Alumni
Non UBC
DSpace
Basak, Debasish
Gregori, Lisney
Johora, Fatema
Deb, Subrata
The incidence and mortality from prostate cancer (PCa) are on the rise which poses a major public health concern worldwide. In this narrative review, we have summarized the characteristics of major in vitro and in vivo PCa models including their utility in developing treatment strategies. Androgens, particularly, testosterone and dihydrotestosterone (DHT) activate the androgen receptor (AR) signaling pathway that facilitates the development and progression of castration resistant PCa. Several enzymes namely, CYP17A1, HSD17B, and SRD5A are essential to furnishing DHT from dehydroepiandrosterone in the classical pathway while DHT is formed from androstanediol in the backdoor pathway. The advancement in delineating the molecular heterogeneity of PCa has been possible through the development of several in vitro and in vivo research models. Generally, tissue culture models are advantageous to understand PCa biology and investigate the efficacy and toxicity of novel agents; nevertheless, animal models are indispensable to studying the PCa etiology and treatment since they can simulate the tumor microenvironment that plays a central role in initiation and progression of the disease. Moreover, the availability of several genetically engineered mouse models has made it possible to study the metastasis process. However, the conventional models are not devoid of limitations. For example, the lack of heterogeneity in tissue culture models and the variation of metastatic characteristics in xenograft models are obviously challenging. Additionally, due to the racial and ethnic disparities in PCa pathophysiology, a new model that can represent PCa encompassing different ethnicities is urgently needed. New models should continue to evolve to address the genetic and molecular complexities as well as to further elucidate the finer details of the steroidogenic pathway associated with PCa.
Citation: Basak, D.; Gregori, L.;Johora, F.; Deb, S. Preclinical andClinical Research Models of ProstateCancer: A Brief Overview. Life 2022,12, 1607. https://doi.org/10.3390/life12101607Academic Editors: Ana Faustino andPaula A. OliveiraReceived: 6 September 2022Accepted: 30 September 2022Published: 14 October 2022Publisher’s Note: MDPI stays neutralwith regard to jurisdictional claims inpublished maps and institutional affil-iations.Copyright: © 2022 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).lifeReviewPreclinical and Clinical Research Models of Prostate Cancer:A Brief OverviewDebasish Basak, Lisney Gregori, Fatema Johora and Subrata Deb *Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA* Correspondence: sdeb@alumni.ubc.ca; Tel.: +1-224-310-7870Abstract: The incidence and mortality from prostate cancer (PCa) are on the rise which poses a majorpublic health concern worldwide. In this narrative review, we have summarized the characteristicsof major in vitro and in vivo PCa models including their utility in developing treatment strategies.Androgens, particularly, testosterone and dihydrotestosterone (DHT) activate the androgen receptor(AR) signaling pathway that facilitates the development and progression of castration resistant PCa.Several enzymes namely, CYP17A1, HSD17B, and SRD5A are essential to furnishing DHT fromdehydroepiandrosterone in the classical pathway while DHT is formed from androstanediol in thebackdoor pathway. The advancement in delineating the molecular heterogeneity of PCa has beenpossible through the development of several in vitro and in vivo research models. Generally, tissueculture models are advantageous to understand PCa biology and investigate the efficacy and toxicityof novel agents; nevertheless, animal models are indispensable to studying the PCa etiology andtreatment since they can simulate the tumor microenvironment that plays a central role in initiationand progression of the disease. Moreover, the availability of several genetically engineered mousemodels has made it possible to study the metastasis process. However, the conventional models arenot devoid of limitations. For example, the lack of heterogeneity in tissue culture models and thevariation of metastatic characteristics in xenograft models are obviously challenging. Additionally,due to the racial and ethnic disparities in PCa pathophysiology, a new model that can represent PCaencompassing different ethnicities is urgently needed. New models should continue to evolve toaddress the genetic and molecular complexities as well as to further elucidate the finer details of thesteroidogenic pathway associated with PCa.Keywords: prostate cancer; research