1. Introduction
Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in men in the United States. It is estimated that PCa will afflict approximately 191,930 men and cause nearly 33,330 deaths this year in the United States alone [
1]. Notably, PCa incidence and associated mortality are nearly two-thirds and over two times higher, respectively, in African-American (AA) men compared to their Caucasian-American (CA) counterparts [
2,
3]. PCa follows a defined pattern of cellular progression but exhibits diverse molecular pathobiology making it one of most highly heterogeneous cancers [
4,
5]. The prostate-specific antigen (PSA) test is the primary detection tool for PCa screening. However, due to the lack of accuracy and specificity, the usefulness of PSA for PCa diagnosis has been questioned [
6,
7,
8]. Most PCa patients are generally subjected to localized radical prostatectomy, radiation therapy, proton beam therapy, and cryosurgery after the initial diagnosis [
9,
10,
11]. However, for patients with metastatic disease or recurrent cancer with locoregional and distant metastases, androgen-deprivation therapy (ADT) or castration therapy is considered the primary line of treatment [
12]. Unfortunately, despite the initial outstanding therapeutic response, most PCa patients treated with ADT eventually have the relapse of PCa in a highly aggressive and therapy-resistant form leading to poor clinical outcomes [
13,
14].
To meet the challenges associated with prostate cancer clinical management, research labs across the world have been working tirelessly to understand underlying molecular diversity and biology of PCa. These efforts have resulted in novel therapies that are currently in clinics, while researchers continue to gather more insights to address new hurdles and failures faced in clinical settings. These advances have been possible through the development of several in vitro and in vivo research models, while new models continue to be developed to address the genetic and biological complexities associated with the PCa. In this review, we discuss the cellular and molecular progression of PCa as well as the available in vitro and in vivo models for PCa research. We believe that the information presented herein will be helpful to the researchers, especially those who are new to the field, in understanding the molecular pathobiology of PCa and guide them in choosing the correct model(s) for their laboratory and preclinical research.
2. Cellular and Molecular Progression of Prostate Cancer
The human prostate is a walnut-size glandular organ that develops from the embryonic urogenital sinus [
15]. Its primary function is to produce seminal fluid containing zinc, citric acid, and various enzymes, including a protease named prostate-specific antigen (PSA). Histologically, the prostate can be divided into central, peripheral, and transition zones comprised of a secretory ductal-acinar structure located within a fibromuscular stroma [
16,
17]. The ductal-acinar structure is formed of tall columnar secretory luminal cells, a flattened basal epithelium attached to the basement membrane, and scattered neuroendocrine cells (
Figure 1). Luminal epithelial cells express cytokeratins (CK) 8 and 18, NKX3.1, androgen receptor (AR), and PSA, whereas basal epithelial cells express CK5, CK14, glutathione S-transferase Pi 1 (GSTP1), p63, and low levels of AR [
18,
19].
The cellular origin of prostate cancer is not very clear, partly because of the lack of well-characterized prostate epithelial lineage [
20,
21,
22]. PCa develops from normal prostate epithelium through a multistep histological transformation process, governed by various underlying molecular changes [
23] (
Figure 2). Low-grade and high-grade prostate intraepithelial neoplasia (PIN) lesions develop from normal prostate epithelium through the loss of phosphatase and the tensin homolog
(PTEN), NK3 Homeobox 1 (
NKX3.1), overexpression of
MYC proto-oncogene, B-cell lymphoma 2 (
BCL-2), and the glutathione S-transferase pi 1 gene (
GSTP1), accompanied with Speckle Type BTB/POZ Protein (
SPOP) mutation and Transmembrane Serine Protease 2- ETS-related gene (
TMPRSS2-ERG) fusion [
24,
25,
26,
27,
28,
29,
30,
31,
32,
33,
34,
35,
36]. Further loss of the retinoblastoma protein (
RB1), along with telomerase activation and frequent Forkhead Box A1 (
FOXA1) mutation, leads to the development of prostate adenocarcinoma from the advanced PIN lesion [
37,
38,
39,
40,
41,
42,
43]. Further molecular aberrations including the loss of SMAD Family Member 4 (
SMAD4), AR corepressors, mutations in AR,
FOXA1, BRCA1/2, ATM, ATR, and
RAD51 accompanied with the gain of function of the AR coactivator,
CXCL12, CXCR4, RANK-RANKL, EMT,
BAI1, and
EZH2 lead to the development of metastatic prostate cancer [
44,
45,
46,
47,
48,
49,
50,
51,
52,
53,
54,
55,
56,
57,
58,
59].
