© 2006 Japanese Cancer Association
Cancer Sci|January 2006|vol. 97|no. 1|1–7
Blackwell Publishing Asia
Molecular mechanisms of pancreatic carcinogenesis
Toru Furukawa,1 Makoto Sunamura2 and Akira Horii1,3
1Departments of Molecular Pathology and 2Gastroenterological Surgery, Tohoku University School of Medicine, 2-1 Seiryo-machi,
Aoba-ku, Sendai 980-8575, Japan
(Received July 3, 2005/Revised 14 October, 2005/Accepted October 18, 2005/Online publication December 2, 2005)
Pancreatic ductal adenocarcinoma is one of the most fatal
malignancies. Intensive investigation of molecular pathogenesis
might lead to identifying useful molecules for diagnosis and
treatment of the disease. Pancreatic ductal adenocarcinoma
harbors complicated aberrations of alleles including losses of 1p,
6q, 9p, 12q, 17p, 18q, and 21q, and gains of 8q and 20q. Pancreatic
cancer is usually initiated by mutation of KRAS and aberrant
expression of SHH. Overexpression of AURKA mapping on 20q13.2
may significantly enhance overt tumorigenesity. Aberrations of
tumor suppressor genes synergistically accelerate progression of
the carcinogenic pathway through pancreatic intraepithelial
neoplasia (PanIN) to invasive ductal adenocarcinoma. Abrogation
of CDKN2A occurs in low-grade/early PanIN, whereas aberrations
of TP53 and SMAD4 occur in high-grade/late PanIN. SMAD4 may
play suppressive roles in tumorigenesis by inhibition of angio-
genesis. Loss of 18q precedes SMAD4 inactivation, and restoration
of chromosome 18 in pancreatic cancer cells results in tumor
suppressive phenotypes regardless of SMAD4 status, indicating
the possible existence of a tumor suppressor gene(s) other than
SMAD4 on 18q. DUSP6 at 12q21-q22 is frequently abrogated by
loss of expression in invasive ductal adenocarcinomas despite
fairly preserved expression in PanIN, which suggests that DUSP6
works as a tumor suppressor in pancreatic carcinogenesis.
Restoration of chromosome 12 also suppresses growths of
pancreatic cancer cells despite the recovery of expression of
DUSP6; the existence of yet another tumor suppressor gene on
12q is strongly suggested. Understanding the molecular
mechanisms of pancreatic carcinogenesis will likely provide
novel clues for preventing, detecting, and ultimately curing this
life-threatening disease. (Cancer Sci 2006; 97: 1–7)
countries.(1) The five-year survival rate for pancreatic cancer
is very low, less than 10%,(1) but both the incidence and
mortality of pancreatic cancer are increasing.(2) This information
indicates that current interventions to prevent, diagnose, and
cure the disease are far from satisfactory. We need to develop
novel and efficient procedures to medicate patients with this
cancer; this need has driven many researchers to intensive
investigations of the molecular mechanisms of the development
and progression of pancreatic cancer to detect the molecular
clues that are valuable for the invention of novel procedures.
This review focuses on the elucidation of current knowledge
about the molecular insights of pancreatic carcinogenesis.
ancreatic cancer is the fifth leading cause of cancer death
in men, the sixth in women, in Japan and other developed
Genomic analysis of pancreatic cancer
Pancreatic ductal adenocarcinoma (PDA), the most common
type of pancreatic cancer, harbors complicated aberrations of
chromosomal alleles, that is, losses in multiple chromosome
arms, including 1p, 3p, 4q, 6q, 8p, 9p, 12q, 17p, 18q, and 21q,
and gains in 8q and 20q.(3) The aberrations are very characteristic
for comparing PDA with other types of cancer, most of which
reveal aberrations in fewer numbers of chromosomal regions.
The regions where losses occur are suggested to harbor tumor
suppressor genes (TSGs); those where gains occur, to harbor
oncogenes. Detailed analyses of loss of heterozygosity (LOH)
using microsatellite markers indicates several particularly
lost regions in 1p, 6q, 9p, 12q, 17p, and 18q; three smallest
regions of overlap (SROs) in 6q(4) and two in 12q(5,6) were
identified. However, no conclusive candidate TSG has been
identified. In 1p, several candidate genes such as TP73, RIZ,
ICAT, and RUNX3 were analyzed,(7–10) but alterations in these
genes were rather rare in pancreatic cancer. Future efforts will
disclose the conclusion of TSGs in these chromosome arms.
