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Role of inflammation in prostate carcinogenesis and prostate cancer growth

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Role of inflammation in prostate carcinogenesis and prostate cancer growth

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Content Role of inflammation in prostate carcinogenesis and prostate cancer
growth

by

Xuejun He
A Thesis Presented to the
FACULTY OF THE USC SCHOOL OF PHARMACY
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(Molecular Pharmacology and Toxicology)

May 2020

Copyright [2020] Xuejun He
ii

Acknowledgements
Firstly, I would like to express my deep and sincere gratitude to my research supervisor, Dr. Jean
Chen Shih, School of Pharmacy, University of Southern California, for giving me the opportunity
to do research and providing me invaluable experience to become a scientist. Dr. Jean Chen Shih
has provided me with help and guidance for my graduate studies and research abilities. I like to
express my appreciation to work with Dr. Jean Chen Shih this year.

Moreover, I would like to extend my sincere gratitude to our technician Bin Qian for his help in
teaching me the techniques used in experiments.

I would also like to give special thanks to Dr. Clay Wang and Dr. Yong Zhang to serve in my
committee to review my work and give me valuable comments.

Finally, I would like to thank my parents for their support and encouragement to help me
complete the MS degree at USC.

iii

Table of Contents
Acknowledgements………………………………………………………………………………ii
List of Figures……………………………………………………………………………………iv
Abbreviations………………………………………………………….…………………………v
Abstract…………………………………………………………………..………………………vi
Chapter 1. Introduction……………………………………………….…………………………1
1.1 Prostate cancer overview……………………………………………………………………1
1.1.1 Stages…………………………………………………………………………………2
1.1.2 Therapies…………………………………………………….………………………2
1.2 Inflammation overview………………………………………...……………………………4

Chapter 2. Cause of Prostate Inflammation…………………………………………….………6
2.1 Infectious agents……………………………………………………………………….……6
2.2 Urine reflux and physical, chemical trauma…………………………………………………7
2.3 Hormones……………………………………………………………………………………7

Chapter 3. Chronic Inflammation Promote Prostate Carcinogenesis ………………...………8
3.1 Proliferative Inflammatory Atrophy (PIA) ………………………………….………………8
3.2 Mechanism of inflammation induced prostate carcinogenesis……………..………………10
3.2.1 Role of ROS and inflammation in prostate cancer……………………..………………10
3.2.2 Hypoxia, ROS, and inflammation………………………………………...……………12
3.3 Role of immune cells in inflammation induced prostate cancer ……………………………14
3.3.1 Neutrophils………………………………………………….…………………………17
3.3.2 Macrophages…………………………………………………..………………………18
3.3.3 Myeloid-derived suppressor cells (MDSCs) ……………………..……………………19
3.3.4 Mast cells………………………………………………………………………………20

Chapter 4. Potential Drugs used for treating Prostate Cancer……………………23
4.1 Aspirin and NSAIDs……………………………….………………………………………23
4.2 Metformin………………………………………………….………………………………24
4.3 Statin……………………………………………….………………………………………26
4.4 MAOA inhibitors…………………………………………………………………………27

Chapter 5. Conclusion…………………………..………………………………………………28

References………………………………….……………………………………………………30
iv

List of Figures
Figure 1. Inflammatory response in normal wound healing verse the organization of invasive
carcinomas in infectious sites……………………………….…………………………………….5

Figure 2. Stages from PIA to invasive carcinoma…………………………...…………………….9

Figure 3. Overview of cellular ROS ………………………………………….………………….11

Figure 4. Correlation between NF-KB and HIF………………………………………………….14

Figure 5. IHC staining immune cells in normal and inflamed tissue……………………………..16

Figure 6. The interaction between immune cells and inflammation…………..………………….22

v

Abbreviations
PCa Prostate Cancer
PSA prostate specific antigen
TGF Transforming growth factor
IL Interleukin
VEGF Vascular endothelial growth factor
PIN Prostatic intraepithelial neoplasia
ROS Reactive oxygen species
HIF Hypoxia inducible factor
NFKB Nuclear factor kappa-light-chain-enhancer of activated B cells
MMP Matrix metallopeptidase
TNF-alpha Tumor necrosis factor alpha
MAOA Monoamine oxidase A
AMPK AMP-activated protein kinase
EMT Epithelial to Mesenchymal Transition
GST Glutathione S-transferase
IFN-gamma Interferon gamma

vi

Abstract
Prostate cancer is the most common and leading death of male cancer in the world. researchers
try to understand the mechanisms of prostate cancer progression and find efficient targets to inhibit
the growth of prostate cancer or even prevent the prostate carcinogenesis. Inflammation is
commonly associated with many solid cancer growths, and the chronic inflammation can be
induced by microorganism infectious, microbe, unhealthy diet and hormones. The chronic
inflammation can induce gene mutation, DNA damage and lead to prostate carcinogenesis.
Inflammatory response is part of immune system, and the secretion of pro-inflammatory and anti-
inflammatory cytokines also contribute to the growth, invasion and metastasis of prostate cancer.
Reactive oxygen species (ROS) is a major factor involved in the tumor inflammatory
microenvironment and prostate cancer progression. Other cytokines and chemokines, including
NF-KB, HIF, IL and TNF-a are downstream factors of the inflammatory signaling pathway.
Therefore, anti-inflammation drugs and the drugs have anti-inflammatory abilities have been
considered as potential medications to inhibit the prostate cancer growth after the first line therapy.

1

Chapter 1 Introduction
Prostate cancer is one of the common and lethal cancer in man, and the progression of
prostate cancer influence by many factors, such as high fat diet, environmental factors and
family history. However, prostatitis is usually found in early stage of prostate cancer diagnosis.
Chronic inflammation induces the prostate carcinogenesis due to various factors, also promotes
the tumor growth in later stages. In this review, I will discuss the mechanisms of inflammation
which induce and promote prostate cancer how immune cells involved in, the cell signaling
pathway involved in the promotion of tumor growth and effects of potential anti-inflammation
drugs used for treating prostate cancer.