models; preclinical; clinical; androgens; steroidogenesis1. IntroductionProstate cancer (PCa) is a frequently diagnosed malignancy that ranks second incancer-related deaths in men in the United States [1]. The growth and survival of PCahave been attributed to the androgens that act by both stimulating proliferation andsuppressing apoptosis. Thus, hormone therapy or androgen deprivation therapy hasbecome the standard approach for PCa treatment. Despite an improved outcome withandrogen deprivation therapy in the initial stages or in castration-sensitive PCa patients, themajority of the patients succumb to metastatic castration-resistant prostate cancer (CRPC).Androgen receptor (AR) amplification and mutations in AR are the most critical molecularaberrations, which basically trigger the development of CRPC. CRPC is characterized bythe presence of androgen-refractory cells that are more aggressive and highly metastaticcompared to androgen-dependent cells [2]. Although the recent FDA-approved agents(e.g., abiraterone, cabazitaxel) offer some benefist, the five-year survival rate of CRPCpatients is only about 28.2% [3]. Figure 1 delineates the flow of research from preclinicalto clinical components. Essentially, the development of PCa involves several steps thatbegin with the formation of prostate intraepithelial neoplasia (PIN). This arises due tothe overexpression of glutathione S-transferase pi 1 gene (GSTP1), B-cell lymphoma 2Life 2022, 12, 1607. https://doi.org/10.3390/life12101607 https://www.mdpi.com/journal/lifeLife 2022, 12, 1607 2 of 18(BCL-2), and proto-oncogene MYC [4–6]. The subsequent loss of phosphatase and tensinhomolog (PTEN), NK3 Homeobox 1 (NKX3.1), and retinoblastoma protein (RB1) resultsin prostate adenocarcinoma [7–9]. The condition is aggravated when metastatic PCadevelops due to the mutations in AR, ATM, BRCA1/2, and loss of SMAD Family Member4 (SMAD4) [10,11].Life 2022, 12, 1607 2 of 19 the formation of prostate intraepithelial neoplasia (PIN). This arises due to the overex-pression of glutathione S-transferase pi 1 gene (GSTP1), B-cell lymphoma 2 (BCL-2), and proto-oncogene MYC [4–6]. The subsequent los of phosphatase and ten in homolog (PTEN), NK3 Homeobox 1 (NKX3.1), and retinoblastoma protein (RB1) r sults in p o ta e aden carcinoma [7–9]. The condition is aggravated when met static PCa develops due to the mutations in AR, ATM, BRCA1/2, and loss of SMAD Family Member 4 (SMAD4) [10,11]. Figure 1. Schematic diagram of the flow of research from preclinical to clinical components. AR usually displays preferential binding to heat shock proteins (HSP) in its dormant form [12]. Upon binding of androgens to its ligand binding domain (LBD), AR gets acti-vated and translocated to the nucleus. Subsequent binding of AR to androgen response elements (AREs) results in the transcription of several downstream genes. This also pro-motes the upregulation of various signaling pathways such as the PI3K/AKT pathway, which has enormous implications for different cancers [13]. Moreover, AR is closely linked to cell growth, proliferation, and metastasis. De novo steroidogenesis drives the maintenance of intratumoral androgens that may deliver an adaptive response in CRPC by activating the AR signaling pathway [14]. Androgens comprise different sex hormones of which testosterone and dihydrotestosterone (DHT) are the most prominent androgenic ligands of AR; others include androstenedione, androstenediol, and dehydroepiandros-terone. Usually, the Leydig cells in testes produce testosterone that gets converted to DHT by 5α-reductase (SRD5A) in the prostate [15]. Two types of steroidogenesis are observed that are designated as “classical” and “backdoor” pathways. In the classical pathway, pregnenolone and progesterone get converted to Dehydroepiandrosterone (DHEA) and androstenedione by the sequential hydroxylase and lyase activity of CYP17A1. After en-tering the prostate, these adrenal androgens yield testosterone with the help of enzymes HSD3B and HSD17B. Finally, testosterone gets converted to the more potent androgen dihydrotestosterone in the presence of SRD5A [16]. In the backdoor pathway, progester-one is first converted to pregnan-3,20-dione that ultimately gets converted to androstane-diol via the enzymes CYP17A1 and HSD17B. Subsequent formation of DHT occurs from androstanediol by the actions of RDH5 and AKR1C [17]. PCa cells elicit an alteration in androgen sensitivity that is mediated by an overexpression of AR. This event is associated with the androgen independence of PCa cells. Overall, AR upregulation results in andro-gen-hypersensitivity that can lead to hormone-resistance in PCa patients [18]. Hence, AR antagonists are heavily employed in the treatment of PCa and