Cytokines and Exocrine Pancreatic Cancer

Cytokines and Exocrine Pancreatic Cancer:
Is There a Link?
 
Daniela Basso, Mario Plebani
 
Department of Laboratory Medicine, University Hospital of Padua, Italy
 
At the beginning of the third millennium, the
prognosis for patients with pancreatic cancer
is still extremely poor, with a five-year
survival of less than 1% [1] in spite of the
availability of sophisticated diagnostic and
treatment aids which have, in recent years,
significantly modified the prognosis for many
patients with solid tumors other than those of
pancreatic origin. The failure to improve upon
the therapeutical approach for this type of
tumor is probably due to the biological
behavior of pancreatic cancer cells which
acquire several molecular and biochemical
advantages in growing, spreading and
escaping host control.
The rapid and uncontrolled growth which
characterizes the pancreatic cancer cell cycle
depends upon many factors, above all,
alterations in key genes involved in controlling
the cell cycle [2]. More than 90% of
pancreatic tumors bear codon 12 K-ras point
mutations. This frequency, the highest to be
reported for any tumor type which has been
described in the early phases of pancreatic
carcinogenesis, determines the synthesis of an
altered p21 protein [3, 4]. Normal p21 shifts
from an active state (bound to GTP) to an
inactive state (bound to GDP) via its intrinsic
GTPase activity, and via its sensitivity to the
activity of GAP (GTPase activating protein).
The transformed p21 becomes insensitive to
GAP thus leading this protein to a constitutive
and permanent activation, which stimulates
cell growth. Another gene frequently found to
be altered in pancreatic cancer is p16
(homozygously deleted in about 40% of
pancreatic carcinomas). It is an inhibitor of
cyclin-dependent kinase (CDK) 4, which
promotes progression of the cell division cycle
through late G1 phase to G1/S [2].
Accelerated pancreatic cancer cell growth is,
however, not only due to mutations of K-ras,
p16 or other genes involved in regulating the
cell cycle, but also to an imbalance between
stimulatory and inhibitory factors, mainly
cytokines. Among the cytokines providing
positive signals for pancreatic cancer cell
growth, are EGF, IGF I, TGFalpha,
interleukin 1alpha [5-13], which originate in
peri-tumoral inflammatory cells, but may also
be produced by the pancreatic cancer itself
thus exerting an autocrine action [9, 14, 15].
To act, all these mediators must first bind to
their transmembrane receptors, the majority of
which have an intrinsic tyrosine kinase activity
which subsequently has a series of intracellular
targets. Among these cytokines are the family
of mitogen-activated protein kinases (MAPKs)
and the extracellular regulated kinases (ERKs)
[13, 16, 17].
It has recently been demonstrated that
cytokines, TGFalpha in particular, and
mutated K-ras may synergistically promote
the growth of human pancreatic cells acting on
similar, although distinct, signal transduction
pathways [18]. This suggests that different
alterations of the pancreatic cancer cell may
co-operate in favoring cell growth.
A peculiar aspect of tumor cells, pancreatic
cancer cells in particular, is their loss of
responsiveness to growth inhibitory cytokines,
such as TGFbeta1 [19, 20]. Pancreatic cancer
cells can escape the cell growth inhibitory
effect of TGFbeta1 since they may bear: 1)
cell
membrane
receptor
mutations
(TGFbetaRII), as occurs in many colorectal