1.1 Prostate cancer overview
Prostate cancer is the second common cancer and second leading cause of cancer death in
American men (Fitzmaurice, 2018), about 190,000 new prostate cancer has been diagonalized
in 2020 and about 30,000 people dead due to prostate cancer ("Key Statistics for Prostate
Cancer ",2020). Anything can be a risk factor of having prostate cancer, age may be a crucial
reason with increasing risk of prostate cancer since over 60% diagnosed patients are 65 years
old or older, and the average age at diagnosed is 66 years old in America. High-fat diet and
inflammation are also the factors influence the prostate cancer risk. Scientists have not found
the role and mechanism of diet on increasing the risk of prostate cancer. However, the statistical
data has shown that high-fat diet tend to have higher chance of having prostate cancer than
people with vegan diet ("Prostate Cancer Risk Factors",2020). Inflammation is a major factor
lead to the prostate cancer growth, but there is no direct evidence showing the inflammation
2

link to the increased risk of having prostate cancer (Nakai & Nonomura, 2012). Prostate cancer
is kind of solid cancer which characterized as the abnormal dividing of cells in the prostate
gland which lead to uncontrolled growth of prostate gland.

1.1.1 Stages of Prostate cancer
With the continued growth of tumor cells, the stages of prostate cancer are changed, and
different treatments are applied. Early detection of prostate cancer is a significant way to
prevent the death rate of prostate cancer since most people who died of prostate cancer occurs
due to the metastasis of cancer cells, which spread out to other areas of body. The prostate
specific antigen (PSA) has been detected and used for most detection of prostate cancer, and
the level of PSA can be used to classify the cancer stage group. For stage 1, the cancer is
restricted in the prostate and not spread, and a PSA is below 10ng/ml. For stage 2, the cancer
is still restricted in the prostate tissue but start differentiated, and the PSA is greater than 10 but
less than 20 ng/ml. High level of PSA is detected in stage 3; the tumor is growing and tend to
spread outside of prostate gland. In stage 4, the cancer starts to metastases to lymph nodes,
bones or other part of body. The PSA level is not the factor to determine stage 3 and 4, since
these two stages are more depend on the invasion and spreading of prostate cancer ("Prostate
Cancer - Stages and Grades", 2019).

1.1.2 Therapies
Based on different stages of prostate cancer, local treatments and systemic treatments are
applied. Local treatments include surgery and radiation therapy which often applied when
3

tumor grows in a limited area of body, which does not spread out in the body ("Prostate Cancer
- Types of Treatment", 2020). Surgery is the primary treatment used on human to removal of
the prostate, depends on the techniques, stages of the tumor and patients’ health, whole prostate,
surrounding lymph nodes and both testicles may be removed ("Prostate Cancer - Types of
Treatment", 2020). Radiation therapy is the use of high energy ray to kill the tumor cells,
including external-beam radiation therapy and internal radiation therapy. Before using either
radiation therapy, a computed tomography (CT) scan is required to confirm the shape, location
and size of the tumor since the high energy rays will also destroy healthy cells. Accurate
information about the tumor will reduce the damage of radiation to the surrounding healthy
tissues and cells ("Prostate Cancer - Types of Treatment", 2020). Systemic treatments are
generally use medication through intravenous (IV) or orally, and the given medication move
through bloodstream to reach the tumor site. Testosterone suppression therapy, chemotherapy
and immunotherapy are types of systemic treatments used commonly in patients ("Prostate
Cancer - Types of Treatment", 2020). Since the growth of prostate cancer is related to the male
sex hormones called androgens, inhibit the expression of androgens or block the androgen
receptors can effectively lower the growth of prostate cancer. Testosterone is a kind of androgen
which produced by testicles, therefore either removal of testicles (surgery) or inhibition of the
expression of testosterone by using drugs can be used for slowing the growth of tumor
("Prostate Cancer - Types of Treatment", 2020). Chemotherapy is a drug treatment cancer are
docetaxel and prednisone. Docetaxel is a microtubule inhibitor, which can prevent the
formation of microtubule during mitotic cell division and further prevent the uncontrolled
growth of cancer cells (Yvon, Wadsworth, & Jordan, 1999). Prednisone is a corticosteroid that
4

commonly has anti-inflammatory function and suppress the immune system, since
inflammation is always associated with tumor growth, combination use of anti-inflammatory
drugs and other therapy may has better efficacy for treating prostate cancer ("Prednisone Uses,
Dosage, Side Effects, Warnings",2020). Immunotherapy is type of biological therapy that
trigger out human’s own immune system to defense the cancer. Our immune system can detect
and destroy the abnormal cells, but some cancer cells can disguise as normal cancer and evade
from the immune system. Immunotherapy use chemicals or materials that can trigger immune
system or target the biomarker on tumor cells to restore the immune system to improve the
efficacy of the self-defense ("Immunology for Cancer",2020). Sipuleucel-T is one of the
immunotherapies used in prostate cancer, it helps immune system to recognize the tumor cells
and kill them, but this therapy cannot directly reduce the PSA level or eliminate the tumor, it
shows work on lengthen lives in patients with metastatic prostate cancer ("Prostate Cancer -
Types of Treatment", 2020). However, the difficulties of treating prostate cancer is the recurring
of tumor and the castration-resistant type of prostate cancer, combination use of the therapies
may show higher efficacy and researchers are also trying to find new targets on prostate cancer
cells to improve the treatments.