Significant concordance of LOHs were found between 6q
and 17p and between 12q and 18q, and LOHs of 12q, 17p and
18q were reported to be associated with poor prognosis of
patients with PDA.(11) A study using probes to detect aberrations
of specific chromosomal regions including 8q24, 9p21,
17p13, 18q21 and 20q11 by fluorescence in situ hybridiza-
tion in cells in pancreatic juice taken from patients undergo-
ing endoscopic retrograde cholangiopancreatography was
performed to test the diagnostic relevance of these allelic
aberrations.(8) Aberrations of copy numbers were detected in
70% of patients with pancreatic neoplasms, but no aberrations
were detected in any of the patients without them. These
results showed that these characteristic allelic aberrations can
be used as diagnostic markers for pancreatic cancer.(12)
The great majority of PDA cases harbor a gain-of-function
mutation of KRAS.(13) RAS is a GTP-binding protein involved
3To whom correspondence should be addressed.
Abbreviations: GTP, guanosine triphosphate; HPDE, human pancreatic duct
epithelium; LOH, loss of heterozygosity; MAPK, mitogen-activated protein
kinase; MMCT, microcell-mediated chromosome transfer; PanIN, pancreatic
intraepithelial neoplasia; PDA, pancreatic ductal adenocarcinoma; SRO, small-
est region of overlap; TSG, tumor suppressor gene.
© 2006 Japanese Cancer Association
in growth factor-mediated signal transduction pathways.(14)
The mutations of KRAS are observed at codons 12, 13 and
61, and the overall frequencies are more than 90% in PDAs.
The mutations result in the generation of a constitutively
active form of RAS. The constitutively active RAS
intrinsically binds to GTP and gives uncontrolled stimulatory
signals to downstream cascades involving mitogen-activated
protein kinases (MAPKs). Mutations of KRAS are frequently
observed in pancreatic ductal precursor lesions/pancreatic
intraepithelial neoplasia (PanIN). The consistent mutations of
KRAS in PanIN as well as in PDA indicate that the activation
of pathways involving RAS is essential for pancreatic
carcinogenesis. However, the mutations of KRAS do not
appear to be sufficient for the development of PDA. Pancreas-
specific endogenous expression of active Kras, KrasG12D, in
genetically engineered mice results in the development of
PanIN frequently, but the development of PDA very
exceptionally.(15) Transfection of the activated KRAS in HPDE
cells, the immortalized near-diploid ductal cells derived from
normal human pancreas, show partially transformed
phenotypes.(16) These results suggest that additional genetic
and/or epigenetic events, in addition to the activation of
KRAS, are necessary for the development of PDA.
SHH is frequently overexpressed in PDAs as well as in
PanINs.(17,18) Pancreas-specific overexpression of SHH in genet-
ically engineered mice resulted in the development of PanIN.(17)
Gene expression profiling of early PanIN indicated the aberrant
expression of foregut markers, which was suggested to be a
result of activation of the Hedgehog pathway in the lesion.(19)
Suppression of the Hedgehog pathway showed suppressive
phenotypes of the cultured pancreatic cancer cells.(17) Hedgehog
is a family molecule regulating cell fates in embryogenesis in
Drosophila as well as in vertebrates. Activation of the Hedgehog
signaling pathway by sporadic mutations or in familial con-
ditions such as Gorlin’s syndrome is known to be associated
with tumorigenesis in skin, the cerebellum, and skeletal mus-
cle.(18) These pieces of information suggest that the activation
of the Hedgehog pathway plays a role at the initial step of the
development of PanIN, subsequently progressing to PDA.
Gain of copy number of 20q is frequently observed in
PDAs, which indicates a possible existence of oncogene(s) in
this chromosome arm.(3) Several candidate oncogenes have
been isolated, including AURKA locating on 20q13.2.(20)
AURKA encodes AURKA/STK15/Aurora-A kinase, an essen-
tial molecule involved in regulating the functions of centro-
somes, spindles, and kinetochores, which are required for
proper mitosis of cells.(17) AURKA is overexpressed in vari-
ous cancer tissues, including PDA, which is associated with
a higher grade of tumor and a poorer survival of patients with
cancer.(17–23) This overexpression can induce checkpoint dis-
ruption by interfering with p53 function and tetraploidiza-
tion, possibly leading to aneuploidy;(24,25) these may be some
of the critical causes for a worsened prognosis. Depletion of
AURKA by RNA interference in human pancreatic cancer
cells resulted in marked growth suppression in vitro, abolish-
ment of tumorigenesity in vivo, and synergistic enhancement
of cytotoxicity of taxanes, chemotherapeutic agents interfer-
ing with the functions of the mitotic spindle.(26) These obser-
vations indicate that the overexpression of AURKA plays
important roles in the progression of PDA.
