alpha is the inhibition of
apoptosis of pancreatic cancer cells [24, 25].
This mechanism was described to be
mediated through the activation of the
transcription factor NF-kappaB, which is
constitutively expressed on pancreatic
epithelial cells during chronic pancreatitis and
cancer. Activation of NF-kappaB may play a
central role in the initiation of the relapsing
inflammatory process by controlling the
transcription of inflammatory genes [27, 28].
The main function of NF-kappaB appears to
be transcriptional gene regulation as a
transactivating factor; binding of NF-kappaB
to specific DNA sequences located in gene
promoter regions is a pivotal event in the
regulation of transcriptional events by the
factor [28]. Furthermore, up-regulation of NF-
kappaB also causes an inhibition of apoptosis
and stimulation of the inducible form of nitric
oxide (iNOS) and cyclooxygenase-2 (COX-
2), both well known key mediators of the
inflammatory process [29].
Just like NF-kappaB, also COX-2 expression
was found to be increased during chronic
pancreatitis and pancreatic cancer, in
comparison to normal tissue [23, 30, 31, 32].
It is well-known that COX-2 is involved in
colorectal cancer converting arachidonic acid
to prostaglandins, which, in turn, induce
inflammatory reactions in damaged tissues
[29]. Moreover COX-2 converts chemical
carcinogens to mutagenic derivatives; it
allows proliferation and angiogenesis; it
inhibits apoptosis in transgenic mice over-
expressing COX-2 and it has been shown to
display progressive cellular alterations,
including dysplasia and loss of normal tissue
architecture as well as cellular
DNA damage found both in chronic
pancreatitis and pancreatic cancer is caused
from the generation of reactive oxygen (ROS)
and nitrogen species produced by leukocytes

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JOP. Journal of the Pancreas – – Vol. 4, No. 5 – September 2003
and other phagocytic cells in the site of the
inflammation. A major target of ROS and
free-radical attack is the cellular genome,
which is subjected to the formation of
numerous genotoxic adducts and DNA strand
breaks [33]. Among the most deleterious of
ROS-induced adducts is 7,8-dihydro-8-
oxoguanine (oxoG). OxoG residues in DNA
frequently mispair with adenine during
replication, giving rise to transversion
mutations. These transversions found in
pancreatic cancer are especially prevalent in
the mutational spectrum of the tumor
suppressor gene p53 [34].
Repeated tissue damage and regeneration
occurring during chronic pancreatitis, in the
presence of highly reactive nitrogen and
oxygen species released from inflammatory
cells, interacts with the DNA of epithelial
pancreatic cells resulting in permanent
genomic alterations such as point mutations,
deletions, or rearrangements.
It is now evident that chronic pancreatitis has
a powerful effect on pancreatic cancer
development. Chronic pancreatitis could be
considered as the field for an attractive
environment for tumor growth, facilitating
genomic instability and promoting
angiogenesis. The inflammatory cells, the
chemokines and cytokines regulate the
growth, migration and differentiation of all
cell types in the tumor microenvironment,
including neoplastic cells, fibroblasts and
endothelial cells.
The challenge for the future could be to
normalize the inflammatory network in order
to regain a normal overall host response, thus
decreasing the high levels of tumor-promoting
properties of the infiltrating cells, such as pro-
inflammatory cytokines while increasing their
tumor-suppressing properties, such as anti-
inflammatory cytokines.
Neoplasms; Pancreatitis
Abbreviations COX-2: cyclooxygenase-2;
iNOS: inducible form of nitric oxide; oxoG:
7,8-dihydro-8-oxoguanine; ROS: reactive
oxygen species
Giulia Martina Cavestro
Dipartimento di Scienze Cliniche
Sezione di Gastroenterologia
Via Gramsci 14
43100 Parma
Phone: +39-0521.702.772
Fax: +39-0521.291.582
1. Niederhuber JE, Brennan MF, Menck HR. The
National Cancer Data Base report on pancreatic cancer.