Page 2
JOP - Journal of the Pancreas 2000; 1(2):19-23.
JOP – Journal Of the Pancreas www.joplink.net
Vol.1, No. 2 July 2000
20
cancers [21], or 2) altered Smad proteins
which are involved in the signal transduction
pathway of TGFbeta1 [22, 23]. The membrane
receptor TGFbetaRII, after coupling with
TGFbeta1, phosphorylates and activates
TGFbetaRI, which then phosphorylates Smad
proteins 2 and 3; the latter can translocate into
the nucleus only after coupling with Smad 4, a
protein encoded by DPC 4 (deleted in
pancreatic carcinoma locus 4), a gene which is
frequently deleted in pancreatic cancer (Figure
1).
Figure 1. Schematic representation of TGFbeta1 signal transduction pathway via Smad proteins.
The devastating evolution of pancreatic cancer
is not only due to the high proliferating
potential of pancreatic cancer cells, but also to
the ability of these cells to metastasize even
when the primary tumor spread is limited. The
metastatic process comprises several steps,
including the detachment of metastatic cells
from the primary tumor, followed by the
degradation of the basement membrane and
the invasion of lymphatic and/or hematic
vessels (intravasation). The growth of
metastatic foci in target organs, such as the
liver, is preceded by the arrest of metastatic
cells in the microvasculature, followed by the
degradation of the basement membrane, the
invasion of the target organ and the growth of
the new metastatic focus (extravasation) [24].
In any of these steps, the interaction between
tumor cells and the extracellular matrix plays a
key role and different cytokines can enhance
or diminish the adhesion of tumor cells to the
ECM. They can also modify the membranal
expression of ECM ligands, such as CD44 or
ICAM 1 [25, 26]. Cytokines may therefore
play a role in favoring or counteracting the
metastatic process in pancreatic cancer, as has
also been demonstrated for other tumors [27,
28].
Each cytokine can evoke a cascade of events
in inflammatory cells, including the synthesis
and release of other cytokines. This
phenomenon can also be observed in
pancreatic cancer cells: the stimulation of
PANC-1 cells with TNFalpha causes the
production of IL-8 and RANTES by tumor
cells [15]. In turn, it has recently been
demonstrated that IL-8 renders human
pancreatic cancer cells more tumorigenic and
metastatic [29]. Each cytokine may thus
simultaneously induce a heightening of one
specific biological effect (e.g. induction of cell
growth) and may trigger a series of different
biological responses.
Among the biological effects evoked by
cytokines, the stimulation or the inhibition of
the immunological host response to tumor
cells deserves consideration. The stimulation
by cytokines of the host immunological

Page 3
JOP - Journal of the Pancreas 2000; 1(2):19-23.
JOP – Journal Of the Pancreas www.joplink.net
Vol.1, No. 2 July 2000
21
response to pancreatic cancer cell has recently
been considered an aid in improving the
outcome of pancreatic cancer patients [30]. In
particular, it has been demonstrated in vitro
that the tumor-associated transforming growth
factor-beta and interleukin 10 favor a Th2-like
phetotype [31], while in vivo IL-2 or IL-4
induce an anti-tumor response, even in an
animal model without mature T cells (nude
mice) [32]. Current research shows that
cytokines play a therapeutical role in
pancreatic cancer: cytokines gene transfer in
pancreatic cancer cells and treatment with
anti-growth factor receptor antibodies [32-34]
are now considered a potential strategy for the
immune gene-therapy of pancreatic cancer.
This may contribute to enhancing the efficacy
of the traditional therapy given to patients
with this type of neoplasia. Furthermore,
tumor cell transfection with antiangiogenetic
cytokines genes is also considered to be of
potential utility in improving pancreatic cancer
treatment in the near future [35].
Table 1. Effects of cytokines on pancreatic cancer cell growth (Growth) and angiogenesis. The autocrine production
by pancreatic cancer cells and the immunomodulatory (IM) effect in patients with pancreatic cancer are also indicated
Cytokines
Autocrine
Growth
Angiogenesis
IM
IL1
+
+
+
IL2
+
IL4
+
IL8
+
+
+
+
IL10
+
BFGF
+
VEGF
+
EGF
+
+
+
TNFalpha
+
+
+
IGF-I
+
+
+
TGF-beta1
+
=
+
PDGF
+
+
RANTES
+
+
MCP-1
+
+
GM-CSF
+
+
+ : stimulatory effect
= : no effect
____________________________________
Abbreviations bFGF: basic fibroblast growth
factor; CDK: cyclin-dependent kinase; DPC 4:
deleted in pancreatic carcinoma locus 4; ECM:
extra-cellular matrix; EGF: epidermal growth
factor; ERKs: extracellular regulated kinases;
GAP: GTPase activating protein; GDP:
guanosine diphosphate; GM-CSF: granulocyte
macrophage colony stimulating factor; GTP:
guanosine triphosphate; ICAM 1: intercellular
adhesion molecule 1; IGF I: insulin-like
growth factor I; IL: interleukin; MAPKs:
mitogen-activated protein kinases; MCP-1:
monocyte chemo-attractant protein-1; PDGF:
platelet derived growth factor; RANTES:
regulated on activation, normal T cell
expressed; TGFalpha: transforming growth
factor alpha; TGF-beta1: transforming growth
factor beta 1; TNFalpha: tumor necrosis factor
alpha; VEGF: vascular endothelial growth
factor
Correspondence
Mario Plebani
Department of Laboratory Medicine
University Hospital of Padua
Via Giustiniani 2
35128 Padova
Phone: +39 049.821.2792
Fax: +39 049.663.240
E-mail: pad08821@pd.nettuno.it
____________________________________
References