Aberrations of suppressive pathways
As discussed in the previous section, PDAs have lost multiple
allelic regions hemizygously or homozygously. These regions
of loss may harbor tumor suppressor genes. Homozygous
deletion of 9p21 is frequently observed in PDA. This
region harbors CDKN2A/INK4A/p16. This gene is inactivated
frequently in PDA by deletion or mutation.(27) Even in
PDAs harboring wild-type CDKN2A, expression of the gene
is transcriptionally silenced by hypermethylation of the
promoter, which indicates that CDKN2A is inactivated in
virtually all PDAs(28) (Fig. 1). Expression of CDKN2A is lost
in moderate/low-grade PanINs.(29,30) Loss of Cdkn2a/Ink4a in
endogenous KrasG12D-expressing mice results in the develop-
ment of a poorly differentiated sarcomatoid locally invasive
carcinoma that is an unusual form in human PDA.(31) The
CDKN2A is a cyclin-dependent kinase inhibitor. It binds
to CDK4 and prevents interaction between CDK4 and
CCND1, which induces cell cycle arrest at G1 phase in
cooperation with normal RB function.(32) These pieces of
information suggest that the loss of CDKN2A occurs early
and enhances the oncogenic potential of activating KRAS in
PDAs have frequently lost 17p13.(5) The region harbors
TP53/p53, the gene frequently mutated in PDAs.(33) The
mutations have been observed as missense or nonsense ones;
the former type is more common than the latter in human
malignant tumors, including PDA.(34) TP53 is a DNA binding
protein functioning as a transcription factor modulating mol-
ecules pertaining to variety of functions mainly involved in
cell cycle arrest and apoptosis.(35) The missense mutations of
TP53 are preferentially observed in its DNA binding domain,
which abrogates the binding capacity. The missense-mutated
TP53 proteins abnormally accumulated in the nucleus by
suppressed turnover, which is observed as if the protein were
overexpressed immunohistochemically (Fig. 1). Abnormal
accumulation of TP53 is frequently observed in high grade/
late PanIN lesions as well.(30) Targeted concomitant endog-
enous expression of Trp53R172H and KrasG12D to the mouse
pancreas revealed the cooperative development of invasive
and metastatic ductal carcinoma characterized by loss of wild
type allele of Trp53 and diverse chromosomal instability,
which recapitulates human PDA.(36) Missense mutated Trp53
can inhibit Trp63 and Trp73 activity and increase its transfor-
mation activity.(37) These observations suggest that the aber-
ration of TP53 function under activated KRAS in pancreatic
ductal cells induces chromosomal instability and additional
genetic aberrations that can advance carcinogenic pathways
to invasive ductal carcinoma.
Familial pancreatic cancer
Some tumors develop in a hereditary manner; examples
include retinoblastoma, familial adenomatous polyposis,
breast cancer, neurofibromatosis, and multiple endocrine
neoplasia. Such familial syndromes gave valuable clues for
the isolation of responsible genes.(38) The isolation of BRCA2
on chromosome 13 was accelerated by the identification of a
homozygous deletion in pancreatic cancer,(39) but the great
majority of pancreatic cancers do not harbor mutation in this
Furukawa et al.
Cancer Sci|January 2006
© 2006 Japanese Cancer Association
| vol. 97| no. 1|3
gene. Several familial pancreatic cancer pedigrees have been
reported and positive linkage analysis was detected,(40,41) but
isolation of the responsible gene(s) is yet to be accomplished.