1.2 Inflammation overview
Inflammation is a biological response to be initiated upon the infections, wounds and
damages on tissues. Since inflammation is part of immune response, it is triggered by pro-
inflammatory cytokines and leads to the cascade of chemicals and factors in body to attempt to
remove harmful pathogens or chemicals from the infectious sites. Leukocytes, mast cells and
5

various chemokines are all involved in the physiological and pathological process. Neutrophils,
a type of leukocytes that first involved in inflammatory response, coordinate with extracellular
matrix (ECM) to form a scaffolding which help endothelial cells and fibroblast to migrate and
proliferate on the infectious sites (Gallin & Snyderman, 1999). Then macrophages also
involved in this repair process, since monocytes are guided by chemotactic factors, such as PF-
4 and TGF-beta, then migrate to the infectious sites and differentiate to macrophages. Since
macrophages play major roles in modulating the growth factors and epithelial, endothelial cells
to repair the damaged tissues (Osuský, Malik, & Ryan, 1997; Dipietro, 1995). Various
chemokines involved in and control the inflammatory responses: collagens, which response to
wounding healing, is secreted by fibroblasts is simulated by TGF-beta and interleukin (IL-1),
IL-4. These chemokines regulate the generation of collagens and wound healing in the damaged
sites, and dysregulation of these chemokines may result to chronic inflammation which may
increase the risk of cancer (Romer, et al., 1996; Coussens & Werb, 2002).

6

Fig 1. Inflammatory response in a. normal wound healing verse the organization of b. invasive
carcinomas in infectious sites. The proliferation of malignant epithelial cells and angiogenesis
are the markers of carcinogenesis (Coussens & Werb, 2002).

Chapter 2. Cause of prostate inflammation
Many studies have shown the chronic inflammation in prostate contribute to the prostate
carcinogenesis and prostate cancer growth. However, what factors causes prostate
inflammation are unclear. A few hypothesizes are applied, including infectious agents, such as
viruses and microorganisms; physical and chemical trauma; urine reflux and hormonal changes.
All these factors may cause chronic prostate inflammation and generate oxidative stress in the
microenvironment, and further contribute to the prostate carcinogenesis with chronic
inflammatory response (Marzo, et al., 2007).
2.1 Infectious agents
Unlike cervical carcinoma which mainly caused by the HPV infectious, no single specific
virus or microorganisms lead to the prostate cancer. However, several sexual transmitted
microorganisms together induce the prostate inflammation, including Neisseria gonorrhoeae
(Pelouze, 1943), Chlamydia trachomatis (Poletti, et al., 1985), and Trichomonas vaginalis
(Gardner, Culerson, & Bennett, 1986). The mixed of microorganism present in the prostate
ducts disrupt the epithelial barrier to cause acute or chronic inflammation, further contribute to
the prostate carcinogenesis. With the increased using of antibiotics, the incidence of the
microorganism infected prostate inflammation is decreased (Marzo, et al., 2007). However, the
7

microorganisms and viruses infectious is still the leading cause of prostate inflammation, and
the prostate inflammation caused by the microorganisms infectious is persist for months or
years even after the cleaning of microorganisms in prostate ducts (Bandarra & Rocha, 2013).

2.2 Urine reflux and physical, chemical trauma
In previous, urine is considered to be sterile after infiltration. However, bacterial DNA has
been detected in the urine which originate in the urinary tract and bladder, the urine reflux will
bring back many toxic chemicals and microorganisms to contribute to the prostate
inflammation and prostatic diseases (Whiteside, Razvi, Dave, Reid, & Burton, 2015; Kirby,
Lowe, Bultitude, & Shuttleworth, 1982). Uric acid has been considered to participate in the
activation of innate immune response, to generate inflammatory responses (Martinon, Pétrilli,
Mayor, Tardivel, & Tschopp, 2006). In addition, the development of corpora amylase which is
a physical trauma directly disrupt the epithelial barrier, contributes to the disruption of
epithelial cells to allow microorganisms and viruses into the lesions of prostate, and further
induce prostate inflammation (Drachenberg & Papadimitriou, 1996;Weinstein & Gardner,
1992).

2.3 Hormones
Androgen is expressed in prostatic development regulated by androgen receptors, and
expression of androgens is essential for the epithelial cell proliferation and differentiation
(Cunha & Chung, 1981). Androgen-deprived therapy is a common way to treat prostate cancer,
but the expression of androgen receptor still high and resistance to the castration. The increased
8

expression of androgen receptors is associated with increased inflammatory response which
AR can promote the recruitment of macrophages and induce the B cell development (Huang,
Luo, Lee, & Chang, 2014 ; Loberg, et al., 2007). Another sex steroid, estrogens, also contribute
to the prostate inflammation and prostate carcinogenesis. Similar to androgen and its receptor,
the estrogens may undergo the pathway related to estrogen receptors to activate the
autoimmune response and further contribute to the chronic inflammation in prostate (Härkönen
& Mäkelä, 2004).

In summary, exposure to outside factors, such as viruses, injury and diet, or infected by
intracellular factors, including microorganisms and hormones, all can induce prostate
inflammation and contribute to prostate cancer. These injury factors directly destroy the
epithelial barrier and disrupt the homeostasis in prostate, allow the infectious materials enter
in cells and cause inflammation in prostate and further induce inflammatory response to
contribute prostate carcinogenesis (Marzo, et al., 2007).

