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Health Professional Student Journal 2015 2(1)
Review of Hallmarks of Prostate Cancer (PCa)
Nilgoon Zarei*
Abstract: Prostate cancer (PCa) is the most frequently diagnosed noncutaneous malignancy in men and is the second and third leading
cause of cancer mortality for American and Canadian men,
respectively1, 2. PCa is a disease of disrupted prostate cell genomes
and corresponding proteins. Cancer progression starting from normal
prostate epithelium to androgen- dependent and eventually hormonerefractory carcinoma is very complex and involves multiple processes
associated with up/down regulation (malfunction) of different
pathways (cell regulatory circuits)3. PCa, like any other cancer, has
stages from I to IV (I corresponds with low-grade benign cancer and
IV is an advanced malignant tumor).To determine the PCa stages, the
Gleason system is being used, which is solely based on cancer
architectural pattern4. In this study, the ten hallmarks of PCa have
been reviewed. It is important to highlight that PCas with low grade
Gleason degree usually do not express all the hallmarks presented
herein and there is debate regarding considering them cancer or not 4.
Keywords: Prostate Cancer (PCa), Hallmarks of Cancer
Introduction
The mechanisms and proteins involved
in cancer development are complex, and
multiple of protein signaling pathways
should disrupt so that a normal cell
develop into cancer. Despite the
complexity,
these
pathways
are
categorized into ten hallmarks, each
representing a different type of breach in a
cell’s anti-cancer mechanism5-6. Although
there are numerous studies on each
hallmark involved with PCa, there is no
well-organized literature summarizing all
PCa hallmarks. In this paper, a short
review on PCa hallmarks is presented.
* Interdisciplinary Oncology, Faculty of Medicine, UBC,
Canada ([email protected])
1. Self-sufficiency in growth signals
Cancer cells generate their own growth
signals to stimulate mitosis5-6
The Epidermal Growth Factor Receptor
(EGFR) is a cell surface receptor which
involves with cell growth regulation,
differentiation, motility, and adhesion
through interaction with different ligands
such as EGF. As a result of these
interactions,
different
downstream
signaling pathways will be activated, as
shown in Figure 1. RAS-MAPK-MEKERK* and PI3K-AKT* pathways are
activated through EGFR, which both are
responsible
for
tumor-progression.
Impaired endocytic down-regulation of
EGFR will result in uncontrolled signaling
and
eventually
development
into
7
cancer .The EGF binding onto the
androgen-independent prostatic carcinoma
cell line PC3 is analyzed with Scatchard
plot, as shown in Fig2. The steep slope of
the line in bound/free plot of Fig.2 shows
very high affinity between the ligand and
receptor (EGF and EGFR). The PC3
solution was being used for two less
aggressive PCa cell lines (human prostate
carcinoma, LnCap, and classical prostate
cancer cell lines, DU 145). This solution
increased cell proliferation for both cell
lines8, as shown in Fig 3.
Fig 3. Effect of PC3 condition medium on
DU145 and LNCab 8.
RAS: Rat sarcoma
MAPK: Mitogen-Activated Protein Kinases
MEK: Mitogen-Activated Protein Kinase Kinase
ERK: Extracellular-Signal-Regulated Kinases
PI3K: Phosphoinositide 3-Kinase
2. Insensitivity to anti-growth signals
Cancer cells become insensitive to the
signals that tell them to stop growing5-6
Fig.1. Different signaling pathways, ERk and Akt
two important ones in PCa 4
Fig. 2. Scatchard Plot of EGF binding onto PC3
cells, Kd= 5.38 nM (very high affinity),
Bound/Free(B/F) 8.
2
Cyclin-Dependent
Kinase,
Cdks,
governs progression through the cell cycle.
In cell cycle the transition from G1 to S is
governed by the D-type cyclins9. In
response to anti-growth signals; cell might
enter a post-mitotic state where they stop
going through all the processes of cell
division and can no longer proliferate.
Cyclin D2, is a cell cycle-regulatory
gene whose abnormal expression will
force the cells to go through unnecessary
replication cycles. This gene is shown to
be silent in PCa cells. Analysis of 101 PCa
samples showed methylation frequency of
Cyclin D2 promoter is significantly high
in PCas (32% for PCa vs 6% for
nonmalignant prostate tissue)9, Fig.4.
Health Professional Student Journal 2015 1(1)
Fig.4 MSP of Cyclin D2 (276 bp) in prostatic
tumors and nonmalignant tissues. N/T
(nonmalignant/tumors); T3–T10, prostate tumor
samples; L and NC negative control; negative
control and P, positive control. P16 (151 bp)
control9.
3. Evading Immune Destruction
Eliminating the monitoring capability of
immune system6
Cells and tissues are constantly under
the control of immune system. This
supervision and observation system will
aggressively target cancer cells and
eliminate them at early stages, however,
few of cancer bodies manage to either win
this battle or hide from the immune system,
in other words evading eradication6. One
way of doing so is by turning off the T cell
switch.