Impact of loss of chromosome 18q
Chromosome 18q is frequently deleted hemizygously and/or
homozygously in a vast majority of PDAs.(3,5) SMAD4 was
identified in the homozygously deleted region at 18q21.1.(42)
SMAD4 is abrogated in approximately 50% of PDAs either
by homozygous deletion or mutation.(42,43) Expression of
SMAD4 is frequently lost in high-grade/late PanIN lesions as
well as in PDA(30,44) (Fig. 1). SMAD4 is a signal mediator
involved in the transforming growth factor-β signaling
pathway that plays important roles in the negative regulation
of cell proliferation, as well as induction of extracellular
adenocarcinoma (P). Note loss of expressions of CDKN2A (panel b),
SMAD4 (panel d), and DUSP6 (panel e) and abnormal accumulation
of TP53 (panel c). Panel a, hematoxylin and eosin staining. N,
Aberrations of multiple molecules in pancreatic ductal
© 2006 Japanese Cancer Association
matrices, angiogenesis, and immune suppression.(45) SMAD4
comprises a hetero-multimer with SMAD2 and SMAD3,
which translocates into the nucleus and functions as a
transcription factor cooperating
Restoration of SMAD4 in SMAD4-deleted pancreatic cancer
cells resulted in no alteration of cell growth in vitro but the
abolition of tumorigenesity in immunodeficient mice due to
suppression of angiogenesis, which suggests that SMAD4
functions as a suppressor of tumorigenesis by interfering
with interactions between epithelial cells and stromal cells.(46)
Although loss of heterozygosity at chromosome 18q is an
overwhelming event in PDAs, occurring in 80–90% of them,
the complete SMAD4 inactivation, namely a two-hit
mutation, is found in approximately 50%.(42) In intraductal
papillary-mucinous neoplasms of the pancreas, one of the
precursor types of neoplasms of PDA, loss of 18q is fre-
quently observed despite exclusive preservations of expres-
sions of SMAD4.(12,47) Homozygous deletion telomeric of the
SMAD4 locus is observed in some fractions of PDAs.(48)
These observations indicate a possible existence of unknown
TSG(s) on 18q. To test this possibility, introduction of an
additional copy of chromosome 18 into cultured pancreatic
cancer cells with or without SMAD4 inactivation was per-
formed by microcell-mediated
(MMCT).(49) The transferred cells revealed a marked growth
retardation, loss of ability for anchorage-independent growth,
and modest invasiveness in vitro. The in vivo tumorigenic
ability of the transferred cells was significantly reduced.
These results were obtained unanimously throughout the
transferred cells despite their different SMAD4 functional
status.(49) Moreover, the chromosome 18-transferred cells
revealed marked reductions of metastatic ability in experi-
mental in vivo models.(50) These observations strongly sug-
gest that a TSG(s), particularly a metastasis-suppressing
gene(s), other than SMAD4, exists on 18q, and it is involved
in pancreatic carcinogenesis.
Tumor suppressor on chromosome 12q
Loss of heterozygosity at chromosome 12q is a frequent
aberration in PDAs.(5) Fine mapping of LOH by micro-
satellite analysis employing markers encompassing the entire
long arm of chromosome 12 at every few centi-morgans
uncovered two SROs; one at 12q21 and the other at 12q22-
q23.1.(6) The mapping of expressed sequence tags in and
around these regions to clone candidate tumor suppressor
genes resulted in the isolation of DUSP6/MKP-3 at 12q21-
q22.(51) No possible function-affecting mutations were
observed, but the DUSP6 mRNA expressions was strongly
suppressed.(51) As shown in Fig. 1, expression of DUSP6 was
markedly reduced and/or abolished in PDAs, especially in
the poorly differentiated type, despite its fairly good
preservation in PanINs.(52) The abrogation of expression of
DUSP6 is associated with hypermethylation of a possible
control region of the DUSP6 gene.(53) DUSP6 is a dual
specificity phosphatase that specifically binds and depho-
sphorylates MAPK1, which makes a feedback loop to
regulate a physiological activity of MAPK1/ERK2.(54) The
cultured pancreatic cancer cells lacking expression of DUSP6
tend to show constitutively active MAPK1, which suggests
that loss of function of DUSP6 could induce constitutive
activation of MAPK1.(52) Exogenous overexpression of DUSP6
in DUSP6-abrogated pancreatic cancer cells results in growth
suppression and the induction of apoptosis.(52) These
observations indicate that epigenetic silencing of DUSP6 is
one of the crucial causes of the pathogenesis of PDAs.
