PANCREATIC DUCTAL ADENOCARCINOMA
Pancreatic cancer is the fourth leading cause of cancer death in
the United States,
with 5-year survival rates of less
than 5%. Pancreatic ductal epithelial adenocarcinoma (PDA) accounts for more
than 90% of the total pancreatic cancers. Currently, surgery is the only
treatment that is partially effective for pancreatic cancer. Most patients with
pancreatic cancer are diagnosed at an advanced stage and are therefore not
candidates for surgical resection. Traditional chemotherapy and radiotherapy do
not provide substantive palliation and improvement in survival for patients
with non-resectable pancreatic cancer. Although a great deal of information has
been added into our understanding of pancreatic cancer during the last decade,
the exact mechanism of pancreatic cancer development is still unknown.
GENETICS
Although the etiology of pancreatic cancer is still elusive, the
last decades have witnessed significant advancements in understanding the
genetic lesions of pancreatic cancer. Similar to the progression model for
colon cancer, a genetic progression model for pancreatic ductal adenocarcinoma
was proposed by Hruban et al. several years ago (Figure 1.1) 59. In this model, normal duct
epithelium progresses to infiltrating cancer through a series of histologically
defined precursors (pancreatic intraepithelial neoplasia, PanINs). This has
been supported by histological studies and clinical observation.
Histologically, PanINs progress with a series of morphological alterations,
which correspond to stages of increasingly dysplastic growth (Fig.1.2) 60. The overexpression of HER-2/neu
and point mutations in the KRAS gene can be detected at pancreatic duct lesions
with minimal cytological and architectural atypia. Inactivation of the p16
gene occurs at an intermediate stage, and the inactivation of p53, DPC4, and BRCA2 occur relatively late in the
development of pancreatic neoplasia.
Despite all the genetic knowledge we have, how these genetic lesions
lead to development of pancreatic cancer is still poorly understood.
KRAS mutation (mostly G12V or G12V) is present in more than 85% of
ductal carcinomas, and the p16
tumor-suppressor gene is inactivated in around 90% of pancreatic cancers 60,61. Mouse models have convincingly
shown that KRAS mutation
is an initiating step in PDA pathogenesis and is also crucial for maintenance 62,63. However, KRAS mutation is
not tumor specific and is also detected at high frequencies in normal
epithelium (19% to 38%) 64,65 and in patients with chronic
pancreatitis (18% to 62.5%) 66,67.
Loss of p16INK4A function by mutation, deletion, or
promoter hypermethylation occurs in 80% to 95% of pancreatic cancers
68,69. INK4A loss is generally seen in moderately advanced lesions
that show features of dysplasia. The 9q21 locus encodes two overlapping tumor suppressors—INK4A and ARF, and their respective protein
products p16INK4A and p19ARF—via distinct
first exons and alternative reading frames in shared downstream
exons 70. INK4A inhibits CDK4/6-mediated
phosphorylation of RB and block cells from entering into the S (DNA
synthesis) phase of the cell cycle. ARF stabilizes p53 by inhibiting
its MDM2-dependent proteolysis. Since homozygous deletion of 9p21 is seen in about 40%
of tumors, many pancreatic cancers sustain loss of INK4A and ARF tumor suppression pathways. INK4A has been indicated to play a central role as a
PDA tumor suppressor 60. Transgenic mouse
studies have shown INK4A
mutations cooperate with KRAS
in the development of PDA and accelerate tumor progression in the
setting of concurrent mutations in p53
71. Moreover, ARF was shown to have an independent,
cooperative function in PDA tumor suppression.
More than 50% of pancreatic cancer cases have mutations in the
P53 gene, which generally are missense alterations of the
DNA-binding domain 68. The p53 transcription factor
is activated in response to DNA damage or oncogene activation. p53 mutation appears in later-stage
PanINs that have acquired significant features of dysplasia 72,73. SMAD4 is another important
tumor suppressor gene that is frequently mutated or lost in pancreatic cancer.