Page 4
JOP - Journal of the Pancreas 2000; 1(2):19-23.
JOP – Journal Of the Pancreas www.joplink.net
Vol.1, No. 2 July 2000
22
1. Warshaw AL, Fernandes del Castillo C.
Pancreatic carcinoma. N Engl J Med 1992;
326:455-65.
2. Kern SE. Advances from genetic clues in
pancreatic cancer. Current Opinion in
Oncology 1998; 10:74-80.
3. Lemoine NR, Jain S, Hughes CM,
Staddon SL, Maillet B, Hall PA, et al. Ki-ras
oncogene activation in preinvasive pancreatic
cancer. Gastroenterology 1992; 102:230-6.
4. Byrne JL, Marshall CJ.The molecular
pathophysiology of myeloid leukaemias: Ras
revisited. Br J Haematol 1998; 100:256-64.
5. Bleday R, Tzanakakis GN, Schwalke
MA, Wanebo HJ, Vezeridis MP. Epidermal
growth factor stimulation and metastatic rate
in human pancreatic carcinoma cell lines. J
Surg Res 1990; 49:276-9.
6. Korc M, Chandrasekar B, Yamanaka Y,
Friess H, Buchler M, Beger HG.
Overexpression of the epidermal growth factor
receptor in human pancreatic cancer is
associated with concomitant increases in the
levels of epidermal growth factor and
transforming growth factor alpha. J Clin Invest
1992; 90:1352-60. [93016866]
7. Lemoine NR, Hughes CM, Barton CM,
Poulsom R, Jeffery RE, Klöppel G, et al. The
epidermal growth factor receptor in human
pancreatic cancer. J Pathol 1992; 166:7-12.
8. Basso D, Plebani M, Fogar P, Panozzo
MP, Meggiato T, De Paoli M, et al. Insulin-
like growth factor-I, interleukin-1 alpha and
beta in pancreatic cancer: role in tumor
invasiveness and associated diabetes. Int J Clin
Lab Res 1995;25:40-3.
9. Schmielau J, Kalthoff H, Roeder C,
Schmiegel W. The role of cytokines in
pancreatic cancer. Int J Pancreatol 1996;
19:157-63. [96400984]
10. Schlosser S, Gansauge F, Schnelldorfer
T, Ramadani M, Schwarz A, Beger HG,
Gansauge S. Inhibition of epidermal growth
factor-induced interleukin-1beta-converting
enzyme expression reduces proliferation in the
pancreatic carcinoma cell line AsPC-1. Cancer
Res 1999; 59:4551-4. [99421248]
11. Ohba N, Funatomi H, Seki T, Makino R,
Mitamura K. Hepatocyte growth factor
stimulates cell growth and enhances the
expression of transforming growth factor
alpha mRNA in AsPC-1 human pancreatic
cancer cells. J Gastroenterol 1999;
34:498-504.
12. Birk D, Gansauge F, Gansauge S,
Formentini A, Lucht A, Beger HG. Serum and
correspondent tissue measurements of
epidermal growth factor (EGF) and epidermal
growth factor receptor (EGF-R). Clinical
relevance in pancreatic cancer and chronic
pancreatitis. Int J Pancreatol 1999; 25:89-96.
13. Burtscher I, Compagni A, Lamm GM,
Christofori G. An insulin-like growth factor-
mediated, phosphatidylinositol 3’ kinase-
independent survival signaling pathway in beta
tumor cells. Cancer Res 1999; 59:3923-6.
14. Ono M, Torisu H, Fukushi JI, Nishie A,
Kuwano M. Biological implications of
macrophage infiltration in human tumor
angiogenesis. Cancer Chemother Pharmacol
1999; 43(Suppl):S69-71.
15. Schwiebert LM, Estell K, Propst SM.
Chemokine expression in CF epithelia:
implications for the role of CFTR in RANTES
expression. Am J Physiol 1999; 276:C700-10.
16. Davis R. The mitogen-activated protein
kinase signal transduction pathway. J Biol
Chem 1993; 268:14553-6.
17. Marshall CJ. Specificity of receptor
tyrosine kinase signaling: transient versus
sustained extracellular signal-regulated kinase
activation. Cell 1995; 80:179-85.
18. Seufferlein T, van Lint J, Liptay S, Adler
G, Schmid RM. Transforming growth factor
alpha activates Ha-Ras in human pancreatic
cancer cells with Ki-ras
mutations.
Gastroenterology 1999; 116:1441-52.
19. Manning AM, Williams AC, Game SM,
Paraskeva C. Differential sensitivity of human
colonic adenoma and carcinoma cells to
transforming growth factor beta (TGF-beta):