Chapter 3 Chronic inflammation promote prostate carcinogenesis

3.1 Proliferative Inflammatory Atrophy (PIA)
Based on many epidemiologic studies, the increased risk of prostate cancer is associated
with chronic inflammation (Philip, Rowley, & Schreiber, 2004). Proliferative inflammatory
atrophy is lesion within prostate which become pathological evidences to prove the link
between inflammation and prostate carcinogenesis. PIA is a focal lesion develops in the
9

absence of androgen, which shown increased number of epithelial cells in the peripheral zone
of the prostate (Rich, 1935&1979). In the genetic level of the mechanism of PIA, the increased
expression of GSTP1, an inducible enzyme that protect cells from oxidative and DNA damages,
is associated with the morphology of PIA. GSTP1 is a major class of GST, which are enzymes
that detoxification of reactive oxidants that produced by inflammation (Parsons, et al., 2001).
The increased expression of GSTP1 with PIA indicates the PIA is vulnerable to cellular stress
and tend to accumulate genetic damages in the inflammatory sites, and finally convert to PIN
and prostate cancer cells. The increased expression of GSTP1 is due to the methylation in the
CpG island which does not shown in normal epithelial cells (Parsons, et al., 2001), and
researchers also found 40% morphological transition from PIA to PIN, and finally grows to
invasive PC, suggest the linkage between inflammation between prostate cancer cells (Putzi &
Marzo, 2000; Marzo, Marchi, Epstein, & Nelson, 1999).
Fig 2.
The stages from normal epithelial cells (a), injury to epithelial cells will lead to PIA, which is
a sign of prostate carcinogenesis (b). Somatic gene mutation initiates the proliferation of
carcinogenesis cells (c). The uncontrolled proliferation of necrotic epithelial cells leads to
progression and invasive carcinoma (d). (Marzo, et al., 2007)

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3.2 Mechanism of inflammation induced prostate carcinogenesis
Inflammation in prostate cancer is related to various factors, such as obesity,
microenvironment and infections. The most well-known mechanism of inflammation induced
inflammation is the generation of ROS caused by chemical stress around the neoplastic cells,
and the elevated immune cells induced by the inflammation accumulated in the necrosis cells
and further transfer to tumor.

3.2.1 Relation of ROS and inflammation in prostate cancer
ROS are produced by O2 metabolism, and fatty acid oxidative in mitochondrial. There are
three major types of ROS produced in human body: hydroxyl radical, superoxide and hydrogen
peroxide. They have different biological and chemical properties, such as half-life, the ability
to bind the biological receptors and reactivity may all influence their toxicities in our body
(Briehl, 2015). Under healthy condition, the generated ROS will be detoxified and leave
through channel out of cell. However, when cells under inflammation situation, such as
prostatitis, the stress will cause the unbalanced ratio of production and detoxification of ROS,
which will induce normal cells transformation into tumor cells (Tafani, et al., 2016). Increased
ROS level generate chronic oxidative stress in the inflamed site, and the oxidative stress
microenvironment induce multiple carcinogenesis of the cells, including DNA double strands
break down, impair the function of repair DNA, mutation in tumor suppressor gene (such as
p53), and inhibit apoptosis of necrotic cells (Ziech, Franco, Pappa, & Panayiotidis, 2011;
Caputo, Vegliante, & Ghibelli, 2012). The lipoperoxidation is the most serious impact induced
by elevated ROS level, degradation of plasma membrane structure will disrupt the ionic
11

gradient between intracellular and extracellular part. And the disrupted permeability will
induce abnormal intracellular hemostasis lead to normal cells transfer to necrotic cells (Tafani,
et al., 2016).

Fig.3 Overview of ROS. ROS are produced mainly in mitochondria, some of ROS are
detoxified quickly, other ROS transfer into cytosol activate HIF, NFkB and HDACs;
proinflammatory cytokines can induce the production of ROS. HIF and NF-KB activate the
target genes for defense and damage repair. Imbalanced ROS ratio in cell will induce
dysfunction of these adaptations which contributes to the tumor progression (Tafani, et al.,
2016).

12

3.2.2 Hypoxia, ROS and inflammation
Hypoxia is a common tumor microenvironment which triggers many cytokines and genes.
ROS is also a downstream factor induced by hypoxia which contribute to inflammation and
cancer growth (Zhou, Schmid, Schnitzer, & Brüne, 2006). Hypoxia condition will generate
ROS to the microenvironment, and hypoxia-inducible factor (HIF), which regulate the cellular
response to oxygen change, is induced by the elevated ROS level. NF-KB is a pathway
response to inflammation, acts part of immune response, and activated by inflammatory
cytokine (such as TNF-a) which induced by the generation of ROS (Dignazio, Batie, & Rocha,
2017).
Recent studies revealed the relation between NF-KB and HIF since they are bi-directional
and share many common target genes involved in carcinogenesis, such as IL-6, MMP9, COX2
and BCl2 (Balamurugan, 2015). Hypoxia, ROS, HIF and NF-KB forms a complex signaling
network to induce inflammatory response and formation of tumor. ROS generated in the
hypoxia area and trigger HIF, the alarmin released from necrotic cells destroyed by ROS bind
to their receptors then trigger a proinflammatory gene expression and lead the activation of
NF-KB. Interestingly, tumor cells can also present the alarmin receptors followed the HIF
activation, trigger the constitutive NF-KB activation at the tumor area which result
inflammation of the area and contribute to the tumor progression (Huang, et al., 2015). NF-KB
and HIF, as two significant transcription factors facilitate tumor growth, induce many
downstream genes which contribute to the carcinogenesis by increasing tumor cell proliferation,
regulating angiogenesis and metastasis, and inhibiting apoptosis of necrotic cells. MMP-9 and
TIMP are downstream genes regulated by NF-KB, MMP-9 regulate the extracellular matrix
13

which responsible for the spread of endothelial cells and tumor cells. Therefore, the constitutive
NF-KB induce disruption of MMP-9 expression will lead to angiogenesis and tumor cell
metastasis (Bond, Fabunmi, Baker, & Newby, 1998). Another target gene for both NF-KB and
HIF which contribute to prostate cancer growth is Vascular Endothelial Growth Factor (VEGF).
Similar to MMP-9 which facilitate the spread of endothelial, VEGF are essential growth factors
that control the growth of vascular endothelial cells. Upregulation of VEGF by the constitutive
activation of NF-KB and HIF leads to the spread of endothelial cells, which help the tumor
proliferation by angiogenesis on the tumor sites (Duffy, Bouchier-Hayes, & Harmey, 2004).
Many other target genes are regulated by both NF-KB and HIF directly or indirectly, their
relationship represent the mechanism of inflammation in tumor, how hypoxia
microenvironment and ROS contribute to inflammation and prostate cancer growth: Hypoxia
area of tumor produced the pro-inflammatory cytokines which trigger NF-KB, and ROS are
generated to activate HIF. Coordination between NF-KB and HIF lead the accumulated
immune cells at the neoplastic site which cause chronic inflammation due to the constitutive
high activity of NF-KB, finally contribute to the tumor growth (Bandarra & Rocha, 2013).
14