Loss of heterozygosity of Smad4 can be seen in around 90% of pancreatic cancers, and 50% of
patients show complete loss of functional Smad4 proteins 74,75. The mechanism by which SMAD4 loss contributes to
tumorigenesis is likely to involve its central role in TGF-β-mediated growth
inhibition. The biological role of the TGF-β pathway in human malignancy is complex, exerting
both growth-inhibitory and growth-promoting effects depending on the
cell type and cell context 76. The loss of SMAD4 in PDA may have a primary role
in modulating the interaction of the tumor with the microenvironment rather
than in controlling the growth of the tumor cells themselves. There is recent
evidence that SMAD4 deficiency may inhibit TGF-β-induced cell cycle arrest and cell migration, while
not affecting EMT, thereby shifting the balance of TGF-β signaling from tumor suppression
to tumor promotion 77. Consistent with these observations,
it appears that elevated TGF-β
expression contributes to PDA progression 78.
LKB1/STK11
mutation is a characteristic genetic alteration in the Peutz-Jeghers syndrome
(PJS) which is a familial cancer syndrome associated with an increased incidence
of PDA 79,80. LKB1 is a tumor suppressor gene encoding a serine/threonine
kinase that is involved in regulation of diverse processes, such as
cell polarity and metabolism, and has been linked to specific
signaling pathways including mTOR and AMPK 81. Heterozygous loss of LKB1 in
mice induces intestinal polyps
formation and highly invasive endometrial adenocarcinomas 82,83. Inherited BRCA2 mutations are typically
associated with familial breast and ovarian cancer syndrome, but
also carry a significant risk for the development of pancreatic
cancer. One study estimates that
17% of pancreatic cancers occurring
in a familial setting harbor mutations in this gene 84. BRCA2 is known to play a
critical role in the maintenance of genomic stability by regulating
homologous recombination-based DNA repair processes. Consequently, BRCA2 deficiency in normal cells
results in the accumulation of procarcinogenic or lethal chromosomal
aberrations 85.

PATHWAYS
Oncogenes and tumor suppressor genes are mutated or deregulated
in pancreatic cancer. Mutational activation of RAS due to amino acid
substitutions at positions 12, 13 or 61 results in oncogenic versions
insensitive to GAP stimulation that persist in the GTP-bound state. Mutated
KRAS is constitutively active and enhances tumorigenesis through its downstream
RAF/MEK/ERK, PI3K/AKT, and RAL pathways. RAS mediates its cellular regulation
effects through its downstream effectors such as Raf and PI3-Kinase 86. Raf phosphorylates and
activates the dual specificity serine/threonine and tyrosine kinase MEK, which
in turn activates the extracellular signal-regulated (ERK) family of mitogen
activated protein (MAP) kinases. The ERKs phosphorylate a variety of targets in
the cytoplasm and the nucleus, and then regulate multiple functional endpoints
through direct phosphorylation and/or regulation of gene transcription,
including cellular proliferation, differentiation, motility and invasion. Stimulation
of PI3-kinase leads to protection from apoptosis via activation of the
serine/threonine kinase AKT and also cytoskeletal re-organization via
regulation of Rho
family GTPases. Oncogenic ras mutation has been considered a key contributor to
the tumorgenesis of pancreatic cancer.
The epidermal growth factor receptor (EGFR) and its endogenous
ligands, epidermal growth factor (EGF) are overexpressed in PDA87,88. When bound to its ligand, EGFR dimerises with
each other or with other ErbB family members, which results in phosphorylation
of tyrosine residues on the intracellular domain. The tyrosine
phosphorylation attracts downstream effectors to bind to the cytoplasmic region
of EGFR and become activated. The major downstream mediators of EGFR include
RAS/MEK/ERK, PI3K/AKT, and the signal transducer and activator of transcription
(STAT) family proteins which are involved in cancer adhesion, invasion,
and cell survival 89.