As evident from the PCa progression model (
Figure 2), inactivation of
PTEN appears to be a critical event in PCa carcinogenesis and associated with aggressive disease manifestation.
PTEN alterations occur in various ways in prostate cancer, such as genomic deletion and rearrangement, intragenic breakage, or translocation. The loss of
PTEN is linked with an upregulation of PI3K/AKT/mTOR signaling that regulates cell survival, proliferation, and energy metabolism [
60,
61]. Another critical determinant of PCa tumorigenesis is
SMAD4, a tumor suppressor gene (18q21.1), which mediates the transforming growth factor β (TGF-β) signaling pathway and suppresses epithelial cell growth. Transcriptome analysis revealed significantly lower levels of
SMAD4 in PCa tissues compared to adjacent non-cancerous tissues [
46]. Of note, in a mouse model, prostate specific ablation of
Smad4 and
Pten leads to the development of an invasive and metastatic potential of PCa (discussed below) [
45].
In the PCa initiation and progression cascade, tumor suppressor
NKX3.1 (8p21) plays a pivotal role and found to be frequently lost due to the loss of heterozygosity (LOH) [
62,
63]. Of note, LOH at 8p21 appears to be an early event in PCa tumorigenesis [
63,
64,
65]. Thus, it is likely that the genes that reside within these frequently deleted regions are associated with PCa initiation. Under the normal condition,
NKX3.1 drives growth-suppressing and differentiating effects on the prostatic epithelium [
66].
Nkx3.1 heterozygous mice develop abnormal prostate morphology with the dysplastic epithelium [
67,
68]. Importantly,
Nkx3.1-null mice show changes in prostate epithelial morphology with severe dysplasia [
67]. Kim et al. demonstrated that the loss of function of
Pten and
Nkx3.1 in mice cooperated in PCa development. Importantly,
Pten;Nkx3.1 compound mutant mice showed a higher incidence of High-grade prostatic intraepithelial neoplasia (HGPIN) [
69]. In addition to the critical tumor suppressor genes described above, the
MYC proto-oncogene is also amplified in PCa [
70,
71,
72].
MYC encodes a transcription factor that regulates the expression of several genes involved in cell proliferation, metabolism, mitochondrial function, and stem cell renewal [
73,
74,
75]. Several studies suggest that
MYC is activated through overexpression, amplification, rearrangement, Wnt/β-catenin pathway activation, germline
MYC promotor variation, and loss of
FOXP3 in PCa [
76,
77,
78,
79], and is a critical oncogenic event driving PCa initiation and progression [
71,
80].
Other than
MYC, TMPRSS2:ERG gene fusion, resulting from the chromosomal rearrangement, is also reported in approximately 45% of PCa. This alteration leads to the expression of the truncated
ERG protein under the control androgen-responsive gene promoter of
TMPRSS2 [
81,
82,
83,
84,
85].
ERG belongs to the
ETS family of transcription factors (
ERG, ETV1, and
ETV4), and its activation is associated with PCa progression in both early- and late-stages [
82,
83,
86].
MYB, another gene encoding a transcription factor, is also reported to be amplified in PCa and exhibits an increased amplification frequency in castration resistant PCa (CRPC) [
87]. Research from our laboratory has shown that
MYB plays a vital role in PCa growth, malignant behavior, and androgen-depletion resistance [
56].