Fig4. Correlation between NF-KB and HIF. Stimuli, target genes, and common regulators are
shown. Shared stimuli, target genes and proteins play essential roles in prostate carcinogenesis
(Bandarra & Rocha, 2013).

3.3 Role of immune cells in inflammation induced prostate cancer
In prostate cancer, chronic inflammation has been found highly prevalent in the neoplastic
site, and finally transfer to tumor cells. Inflammation is part of immune response since both
innate and adaptive immune cells are involved, but inflammatory response is mainly controlled
by innate immune cells in early stage of prostate cancer. Tumor cells generate pro-
inflammatory cytokines or other chemokines to activate innate immune cells and the
downstream cell signaling (Shalapour & Karin, 2015). By epidemiological evidences show, the
number of lymphocytes, kind of adaptive immune cells, increased in the peripheral zone which
15

is the origin of prostate cancer (Bostwick, Roza, Dundore, Corica, & Iczkowski, 2003). Fig5
shows the IHC data which indicates the presence of immune cells is rare under normal prostate
condition, but the number of immune cells, including both innate and acquired, has increased
under inflammation condition (Sfanos, Yegnasubramanian, Nelson, & Marzo, 2017).
16

17

Fig 5. IHC staining immune cells in normal and inflamed tissue, a) T cell, b) B cell, c)
Monocytes d) Mast cells. Increased number of immune cells in the inflamed tissue which
indicates the upregulation of immune response in inflammation (Sfanos, Yegnasubramanian,
Nelson, & Marzo, 2017).

3.3.1 Neutrophils
Neutrophil is one type of eosinophils which help heal damaged tissues and have antibacterial
immune response ("Neutrophils: Functions and count result meanings",2020). Neutrophils are
activated by tumor secreted cytokines, including IL-6, TNF-a and G-CSF which can increase
the half-life of the neutrophil, help the immune cells stay in inflamed site longer to promote
the chronic inflammation (Shaul & Fridlender, 2019; Coffelt, Wellenstein, & Visser, 2016).
The tumor secrete chemokine can link with neutrophils to form tumor-associated neutrophils
(TANs) which are immunosuppression (Shaul & Fridlender, 2019). However, TANs have the
paradoxical roles as many immune cells in tumor growth since TANs have two subtypes: N1
and N2. Overexpression of pro-inflammatory proteins, iNOS and TNF, in N1 TANs may
contribute to the inhibition of tumor growth. N2 TANs are immunosuppressive which induce
tumor cell proliferation and increased tumor angiogenesis that may help prostate cancer growth.
However, the expression of inflammatory mediators, such as IL-6 and MMP, in both N1 and
N2 TANs show both pro-tumor and antitumor effects in neutrophils. This may be the reason
neutrophils have both immunosuppression and antitumor activity (Shaul & Fridlender, 2019).

18

3.3.2 Macrophages
Macrophages are the most abundant immune cells play roles in prostate cancer growth and
metastasis. Macrophages also responsible for inflammatory response which contribute to the
prostate cancer. Depends on different stimuli secreted tumor cells or other cells, macrophages
also play paradoxical role that can polarize to anti-inflammatory type and pro-inflammatory
type (Lo & Lynch, 2018). For the pro-inflammatory macrophages, necrotic cells secrete the
inflammatory cytokines, such as ROS and IL-12 (Wang, Liang, & Zen, 2014). These cytokines
induce the generation of pro-inflammatory macrophages, and the macrophages secrete TNF, a
pro-apoptosis cytokine that induce cell apoptosis. The pro-inflammatory macrophages clean
the apoptosis cells in neighboring cells and present the tumor antigens to T cells. The pro-
inflammatory macrophages, called M1, has the anti-tumor activity with the secretion of the
cytokines, IL-12 and TNF, to help immune system target the damaged sites. (Allen & Rückerl,
2017; Michlewska, Dransfield, Megson, & Rossi, 2009; Roberts, Dickinson, & Taams, 2015).
Anti-inflammatory macrophages, called M2, are induced by the IL-10 and TGF-beta, the
factors secreted from fibroblast and platelets. The anti-inflammatory macrophages suppress
inflammation by secreting VGEF and ROS to deactivate T cells activities, result in
immunosuppression tumor microenvironment and promoting tumor growth (Gelderman, et al.,
2007). The presence of M2 in the inflamed sites lead to immune tolerance and increase the
tumor cell proliferation. In prostate cancer, the tumor cells can secrete factors, such as CSF-1,
to recruit phenotype of macrophages to microenvironment, and secret new stimulus to polarize
the macrophages as pro-inflammatory or anti-inflammatory (Lo & Lynch, 2018). Since
monocytes are the blood circulating macrophage, differentiate to macrophage when they move
19

into cells [48]. Monocytes and macrophages can also function as a negative predictor in
prostate cancer diagnosis, since the number of monocytes in peripheral blood, the mainly origin
zone of prostate cancer, is increased in high-grade of prostate cancer, which indicate the
infiltrating macrophages in tumor cells (Elliott, Doherty, Sheahan, & Ryan, 2017; Hayashi, et
al., 2016,2017).