Tumor suppressor genes p16, p53 and BRCA1 are commonly
inactivated in PDA. The p16 gene binds and inhibits cyclin-dependent kinases
(CDKs) CDK4/6, which sense of mitogenic signals and phosphorylate
retinoblastoma (Rb). Phosphorylated Rb promotes the transcription of
E2F-regulated genes and consequent entry into the S-phase 90,91. Therefore, in pancreatic
cancer, abrogation of p16 activity leads to uncontrolled CDK4/6 activity and
enhanced Rb phosphorylation, and then more cells enter the S-phase. The other
frequently mutated tumor suppressor, Smad4, has important effects on
the tumor microenvironment and potentiation of invasion 92,93. The Smad4 protein belongs to
the Smad family of transcription factors and mediates signal
transmission of the TGF-β
superfamily of cytokines 94. TGF-β ligands regulate cell growth, differentiation, and
migration and have both tumor suppressor and tumor promoter functions. Loss
of Smad4 seems to abolish TGF-β-mediated
tumor suppressive functions, while maintaining some TGF-β-mediated tumor promoting
functions 77.
In addition, reactivation of developmental signaling, such as
Notch and hedgehog pathways, has been demonstrated in pancreatic cancer. While
playing an important role in directing decisions about the fate of
cells in the development of the pancreas, the Notch pathway is also critical
for pancreatic cancer initiation and invasion 95,96. Binding of Notch receptors
to their ligands, such as Delta, Serrate, and Lag-2, activates the
Notch pathway and leads to proteolytic cleavage of Notch receptors.
The cleaved product is the intracellular domain, which translocates
to the nucleus and binds to the transcription factor CSL (RBP-Jκ/CBF in mammals; Suppressor of
Hairless (Su(H)) in Drosophilia) inducing the transcription of a
variety of target genes including the hairy enhancer of split (HES)
family of transcriptional repressors. HES family members act to
maintain cells in a precursor state. The pathway is turned off in
the adult pancreas, but upregulated in pre-neoplastic lesions and in invasive
pancreatic cancer 97,98.
TREATMENT
The current treatment options of PDA include surgery,
chemotherapy, radiation therapy, and symptom control. More than 80% of PDA
patients are diagnosed at an advanced stage and are not suitable candidates for
surgery, which is the only potential cure. PDA is highly resistant to
traditional chemotherapy and radiation therapy. Few chemotherapeutic agents
have been shown to have reproducible response rates of more than
10%. 5-Fluorouracil (5-FU) is an inhibitor of thymidylate
synthetase, which is essential for synthesis of DNA nucleotides, and
has been the most widely used in advanced pancreatic cancer, with a
median survival of around 5–6 months and is better than the best
supportive care 99-101. The current preferred
chemotherapeutic agent is gemcitabine, which showed an improved 1-year survival
rate compared to 5-FU (18% vs. 2%). Gemcitabine also is less toxic and has
higher clinical response when compared to 5-FU (24% vs. 5%) 102. Recent clinical trials
suggested that a combination treatment of gemcitabine and other
chemotherapeutics showed better survival than gemcitabine alone. The best
combinations may be with capecitabine or platinum-based agents, which induces less toxicity 101,103. Target based drugs such as
Erlotinib (an EGFR tyrosine kinase inhibitor) and cetuximab (antibody to EGFR)
are also being explored to treat pancreatic cancer in combination with
gemcitabine.
Radiotherapy has been widely used for the treatment of pancreatic
cancer. However, there is no evidence showing that radiation provides any
additional beneficial effects 101. Results from clinical trials
demonstrated that radiation induced strong toxicity and significantly reduced
median survival when combined with gemcitabine 101.
Radical resection alone will result in a 5-year survival rate of
only 10% owing to recurrence after surgery 104. Nearly all patients develop
metastatic disease, most commonly of the liver and peritoneum but
also the lungs, and this may occur with or without local recurrence 100,104. After pancreatic resection,
adjuvant systemic chemotherapy is preferred and increases the 5-year
survival from 9% to 12% with resection alone to 21% to 29% and 23%
with either 5FU and folinic acid or gemcitabine, respectively 105-107.
Post Comment
No comments