a better understanding of AR function as well as AR sensitivity is of paramount importance to devise more effective PCa therapeutics. Apart from AR, a good number of markers are also available in PCa. These include but are not limited to cytokeratins, p53, PTEN, Rb, NKx3.1, Ki-67, β-catenin, EGFR, etc. fl li i l t cli ic l c e ts.s all is la s refere tial i i t eat s c r tei s ( S ) i its r a tfor [12]. pon binding of androgens to its ligand binding domain (LBD), AR gets activatedand translocated to the nucleus. Subsequent binding of AR to androgen response elements(AREs) results in the transcription of several downstream genes. This also promotes theupregulation of various signaling pathways such as the PI3K/AKT pathway, which hasenormous implications for different cancers [13]. Moreover, AR is closely linked to cellgrowth, proliferation, and metastasis. De novo steroidogenesis drives the maintenanceof intratumoral androgens that may deliver an adaptive response in CRPC by activatingthe AR signaling pathway [14]. Androgens comprise different sex hormones of whichtestosterone and dihydrotestosterone (DHT) are the most prominent androgenic ligands ofAR; others include androstenedione, androstenediol, and dehydroepiandrosterone. Usually,the Leydig cells in testes produce testosterone that gets converted to DHT by 5α-reductase(SRD5A) in the prostate [15]. Two types of steroidogenesis are observed that are designatedas “classical” and “backdoor” pathways. In the classical pathway, pregnenolone andprogesterone get converted to Dehydroepiandrosterone (DHEA) and androstenedione bythe sequential hydroxylase and lyase activity of CYP17A1. After entering the prostate,these adrenal androgens yield testosterone with the help of enzymes HSD3B and HSD17B.Finally, testosterone gets converted to the more potent androgen dihydrotestosterone inthe presence of SRD5A [16]. In the backdoor pathway, progesterone is first convertedto pregnan-3,20-dione that ultimately gets converted to androstanediol via the enzymesCYP17A1 and HSD17B. Subsequent formation of DHT occurs from androstanediol by theactions of RDH5 and AKR1C [17]. PCa cells elicit an alteration in androgen sensitivitythat is mediated by an overexpression of AR. This event is associated with the androgenindependence of PCa cells. Overall, AR upregulation results in androgen-hypersensitivitythat can lead to hormone-resistance in PCa patients [18]. Hence, AR antagonists are heavilyemployed in the treatment of PCa and a better understanding of AR function as well as ARsensitivity is of paramount importance to devise more effective PCa therapeutics. Apartfrom AR, a good number of markers are also available in PCa. These include but are notlimited to cytokeratins, p53, PTEN, Rb, NKx3.1, Ki-67, β-catenin, EGFR, etc.Several PCa cell lines were developed in the early 1970s and 1980s, such as LNCaP,DU145, and PC-3 which are still indispensable in research [19–21]. Nevertheless, the com-mon PCa cell lines are not devoid of limitations. For example, these cell lines do notaccurately simulate the heterogeneity that is frequently observed in human tumors [22].Life 2022, 12, 1607 3 of 18Therefore, patient-derived cancer models such as patient-derived xenografts (PDXs) area better alternative to drug screening since they can more precisely simulate clinical re-sponses in patients [23]. Presently, several PCa PDX models are used worldwide [24].Human prostate tissue and PCa patients are one of the most sought PCa research models.In this narrative review article, we have summarized the major in vitro and in vivo PCamodels that could be helpful for the investigators to decide on the appropriate models forconducting research and developing treatment strategies. Overall, PCa research modelscan be classified into preclinical and clinical models, where preclinical models are higher inboth number and frequency of use. Preclinical models include primary and secondary celllines, patient-derived or cell-line derived xenografts, transgenic mouse, knockout mouse,and cancer-related inflammation models. Likewise, clinical models are limited in natureand mainly comprised of human prostate tissues and patients.2. Cell Culture Models2.1. Androgen-Dependent Cells: LNCaPThe androgen responsive LNCaP cell line possesses the mRNA/protein expressionof both AR and prostate specific antigen (PSA). This cell line was established from lymphnode metastasis [19]. In the AR coding sequence, LNCaP displays a mutation in T877Athat results in unsolicited affinity to different steroid compounds [25]. Their doublingtime is 60–72 h and they express IGF-1-R, EGF/TGF-α-R, and FGF-R [26,27]. Moreover,they exhibit wild type (WT) p53 and PTEN inactivation [28–30]. Some sublines thatwere established from LNCaP showed the ability to grow in vivo after subcutaneousor orthotopic implantation. Among the sublines, LNCaP-LN3 produced lymph nodemetastases more frequently after being implanted into the prostate. Additionally, afterintrasplenic implantation LNCaP-LN3 resulted in liver metastases. LNCaP-LN3 furnishedhigh levels of PSA and showed less androgen sensitivity [31,32]. This cell line shows a highexpression of SRD5A1, a very low level of SRD5A2, and no expression of CYP17A1 [33,34].2.2. Androgen-Independent Cells2.2.1. PC-3PC-3 cells that do not exhibit AR or PSA mRNA/protein were obtained from vertebralmetastasis of prostate tumor. Their doubling time is about 33 h. This cell line expressesaberrant p53 with a nonsense codon that demonstrates a loss of heterozygosity [35,36]. Theyalso express transferrin receptor [37,38] and their independent growth is due to elevatedexpression of TGF-α and EGF-R [39]. Due to its robust tumorigenicity, PC-3 remains afrequently used cell line that can grow easily in vivo [40]. It is worth mentioning that PC-3is more characteristic of neuroendocrine rather than adenocarcinoma [41]. A metastaticvariant of PC-3 is PC-3M. Tumors were excised from the prostate or lymph nodes and later,these tumor cells were reintroduced into the prostate. The cycle was repeated several timesthat generated the sublines, PC-3M-Pro4 and PC-3M-LN4. PC-3M-LN4 cells exhibiteda greater level of lymph node, lung, and bone metastasis [32]. PC-3 shows very lowexpression of CYP17A1, moderate level of SRD5A1, and very low level of SRD5A2 [33,42].2.2.2. C4-2BLNCaP C4-2B subline is androgen independent and has a doubling time of 48 h.These cells possess a greater metastatic potential than the parental LNCaP cell line. Whenthese cells are injected intraosseous or intracardially into the immunodeficient mice, theyproduce osteoblastic or mixed osteolytic–osteoblastic lesions. Due to the elimination ofdifferent molecular properties of localized and treatment-naive PCa, this cell line attainsthe most undifferentiated state of PCa [40]. LNCaP and human osteosarcoma MS cells weresubcutaneously co-injected into the mice from which C4 cells were generated. Later, C4cells were subcutaneously injected into a castrated mouse followed by the culturing of thetumor cells and development of C4-2 cells. These cells finally resulted in a cell line thatLife 2022, 12, 1607 4 of 18produced bone metastasis and this metastatic line was named C4-2B [43]. The steroidogenicenzyme expression in C4-2B is yet to be reported.2.3. Wild-Type AR2.3.1. LAPC-4LAPC-4 cell line was generated from the lymph node metastasis of a hormone-refractory PCa patient through sequential subcutaneous xenografting into SCID mice.While developing this cell line, the explants from the PCa patients were xenografted intomice from which the tumor cells were later grown in culture dishes [44]. The doubling timeof this cell line is about 72 h and the cells can grow subcutaneously, orthotopically, or intrat-ibially in nude mice [45]. They express wild type AR, PSA, and PTEN and demonstrate p53mutations (P72R and R175H) [46]. The available evidence also reported the expression of abasal epithelial and a luminal epithelial marker called CK5 and CK8 [44]. LAPC-4 displaysthe high expression of SRD5A1 [47].2.3.2. VCaPThe VCaP cell line was generated from a hormone-refractory metastatic PCa pa-tient [48]. This cell line displays AR, PSA, prostatic acid phosphatase (PAP), and retinoblas-toma (Rb). Moreover, it expresses CK-8, CK-18, PTEN, and p53 which have an A248Wmutation. Its doubling time is about 51 h and it grows reasonably well both in normal andcastrated mice [49]. VCaP cells exhibit the TMPRSS2:ERG fusion gene that was reportedto form tumors orthotopically [50]. It is also tumorigenic to SCID mice when injectedsubcutaneously [51]. VCaP cell line exhibits a high expression of CYP17A1 [52].2.4. Normal Prostate Epithelium Cells RWPE-1The RWPE-1 cell line was obtained from a 54-year-old man’s prostate and human pa-pillomavirus 18 (HPV-18) was used to make the cell immortalized [53]. Their doubling timeis about 120 h and they express AR, PSA, and luminal prostatic epithelium markers, CK8and CK18. They also display heterogenous nuclear staining for p53 and Rb proteins [54].The epidermal growth factor (EGF) and fibroblast growth factor (FGF) promote the growthof RWPE-1 and TGF-β suppresses their growth [55,56]. It is important to note that theRWPE-2 cell line that can form a tumor in the nude mice after subcutaneous injection wasdeveloped by the transformation of RWPE-1 with Ki-ras [54]. The steroidogenic enzymeexpression is absent in this cell