3.3.3 Myeloid-derived suppressor cells (MSDCs)
Myeloid-derived suppressor cells (MSDCs) are immature myeloid cells which has
immunosuppression function. Accumulation of MSDCs are found in tumor cells, which are
generated by the pro-inflammatory mediators that secreted by these tumor cells. And the
accumulated MSDCs promote tumor growth because of the role of immunosuppression (Diaz-
Montero, et al., 2008). Myeloid cells are precursor of many immune cells, such as macrophage,
neutrophils and dendritic cells (Ostrand-Rosenberg & Sinha, 2009). Then MSDCs are
characterized to Macrophage-like MSDCs and Neutrophils-like MSDCs, depend on the cell
surface marker, Abs, on MSDC detected by Grl or CD11b. Grl include markers Ly6G and Ly6C,
Ly6C and CD11b belong to macrophage markers and Ly6G belongs to neutrophils markers.
Based on the concept of MDSCs, they are the precursors and intermediate phages of myeloid
cells, the final phenotypes of MDSCs are depends on the stimuli factors secreted by tumor
(Youn, Nagaraj, Collazo, & Gabrilovich, 2008; Sawanobori, et al., 2008; Movahedi, et al.,
2008). Chronic inflammation induces increased number of MDSCs promote tumor growth,
MDSCs promote tumor proliferation by inhibiting the T cell activity directly or indirectly.
MDSC can directly inhibit T cell activity by uptake of arginine and decreased the intracellular
20

level of arginine around T cells, which is a key amino acid for T cell activation, depletion of
the arginine around the T cells to inhibit the activation of T cells for inflammatory response
(Kusmartsev, Nefedova, Yoder, & Gabrilovich, 2004; Bronte, Serafini, Mazzoni, Segal, &
Zanovello, 2003). On the other hands, MDSCs can produce ROS to prevent the recognition
between T cells and antigen presenting MHC, shut down the recognition process and inhibit
the further action of T cell (Nagaraj, et al., 2007). Furthermore, MDSCs can also secreting
factors IL10 and TGF-beta to induce the activation of regulatory T cells, which responsible for
downregulating the immune response, indirectly suppress the T cell activity (Huang, et al.,
2006). Interestingly, macrophage like MDSCs inhibit T cells via NO production whereas
neutrophil like MDSCs inhibit T cells activation via ROS, and the secretion of both NO and
ROS required the generation of factor IFN-y, which is an immunosuppressive molecule in
MDSCs. Therefore, both macrophage like MDSCs and neutrophil like MDSCs activated
depend on the secretion of IFN-y (Youn, Nagaraj, Collazo, & Gabrilovich, 2008; Movahedi,
et al., 2008; Huang, et al., 2006).

3.3.4 Mast Cells
Mast cells are one of the major effector cells responsible for immune responses and
contribute to both innate and adaptive immune immunity (Theoharides & Conti, 2004). Since
mast cells are infiltrated in tumor sites and play roles in allergy and inflammation, the
correlation between inflammatory response and tumor progression has been studied. Similar to
many immune cells involved in tumor, mast cells can promote prostate cancer growth and also
contain protective function. The paradoxical function of mast cells depends on the secretion of
21

cytokines and factors, and studies show that different stages of prostate cancer induce different
densities of mast in the neoplastic foci (Pittoni & Colombo, 2012). MMP-9 and IL-10 are
released by mast cells to promote the tumor growth, since MMP-9 is a pro-angiogenic factor,
an essential factor in tissue remodeling, contributes to tumor invasion. IL-10 is also a common
immunosuppressive cytokine secreted by mast cell which modulates the expression regulatory
T cell, inhibit the T cell activity in inflammatory response at the neoplastic sites in prostate
cancer (Maltby, Khazaie, & Mcnagny, 2009). However, mast cell can also induce the
production of TNF-a, a proinflammatory cytokines which can trigger the inflammatory
response and further eliminate the cell debris and apoptotic cell by macrophages, contributes
to the inhibition of prostate cancer growth (Pittoni & Colombo, 2012; Echtenacher, Männel,
& Hültner, 1996). On the other hands, expression of mast is not ubiquitous in every stages of
prostate cancer. MMP-9 is the major factor regulates the presence of mast cells in prostate
cancer (Coussens, Tinkle, Hanahan, & Werb, 2000). In early stage, the differentiated of
epithelial cells are not well, the tumor need mast cells to produce MMP-9 to help forming new
blood vessels and promote the invasion to neighboring tissue. However, in the later stage of
prostate cancer, the tumor can undergo EMT to produce MMP-9 for invasion and angiogenesis
instead of the presence of mast cells (Pittoni, et al., 2011; Kanbe, et al., 1999). Therefore,
increased number of mast cells are found in early stage of prostate, which may be a marker for
early diagnosis, and the number decreased in the later stage of prostate cancer since the
production of MMP-9 does not need the involvement of mast cells (Pittoni & Colombo, 2012).

In summary, inflammatory response and tumor growth are regulated by both innate and
22

adaptive immune cells, these cells are not independently work to defense tumor or promote
tumor. They are regulating by the common cytokines and factors, such as the proinflammatory
factors TNF-a involved in the function of mast cells, neutrophils and macrophages, even the
production of ROS, the upstream stimuli trigger inflammation. Then these innate immune cells
trigger the cytotoxic T cell and induce the inflammatory response. The relation between
cytokines, growth factors and immune cells triggers the different responses of immunity to
respond to the tumor growth or inhibition.

Fig 6. The interaction between immune cells and inflammation. Inflammation induce prostate
cancer progression. Immune cells induced by tumor cell secreted cytokines (Hayashi, Fujita,
Matsushita, & Nonomura, 2019).