How can the abrogation of DUSP6 be interpreted in pan-
creatic carcinogenesis and progression? As already noted,
80–90% of PDAs harbor the gain-of-function mutation of
KRAS.(9) KRAS encodes RAS, which acts as a molecular
switch of downstream signal cascades including RAF1-
MAP2K-MAPK1. The mutated KRAS generates a constitu-
tively active RAS that hyperstimulates the downstream
cascades. In the negative feedback loop manner, the hyperac-
tivated MAPK1 would activate DUSP6, which in turn can
suppress the extraordinarily activated MAPK1. However, the
abrogation of DUSP6 may result in loss of the feedback loop,
which can lead to constitutive activation of MAPK1. The
constitutive active MAPK1 may translocate into the nucleus
and activate transcription factors that drive numerous effector
genes, which could contribute to uncontrolled cell growth
and cellular oncogenesis (Fig. 2). From these points of view,
DUSP6 functions as a tumor suppressor in the pancreatic car-
cinogenic pathway that is exclusively surmounted under the
activated RAS phenotype.(55) The tumor suppressive activity
of DUSP6 is also interpreted by recent reports that include
the downregulation of DUSP6 in leukemic cells, involvement
in induction of apoptosis by chemotherapy in leukemic cells,
suppressive roles in experimental skin carcinogenesis, and
involvement in the growth suppression of Jurkat T cells.(56–59)
The abrogation of expression of DUSP6 is confined in invasive
carcinoma, whereas aberrations of other major suppressive
molecules are observed in PanINs.(30) This final finding
suggests that DUSP6 functions as a gatekeeper from PanIN
to invasive carcinoma, which is independent of other major
tumor suppressors (Fig. 3).
Because the precise localization of DUSP6, the candidate
TSG in 12q, is outside of SRO in this region,(51) MMCT-
mediated introduction of chromosome 12 was performed, and
it was found that the hybrid cells showed growth suppression
RAS generated by mutated KRAS activates downstream cascades
including RAF1-MAP2K1-MAPK1. Loss of expression of DUSP6 results
in abrogation of the feedback loop between MAPK1 and DUSP6
and leads to constitutive activation of MAPK1, which eventually
results in invasive phenotypes.
The RAS-MAPK pathway with abrogation of DUSP6. Active
Furukawa et al.
Cancer Sci| January 2006
© 2006 Japanese Cancer Association
| vol. 97| no. 1|5
in vivo through angiogenesis inhibition.(60) Microarray analy-
sis revealed that expression of DUSP6 remained at the sup-
pressed level even in hybrid cells.(60) Therefore, a TSG(s)
beside DUSP6 is hidden in 12q that should be unveiled in
PDAs harbor complicated combinations of aberrations of
alleles. These aberrations are distinctive in pancreatic ductal
adenocarcinoma and are useful as diagnostic markers. The
promotion of pancreatic carcinogenesis is obviously initiated
by mutation of KRAS and aberrant expression of SHH. Over-
expression of AURKA mapping on 20q13.2 may significantly
enhance overt tumorigenesity. Aberrations of tumor suppressor
genes synergistically accelerate the progression of carcinogenesis
through PanIN to PDA. Abrogation of CDKN2A occurs in
low-grade/early PanIN, whereas aberrations of TP53 occur in
high-grade/late PanIN; they may play different roles in the
progression of carcinogenesis. SMAD4 may play a
suppressive role in tumorigenesis by inhibiting angiogenesis.
Restoration of chromosome 18 in pancreatic cancer cells
results in tumor suppressive phenotypes regardless of
SMAD4 status, which suggests the possible existence of a
yet-to-be discovered TSG(s) in addition to SMAD4. DUSP6
at 12q21-q22 is frequently abrogated by loss of expression in
invasive ductal adenocarcinomas despite fairly preserved
expression in PanINs, which suggests that DUSP6 is a tumor
suppressor functioning as a gatekeeper of pancreatic
carcinogenesis. Restoration of chromosome 12 in pancreatic
cancer cells has revealed tumor suppressive phenotypes in
vivo without recovery of DUSP6 expression; a buried TSG(s)
in 12q is awaiting our discovery. At present, the major
pancreatic carcinogenic pathway can be modeled by
involving these key molecules (Fig. 3). There is a possibility
of innovation for accurate and effective diagnosis using the
cells obtained from the pancreatic juice and the molecules in
this schema. For this purpose, we must improve this schema
by adding more molecules. The understanding of the
molecular mechanisms of pancreatic carcinogenesis will
likely provide novel clues for preventing, detecting and
ultimately curing patients with this life-threatening disease.
We are grateful to all the members of the pancreatic cancer
research group in our laboratory, the surgeons and physicians
led by Drs Seiki Matsuno and Tooru Shimosegawa, respec-
tively, at Tohoku University Hospital, and all the collabora-
tors for continuing fruitful collaborations for many years. We
are also grateful to Dr Barbara Lee Smith Pierce (Professor,
University of Maryland University College) for editorial
work in the preparation of this manuscript. This work was
supported by the Ministries of Education, Culture, Sports,
Science and Technology of Japan, Health, Labor and Welfare
of Japan, and many non-profit foundations.
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