Cancer 1995; 76:1671-7. [PMID 8635074]
2. Greenlee RT, Hill-Harmon M, Murray T, Thun M.
Cancer statistics, 2001. CA Cancer J Clin 2001; 51:15-
36. [PMID 11577478]
3. Talamini G, Bassi C, Falconi M, Sartori N, Salvia
R, Rigo L, et al. Alcohol and smoking as risk factors in
chronic pancreatitis and pancreatic cancer. Dig Dis Sci
1999; 44:1303-11. [PMID 10489910]
4. DiMagno EP, Reber HA, Tempero MA. AGA
technical review on the epidemiology, diagnosis, and
treatment of pancreatic ductal adenocarcinoma.
Gastroenterology 1999; 117:1464-84. [PMID
5. Michaud DS, Giovannucci E, Willett WC, Colditz
GA, Stampfer MJ, Fuchs CS. Physical activity, obesity,
height, and the risk of pancreatic cancer. JAMA 2001;
286:921-9. [PMID 11509056]
6. Potter JD. Pancreas cancer--we know about
smoking, but do we know anything else? Am J
Epidemiol 2002; 155:793-5. [PMID 11978581]
7. Bardeesy N, DePinho RA. Pancreatic cancer
biology and genetics. Nat Rev Cancer 2002; 2:897-909.
[PMID 12459728]
8. Lowenfels AB, Maisonneuve P, Cavallini G,
Ammann RW, Lankisch PG, Andersen JR, Dimagno
EP, Andren-Sandberg A, Domellof L. Pancreatitis and
the risk of pancreatic cancer. International Pancreatitis
Study Group. N Engl J Med 1993; 328:1433-7. [PMID
9. Bansal P, Sonnenberg A. Pancreatitis is a risk
factor for pancreatic cancer. Gastroenterology
1995;109:247-51. [PMID 7797022]

Page 4
JOP. J Pancreas (Online) 2003; 4(5):165-168.
JOP. Journal of the Pancreas – – Vol. 4, No. 5 – September 2003
10. Fernandez E, La Vecchia C, Porta M, Negri E,
d'Avanzo B, Boyle P. Pancreatitis and the risk of
pancreatic cancer. Pancreas 1995; 11:185-9. [PMID
11. Talamini G, Bassi C, Falconi M, Sartori N, Pasetto
M, Salvia R, et al. Early detection of pancreatic cancer
following the diagnosis of chronic pancreatitis.
Digestion 1999; 60:554-61. [PMID 10545726]
12. Talamini G, Falconi M, Bassi C, Sartori N, Salvia
R, Caldiron E, et al. Incidence of cancer in the course
of chronic pancreatitis. Am J Gastroenterol 1999;
94:1253-60. [PMID 10235203]
13. Howes N, Neoptolemos JP. Risk of pancreatic
ductal adenocarcinoma in chronic pancreatitis. Gut
2002; 51:765-6. [PMID 12427771]
14. Malka D, Hammel P, Maire F, Rufat P, Madeira I,
Pessione F, et al. Risk of pancreatic adenocarcinoma in
chronic pancreatitis. Gut 2002; 51:849-52. [PMID
15. Maisonneuve P, Lowenfels AB. Chronic
pancreatitis and pancreatic cancer. Dig Dis 2002;
20:32-7. [PMID 12145418]
16. Matsubayashi H, Watanabe H, Nishikura K,
Ajioka Y, Kijima H, Saito T. Determination of
pancreatic ductal carcinoma histogenesis by analysis of
mucous quality and K-ras mutation. Cancer 1998;
82:651-60 [PMID 9477096]
17. Wilentz RE, Geradts J, Maynard R, Offerhaus GJ,
Kang M, Goggins M, Yeo CJ, Kern SE, Hruban RH.