23

Chapter 4. Potential drugs used for treating prostate cancer

Since studies show chronic inflammation can induce prostate carcinogenesis and promote
the prostate cancer growth by induce gene mutation, damaged DNA repair proteins and
promote tumor cell proliferation and invasion (Colotta, Allavena, Sica, Garlanda, & Mantovani,
2009). Using drugs to directly or indirectly inhibit inflammation becomes a marker to treat
prostate cancer associated with traditional therapies.

4.1 Aspirin and NSAIDs
The original function of aspirin and NSAIDs is anti-inflammation, so NSAIDs are the first
considered drugs to confirm whether inhibit chronic inflammation can reduce the cancer
incidence or even treat the cancer (Cuzick, et al., 2009). Aspirin is the most common NSAIDs
used in the world, and I also use this drug to test its effect on treating prostate cancer cells.
Many large epidemiological studies indicate intake of regular amount (75mg-300mg) daily for
long time can reduce the incidence of cancer, especially for colon and lung cancers (Rothwell,
et al., 2012). And other studies show aspirin can also inhibit the metastasis of tumor and
increase the survival rate of patients (Pearson, 2011). Based on my experiments, I also find the
presence of aspirin can reduce the prostate cancer cell proliferation.
The anti-tumor mechanism of NSAIDs is mainly depend on COX2, since NSAIDs as anti-
inflammation drugs inhibit inflammation response via COX pathway (Benamouzig, et al.,
2010). COX1 is constitutively expressed in human body, and COX2 is activated by
inflammatory factors such as interleukin. Increased expression of COX2 is found in tumor,
24

which induce the upregulated expression of Bcl2, the gene contributes to increased anti-
apoptotic effect (Chen, 2005). Less apoptosis of necrotic cells in tumor site, higher the tumor
growth. On the other hands, Bcl-2 also contributes to the mitochondrial hemostasis and
permeability for precursor of apoptotic factors (Zhang, Chen, & Shang, 2018). EGFR and
MMP-2 is also the other downstream factor controlled by COX2, which promote the
transformation from normal cells to malignant tumor cells and the tumor invasion and
angiogenesis (Leung, Mcarthur, Morris, & Williams, 2008; Li, et al., 2015). Therefore,
NSAIDs as anti-inflammatory drugs, can inhibit COX2 expression and further downregulate
the expression of Bcl-2, EGFR and MMP-2 which inhibit tumor growth and invasion via
increased apoptosis of necrotic cells (Zhang, Chen, & Shang, 2018). However, the analysis of
aspirin and other NSAIDs happen in other cancer, especially colon cancer. More researches
about the effects of NSAID in prostate cancer need to be provided.

4.2 Metformin
The common anti-type 2 diabetes drug, metformin has shown anti-tumor activities in recent
researches. The meta-analysis indicates the relation between metformin and prostate cancer,
intake of metformin can improve the overall survival rate in prostate cancer but cannot reduce
the incidence of prostate cancer (He, et al., 2019). However, controversial studies also show
metformin can reduce the incidence of prostate cancer (Häggström, et al., 2016). More data
need to be applied to verify the incidence of having prostate cancer and intake of metformin.
The common mechanism of metformin of its anti-tumor effect is to activate AMPK pathway
and reduce the mTOR activity further reduce the cancer growth, since high expression of
25

mTOR is found in prostate cancer (Dowling, Zakikhani, Fantus, Pollak, & Sonenberg, 2007).
The anti-tumor activity of metformin in prostate cancer also relate to the inflammatory
infiltration in the neoplastic sites. NF-KB is the major protein complex control the transcription
of DNA, and secretion of cytokines in inflammatory response. Inhibition of NF-KB can reduce
the prostate cancer growth by inhibiting the tumor cell proliferation. Study has shown that
activation of NF-KB can inhibit the AMPK pathway and also upregulate the expression of
MDR1, which highly expressed in prostate cancer. Metformin can downregulate the expression
of NF-KB and further inhibit the expression of MDR1 by the activation of AMPK pathway,
result in the reduced prostate cancer growth (Kim, et al., 2011). Furthermore, previous section
describes the networking of NF-KB, ROS and HIF in inflammatory response in prostate cancer,
these cells signaling are involved together and affect each other to reduce the prostate cancer
growth.
Decreased the recruitment of macrophage is also driven by the metformin to reduce the
inflammatory response on neoplastic site. The phenotypes of macrophages differentiated by
monocytes are depend on the cytokines and microenvironment. As mentioned in macrophage
section, two subtypes of macrophages are generated due to different factors. M1 and M2 has
converse function, but it can be transformed from one to another under the secreted stimuli.
Metformin can inhibit the recruitment of macrophage to decrease the number of M2 in the
tumor site, which can reduce the prostate cancer cell proliferation and invasion (Liu, et al.,
2018).

26

4.3 Statin
Statin is a common drug used to treat lipid disorders, and recent studies reveal the anti-tumor
activity in many solid cancers, including prostate cancer (Sassano & Platanias, 2008). However,
whether the statin can reduce the incidence of prostate cancer is still controversial, more meta-
analysis are required to confirm the effects of statin (Loehrer, 2006; Shannon, et al., 2005). The
basic mechanism of statin to treat lipid disorders is to inhibit the cholesterol synthesis by
inhibiting HMG-CoA reductase. And two types of statins are classified by their solubility,
hydrophobic and hydrophilic types of statin transfer into the tissue via passive diffusion
(hydrophobic) and facilitated transporters (hydrophilic). Ideally, hydrophobic statin seems
easier to transfer into prostate, but no observation support (Alfaqih, Allott, Hamilton, Freeman,
& Freedland, 2016).
Statin can reduce the prostate cancer growth by inhibiting inflammation on neoplastic site,
reduce angiogenesis, inhibit tumor cell proliferation and tumor invasion. The mechanism of
statin to reduce prostate cancer growth via inflammatory response depends on the modulation
of differentiation of T cells. Statin can decrease the expression of STA T4 which further reduce
the generation of Th1 and its cytokines, including IL-2, IL-12 IFN-y and TNF-a, which are
pro-inflammatory. On the other hands, statins can increase the phosphorylation of STA T6
which can increase the generation of Th2 and its cytokines (IL-4, IL-10 and TGF-beta) as anti-
inflammatory cells. Statins regulate the generation of T cells to prevent the chronic
inflammation and inflammatory response in prostate tumor site for inhibiting the tumor growth
(Youssef, et al., 2002; Demierre, Higgins, Gruber, Hawk, & Lippman, 2005).
Furthermore, statin can reduce the prostate cancer growth by downregulating MMP-9, which
27