Page 5
JOP - Journal of the Pancreas 2000; 1(2):19-23.
JOP – Journal Of the Pancreas www.joplink.net
Vol.1, No. 2 July 2000
23
conversion of an adenoma cell line to a
tumorigenic phenotype is accompanied by a
reduced response to the inhibitory effects of
TGF-beta. Oncogene 1991; 6:1471-6.
20. Panozzo MP, Basso D, De Paoli M,
Carraro P, Burighel D, Plebani M. Cytokines
may influence tumor growth and spread. An in
vitro study in two human cancer cell lines. Int
J Clin Lab Res 1996; 26:240-4.
21. Iacopetta BJ, Welch J, Soong R, House
AK, Zhou XP, Hamelin R. Mutation of the
transforming growth factor-beta type II
receptor gene in right-sided colorectal cancer:
relationship to clinicopathological features and
genetic alterations. J Pathol 1998; 184:390-5.
22. Le Dai J, Schutte M, Bansal RK,
Wilentz RE, Sugar AY, Kern SE.
Transforming
growth
factor-beta
responsiveness in DPC4/SMAD4-null cancer
cells. Mol Carcinog 1999; 26:37-43.
[99415461]
23. Schutte M. DPC4/SMAD4
gene
alterations in human cancer, and their
functional implications. Ann Oncol 1999;
10(Suppl 4):S56-9.
24. Ellenrieder V, Adler G, Gress TM.
Invasion and metastasis in pancreatic cancer.
Ann Oncol 1999; 10(Suppl 4):S46-50.
25. Shimoyama S, Gansauge F, Gansauge S,
Kaminishi M, Beger HG. Basal expression and
cytokine induction of intercellular adhesion
molecule-1 in human pancreatic cancer cell
lines. J Exp Clin Cancer Res 1999; 18:107-10.
26. Stefani AL, Basso D, Panozzo MP,
Greco E, Mazza S, Zancanaro F, et al.
Cytokines modulate MIA PaCa 2 and
CAPAN-1 adhesion to extracellular matrix
proteins. Pancreas 1999; 19:362-9.
[20012687]
27. Giavazzi R, Garofalo A, Bani MR,
Abbate M, Ghezzi P, Boraschi D, et al.
Interleukin 1-induced augmentation of
experimental metastases from a human
melanoma in nude mice. Cancer Res 1990;
50:4771-5.
28. Vidal Vanaclocha F, Amézaga C,
Asumendi A, Kaplanski G, Dinarello CA.
Interleukin-1 receptor blockade reduces the
number and size of murine B16 melanoma
hepatic metastases. Cancer Res 1994;
54:2667-72.
29. Shi Q, Abbruzzese JL, Huang S, Fidler
IJ, Xiong Q, Xie K. Constitutive and inducible
interleukin 8 expression by hypoxia and
acidosis renders human pancreatic cancer cells
more tumorigenic and metastatic. Clin Cancer
Res 1999; 5:3711-21. [20055708]
30. McKenzie IFC, Apostolopoulos V.
Towards immunotherapy of pancreatic cancer.
Gut 1999; 44:767-9.
31. Bellone G, Turletti A, Artusio E,
Mareschi K, Carbone A, Tibaudi D, et al.
Tumor-associated transforming growth factor-
beta and interleukin-10 contribute to a
systemic Th2 immune phenotype in pancreatic
carcinoma patients. Am J Pathol 1999;
155:537-47.
32. Kimura M, Yoshida Y, Narita M,
Takenaga K, Takenouchi T, Yamaguchi T, et
al. Acquired immunity in nude mice induced
by expression of the IL-2 or IL-4 gene in
human pancreatic carcinoma cells and anti-
tumor effect generated by in vivo gene transfer
using retrovirus. Int J Cancer 1999;
82:549-55.
33. Aspinall RJ, Lemoine NR. Gene therapy
for pancreatic and biliary malignancies. Ann
Oncol 1999; 10(Suppl 4):S188-92.
34. Fan Z, Mendelsohn J. Therapeutic
application of anti-growth factor receptor
antibodies. Current Opinion in Oncology
1998; 10:67-73.
35. van Hinsbergh VWM, Collen A,
Koolwijk P. Angiogenesis and anti-
angiogenenesis: perspectives for the treatment
of solid tumors. Ann Oncol 1999; 10(Suppl
4):S69-3

There are no products listed under this category.