Cytotoxic
T-LymphocyteAssociated protein 4(CTLA-4), is a
protein on the surface of T cells and acts
as an off switch for T cells. In PCa, it is
shown that blocking CTLA-4 will
significantly help to shrink tumors10.
4. Limitless replication potential
Long DNA ends – cancer cells have
limitless replication potential5-6
To protect the genome, an enzyme
called telomerase adds “extra” base pairs
at the ends of the chromosomes and
lengthens the DNA. Telomerase is active
during embryogenesis and in cells that
need to undergo many cell division cycles,
such as stem cells in the bone marrow, but
is inactive in adult cells. Therefore,
chromosomal DNA becomes shorter with
each successive cell division cycle, which
sets a limit on the number of cell divisions
a cell can undergo. The human telomerase
(such as HumanTelomerase Reverse
Transcriptase, hTERT) is regulated by
Androgen Receptor (AR) signaling.
LNCaP which expresses a mutant but
functional AR, meditates telomerase
activity and increase transcription11.
5. Tumor promoting inflammation
Cancer initiation/progression via
inflammation6
Inflammation has a profound effect on
cancer
development
(initiation
to
metastasis).
It
is
believed
that
inflammation stimulates carcinogenesis12.
Inflammation causes cell/genomic damage,
enhances cell replication, and carries
many more destructive effects12. There is a
strong relationship between inflammation
and PCas13. The level of proinflammaorty
cytokines is shown to be significantly
higher in chronic prostatitis sections
comparing to normal samples. Moreover,
there exists evidence confirming the
higher risk of PCa for men with prostatic
inflammation history13.
6. Tissue invasion and metastasis
Cancer cells invade neighboring cells and
spread throughout the body to new sites5
Spread of cancer cells to other distant
tissues and starting new colonies is known
as cancer invasion or metastasis. Cancer
cells release protease enzyme which
allows them to dissociate, and migrate
independently in the extracellular space
and eventually reside in distant locations
and form colonies14.
Interaction between the stromal cellderived factor 1 (SDF-1), known as C-X-C
motif Chemokine 12 (CXCL12), and C-XC Chemokine Receptor type 4 (CXCR-4),
also known as fusin, plays a critical role in
PCa metastasis into the bone. The
expression of CXCL4 is shown in both
PCa and bone stromal cells. In fact
migration and culturing of PC-3 cells in
bone depends on CXCL12/CXCR4
signaling and Akt activation through PI3kinase14, as shown in Fig1. Also CXCL12
induces expression of Matrix Metallo
Peptidase 9 (MMP-9) in PCa cells, which
is associated with tumor progression and
metastasis.
7. Sustained angiogenesis
The growth of new blood vessels5
Cancerous bodies which reach a size of
1 mm need to initiate angiogenesis, to
receive oxygen and nutrients from the
vessels. So they turn on the angiogenic
switch and start to secrete angiogenesisinducing factors. One such important
factor is Vascular Endothelial Growth
4
Factor (VEGF) which is mediated by
hypoxia, cytokines and androgen5, 15.
VEGF also involves in other pathways
such as (Ras, Raf, and Src**) activation
and inactivation of genes responsible for
tumor suppression15. VEGF levels,
measured
by
immunohistochemical
analysis showed higher level of VEGF in
patients with metastatic prostatic cancer
than those with localized prostatic cancer15.
8. Genome Instability
DNA mutation and repair6
Certain genome alteration during
mutation can simply enforce the normal
cells to outgrow and develop into cancer.
Poly (ADP-ribose) Polymerase, PARP, is a
protein involved in repairing DNA damage
of cancerous cell (the natural damage
during fast replication and the artificial
damage during cancer treatment) 16.
PCa of patients which lacks the
homologous recombination DNA repair
(due to loss-of-function BRCA1* or
BRCA2* mutations) can be treated with
PARP inhibitors. PARP also impacts ERG
transcription and androgen signaling
which are very important pathways in
PCas16.
* BRCA1: the official name of this gene is “breast
cancer 1, early onset.
* BRCA2: the official name of this gene is “breast
cancer 2, early onset.
** RAS: Rat sarcoma, RAF:Rapidly Accelerated
Fibrosarcoma, SRC: Steroid Receptor Coactivator,
Health Professional Student Journal 2015 1(1)
9. Evading apoptosis
Cancer cells resist apoptosis5
All healthy cells will go through natural
(programmed) cell death process known as
apoptosis. Apoptosis can be triggered from
both internal and external signals.