Inactivation of the p16 (INK4A) tumor-suppressor
gene in pancreatic duct lesions: loss of intranuclear
expression. Cancer Res 1998; 58:4740-4. [PMID
18. Berger DH, Chang H, Wood M, Huang L, Heath
CW, Lehman T, Ruggeri BA. Mutational activation of
K-ras in nonneoplastic exocrine pancreatic lesions in
relation to cigarette smoking status. Cancer 1999;
85:326-32. [PMID 10023699]
19. Luttges J, Schlehe B, Menke MA, Vogel I, Henne-
Bruns D, Kloppel G. The K-ras mutation pattern in
pancreatic ductal adenocarcinoma usually is identical
to that in associated normal, hyperplastic, and
metaplastic ductal epithelium. Cancer 1999; 85:1703-
10. [PMID 10223563]
20. Wilentz RE, Iacobuzio-Donahue CA, Argani P,
McCarthy DM, Parsons JL, Yeo CJ, et al. Loss of
expression of DPC4 in pancreatic intraepithelial
neoplasia: evidence that DPC4 inactivation occurs late
in neoplastic progression. Cancer Res 2000; 60:2002-6.
[PMID 10766191]
21. Gerdes B, Ramaswamy A, Kersting M, Ernst M,
Lang S, Schuermann M, et al. p16 (INK4a) alterations
in chronic pancreatitis-indicator for high-risk lesions
for pancreatic cancer. Surgery 2001; 129:490-7. [PMID
22. Balkwill F, Mantovani A. Inflammation and
cancer: back to Virchow? Lancet 2001; 357:539-45.
[PMID 11229684]
23. Farrow B, Evers BM. Inflammation and the
development of pancreatic cancer. Surg Oncol
2002;10:153-69. [PMID 12020670]
24. Liotta LA, Kohn EC. The microenvironment of the
tumour–host interface. Nature 2001; 411:375-9. [PMID
25. Friess H, Guo XZ, Nan BC, Kleeff O, Buchler
MW. Growth factors and cytokines in pancreatic
carcinogenesis. Ann N Y Acad Sci 1999; 880:110-21.
[PMID 10415856]
26. Basso D, Plebani M. Cytokines and exocrine
pancreatic cancer: is there a link? JOP. J Pancreas
(Online) 2000; 1:19-23. [PMID 11852286]
27. McDade TP, Perugini RA, Vittimberga FJ,
Carrigan RC, Callery MP. Salicylates inhibit NF-
kappaB activation and enhance TNF-alpha-induced
apoptosis in human pancreatic cancer cells. J Surg Res
1999; 83:56-61. [PMID 10210643]
28. Tak PP, Firestein GS. NF-kappaB: a key role in
inflammatory diseases. J Clin Invest 2001; 107:7-11.
[PMID 11134171]
29. Williams C, Shattuck-Brandt RL, DuBois RN. The
role of COX-2 in intestinal cancer. Ann N Y Acad Sci
1999; 889:72-83. [PMID 10668484]
30. Kokawa A, Kondo H, Gotoda T, Ono H, Saito D,
Nakadaira S, et al. Increased expression of
cyclooxygenase-2 in human pancreatic neoplasms and
potential for chemoprevention by cyclooxygenase
inhibitors. Cancer 2001; 91:333-8. [PMID 11180079]
31. Tucker ON, Dannenberg AJ, Yang EK, Zhang F,
Teng L, Daly JM, et al. Cyclooxygenase-2 expression
is up-regulated in human pancreatic cancer. Cancer Res
1999; 59:987-90. [PMID 10070951]
32. Okami J, Yamamoto H, Fujiwara Y, Tsujie M,
Kondo M, Noura S, et al. Overexpression of
cyclooxygenase-2 in carcinoma of the pancreas. Clin
Cancer Res 1999; 5:2018-24. [PMID 10473081]
33. Weitzman SA, Gordon LI. Inflammation and
cancer: role of phagocyte-generated oxidants in
carcinogenesis. Blood 1990; 76:655-63. [PMID
34. Cerutti PA. Oxy-radicals and cancer. Lancet 1994;
344:862-3. [PMID 7916406

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