involved in basement membrane degradation and contributes to tumor invasion. Also, Bcl-2 is
downregulated by statin which induce tumor cell apoptosis, which inhibit the prostate cancer
growth (Demierre, Higgins, Gruber, Hawk, & Lippman, 2005; Wong, et al., 2001). Both of
MMP-9 and Bcl-2 involved in the cell signaling of inflammatory response, which indicates the
complex signaling cascades are communicating with each other. And statin as anti-cholesterol
synthesized drugs for treating lipid disorders, can also inhibit prostate cancer growth, which
indicates the cholesterol may contribute to the growth of certain cancer, and the cell signaling
pathways of cholesterol may be the target for treating prostate cancer.

4.4 MAOA Inhibitor
Monoamine Oxidase A is a mitochondrial bound enzyme that catalyze the monoamine
neurotransmitters, and generate hydrogen peroxide as product, which is the major source of
ROS (Shih, Chen, & Ridd, 1999). The original role of MAOA inhibitor is to treat depression
and other neuro diseases. In recent year, researchers found MAOA also highly expressed in
high grade prostate cancer, especially on epithelial cells. Based on the studies, MAOA can
induce EMT through VEGF pathway and further contribute to the proliferation and
differentiation of prostate epithelial cells (Zhao, Nolley, Chen, Reese, & Peehl, 2008). Further
studies investigate the relationship between MAOA and inflammatory microenvironment.
Since the byproduct of MAOA is ROS which contribute to the inflammatory response and
prostate carcinogenesis, and stabilizing HIF1a also contribute to the hypoxia and inflammatory
tumor microenvironment (Wu, et al., 2014). In addition, increased MAOA expression induce
the increased transcription of pro-inflammatory cytokines IL-6, which is a regulator of immune
28

and inflammatory response. IL-6 can activate STA T3 pathway, which promote the prostate
cancer cell proliferation and invasion (Culig & Puhr, 2018). Since MAOA plays a role in
promoting prostate cancer growth through inflammatory response pathway, MAOA inhibitors
may also as a potential therapy to treat chronic inflammation induced prostate cancer. Inhibition
of MAOA may reduce the production of ROS, the factor contributes to hypoxia and
inflammation, and reduce the expression of pro-inflammatory response cytokine. Based on
previous discussion, increased ROS induce oncogene mutation and responsible for prostate
carcinogenesis, and further activate NF-KB and HIF pathway which contribute to the prostate
tumor growth. The generation of pro-inflammatory cytokines also promote the inflammatory
tumor microenvironment. Inhibition of overproduction of ROS and proinflammatory by
MAOA inhibitor may potentially become a way to control the chronic inflammation induced
prostate cancer.

Chapter 5. Conclusion
Even the function of inflammation in prostate cancer has been studied, further investigation
of its role of prevention and detailed mechanisms are still required. Both innate and adaptive
immune systems and immune cells are involved in inflammatory response and progression of
prostate cancer, which indicates prevention of inflammation and immunotherapy may be
applied to inhibit the prostate carcinogenesis and progression of prostate cancer. In addition,
further meta-analysis of anti-inflammation drugs in prostate cancer treatment are required to
confirm their ability to inhibit cancer growth since there are controversial effects in different
29

studies. Prevention of prostate cancer related to inflammation seems to need further
investigation, either taking anti-inflammation drugs to prevent inflammation or avoid from
chemicals and microorganisms which can cause chronic inflammation.

30

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Abstract (if available)

Abstract Prostate cancer is the most common and leading death of male cancer in the world. Researchers try to understand the mechanisms of prostate cancer progression and find efficient targets to inhibit the growth of prostate cancer or even prevent the prostate carcinogenesis. Inflammation is commonly associated with many solid cancer growths, and the chronic inflammation can be induced by microorganism infectious, microbe, unhealthy diet and hormones. The chronic inflammation can induce gene mutation, DNA damage and lead to prostate carcinogenesis. Inflammatory response is part of immune system, and the secretion of pro-inflammatory and anti-inflammatory cytokines also contribute to the growth, invasion and metastasis of prostate cancer. Reactive oxygen species (ROS) is a major factor involved in the tumor inflammatory microenvironment and prostate cancer progression. Other cytokines and chemokines, including NF-KB, HIF, IL and TNF-a are downstream factors of the inflammatory signaling pathway. Therefore, anti-inflammation drugs and the drugs have anti-inflammatory abilities have been considered as potential medications to inhibit the prostate cancer growth after the first line therapy.

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Asset Metadata

Creator He, Xuejun (author)

Core Title Role of inflammation in prostate carcinogenesis and prostate cancer growth

School School of Pharmacy

Degree Master of Science

Degree Program Molecular Pharmacology and Toxicology

Publication Date 05/04/2020

Defense Date 05/01/2020

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag Inflammation,OAI-PMH Harvest,prostate cancer

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Shih, Jean Chen (committee chair), Wang, Clay (committee member), Zhang, Yong (committee member)

Creator Email hexuejun1996@126.com,xuejunhe@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c89-296459

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Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

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