Defender Against Cell Death 1, DAD1,
is a downstream target of the
NFkB(Nuclear Factor Kappa-Light-ChainEnhancer of activated B cells) survival
pathway and boosts cell resistance to
apoptosis. High DAD1 expression is
associated with cancerous epithelium and
its protein level also exhibited a strong
association with microscopic tumor
architecture (Gleason pattern) 17
10. Deregulating cellular energetics
Reprogrammed metabolism to support
proliferation6
Cancer cells reprogram glucose
metabolism, which increases the uptake of
glucose into the cell and also favor
glycolysis even under aerobic condition.
Pyruvate kinase M2 (PKM2) is essential
for
aerobic
glycolysis.
By
immunohistochemistry the researchers
have shown that the expression level of
PKM2 is higher in aggressive prostate
tumor18.
Conclusion
In this survey, ten hallmarks of PCa
have been reviewed and summarized. As
explained in this paper, interruption in
cells’ regulatory
mechanisms
can
eventually result in modified biological
capabilities
(hallmarks)
and
cell
development into tumor. Any prostate
lesion should adopt all the aforementioned
hallmarks of cancer in order to be
considered cancerous.
References
1. Canadian Cancer Society: Canadian Cancer
Statistics. (2012).
2. American Cancer Society. Cancer Facts &
Figures. (2013).
3. Tindall, D. ( 2013). Prostate Cancer
Biochemistry, Molecular Biology and
Genetics, Springer New York, ISBN 1-46146827-2, 978-1-4614-6827-1.
4. Huang, Y. et al. (2010). Epidermal Growth
Factor Receptor (EGFR). Phosphorylation ,
Signaling and Trafficking in Prostate
Cancer.
Oncogene 29, 4947–4958;
doi:10.1038/onc.2010.240.
5. Hanahan, D., Weinberg, R. A., & Francisco,
S. (2000). The Hallmarks of Cancer Review
University of California at San Francisco,
100, 57–70.
6. Hanahan, D., & Weinberg, R. a. (2011).
Hallmarks of cancer: the next generation.
Cell,
144(5),
646–74.
doi:10.1016/j.cell.2011.02.013
7. Balducci J. et al.(2010) Differential roles of
ERK and Akt pathways in regulation of
EGFR-mediated signaling and motility in
prostate cancer cells, Oncogene. 29.35
p4947.DOI:
http://dx.doi.org.ezproxy.library.ubc.ca/10.1
038/onc.2010.240
8. Hofer, D. R, et al. (1991). Autonomous
Growth of Androgen-independent Human
Prostatic Carcinoma Cells : Role of
Transforming Growth Factor α Autonomous
Growth of Androgen-independent Role of
Transforming Growth Factor a1, 2780–2785
9. Padar, A., et al.(2003). Inactivation of
Cyclin D2 Gene in Prostate Cancers by
Aberrant Promoter Methylation, 4730–4734.
10. Klyushnenkova, E. N., et al. (2014).
Breaking immune tolerance by targeting
CD25+ regulatory T cells is essential for the
anti-tumor effect of the CTLA-4 blockade in
an HLA-DR transgenic mouse model of
prostate cancer. The Prostate, 74(14), 1423–
32. doi:10.1002/pros.22858
11. Hendriksen, P. J. M., et al. (2006). Evolution
of the androgen receptor pathway during
progression of prostate cancer. Cancer
research,
66(10),
5012–20.
doi:10.1158/0008-5472.CAN-05-3082
12. Grivennikov, S. et al. (2010). Immunity,
Inflammation, and Cancer, Cell, 140(6) 883899
13. Dal Moro, F., et al. (2013). Inflammation
and prostate cancer. Urologic oncology,
31(5),
712.
doi:10.1016/j.urolonc.2013.03.002
14. Cxcl, M. et al. (2006). CXCL12 / CXCR4
Signaling Activates Akt-1and MMP-9
Expression in Prostate Cancer Cells : The
Role of Bone, 48(April 2005), 32–48.
doi:10.1002/pros.20318
15. Russo, G., et al. (2012). Angiogenesis in
prostate cancer: onset, progression and
imaging. BJU international, 110(11 Pt C),
E794–808.
doi:10.1111/j.1464410X.2012.11444.x
16. Pusceddu, S. et al. (2013). Pancreatic welldifferentiated neuroendocrine neoplasms
(pWDNENs): what place for everolimus and
sunitinib derived from ESMO clinical
practice guidelines in the therapeutic
algorithm? Annals of oncology : official
journal of the European Society for Medical
Oncology / ESMO, 24(5), 1415–6.
doi:10.1093/annonc/mdt102
6
17. Jung, K. (2007). A molecular correlate to the
Gleason grading system for prostate
adenocarcinoma. European urology, 51(3),
851–2.
Retrieved
from
http://www.ncbi.nlm.nih.gov/pubmed/17421
063
18. Wong N, et al. (2014). Changes in PKM2
associate with prostate cancer progression,
Cancer
invest,
32(7):330-8.
doi:
10.3109/07357907.2014.919306