line. Table 1 summarizes the primary characteristics ofmajor PCa cell lines.Life 2022, 12, 1607 5 of 18Table 1. General properties of prostate cancer cell lines. Compiled from published literature [19,21,26,33,34,42–44,47,48,52,54].Cell Line Source Doubling Time PSA AR Markers Steroidogenesis Markers Advantage DisadvantageLNCaP Lymph nodemetastasis 60–72 h + +p53, absence of PTEN,vimentinSRD5A1—highSRD5A2—very lowSublines have growthpotential in vivoInsensitivity to androgenand mutated ARPC-3 Vertebralmetastasis 33 h - -Absence of p53, loss ofPTEN, TGF-α, EGFRCYP17A1—very low,SRD5A1—moderate,SRD5A2—very lowGreater extent ofmetastasis AR-negativeC4-2BXenograft ofLNCaP cell innude mice48 h + + p53, absence of PTEN UndocumentedVery good growthpotential both in intactand castrated miceLAPC-4Lymph node ofandrogeninsensitive patient72 h + + Mutation in p53 SRD5A1—high Hormone-responsivePossibility ofandrogen-independenceif grown in female orcastrated male miceVCaP Vertebralmetastasis 51 h + +Mutation in p53,PTEN, Rb CYP17A1—highSensitivity toandrogen; expressesPSA, and ARThe availability ofwild-type TMPRSS2 andERG genes obstructs theprobe of TMPRSS2-ERGrearrangement in vitroRWPE-1 HPE cells from theperipheral zone 120 h + + P53, Rb No expressionBeneficial toinvestigate themolecularmechanisms of benignprostatic epithelial cellproliferationNo tumor formationin miceLife 2022, 12, 1607 6 of 182.5. Drug Resistant Cell LinesLike most other cancers, the development of drug resistance is frequently observedin PCa. Therefore, drug-resistant cell lines can be employed in research to identify novelmolecular mechanisms of chemoresistance. Mohr et al. reported the generation of docetaxel-resistant PCa cell lines. In their study, they initially treated DU145 and 22Rv1 cells with10 nM of docetaxel followed by an increase in drug concentrations (25 nM, 50 nM, 100 nMand 250 nM). They confirmed docetaxel resistance by colony formation assay and pheno-typic characterization by qRT-PCR [57]. Hongo et al., generated cabazitaxel-resistant DU145and PC-3 cells where they began cabazitaxel treatment at a concentration of 0.3 nmol/L andlater, progressively increased the dose to a final concentration of 3 nmol/L. In this study,they found that DU145CR cells exhibited resistance against cabazitaxel-mediated G2/Marrest through the upregulation of ERK signaling and PC-3CR cells displayed amplifiedPI3K/AKT signaling [58]. In a follow-up study, they reported an elevated expression ofAURKB and KIF20A in DU145CR compared to a non-CBZ-resistant cell line [59]. Kregelet al., reported the development of enzalutamide-resistant (EnzR) cell lines where theytreated CWR-R1, LAPC4, LNCaP, and VCaP cell lines with 10 Mm enzalutamide for atleast 6 months before carrying out experiments. They found that enzalutamide-resistantLNCaP and CWR-R1 cells presented enhanced castration-resistant and metastatic growthin vivo [60]. Liu et al., reported the development of abiraterone resistant C4-2B cells thatwere exposed to 5–20 Mm abiraterone acetate over 12 months. They demonstrated thatthe overexpression of AR-V7 was associated with resistance to abiraterone, which sug-gested that the addition of an AR-V7 inhibitor could be instrumental for treating advancedCRPC [61].3. Xenograft ModelsLNCaP cell line is very commonly used for developing mouse xenografts. This cellline was isolated from lymph node metastasis [19]. After isolation, its tumor forming abilityin mice was about 50% through subcutaneous injection [62]. Nowadays, matrigel use canproduce higher rates of tumor and form faster in male mice. It is unique due to its abilityto express both AR and ER. They carry a mutated androgen receptor (AR) (T877A) [25].Its tumorigenicity is inadequate in athymic nude mice and that is why LNCaP sublineswere created that have better growth potential in vivo [31,32]. These include LNCaP-Pro3–5and LNCaP-LN3–4. LNCaP-LN3 cells generate lymph nodes and liver metastases to agreater extent.The PC-3 cell line can also be used for developing mouse xenografts. Stephensonet al. reported the formation of lymph node metastases through orthotopic implantation ofPC-3 cells [63]. PC-3M is a metastatic variant of PC-3. Basically, tumors were harvestedfrom the prostate or lymph nodes, and these tumor cells were reinjected into the prostate.This resulted in the cell lines, PC-3M-Pro4 and PC-3M-LN4. PC-3M-LN4 cells were reportedto display significantly more metastatic potential in lymph node, lung, and bone [32].The DU145 cell line is another variant that is also used for developing xenografts.Both PC-3 and DU145 cells are androgen-independent and they do not express AR. Culiget al. created an LNCaP-abl cell line after culturing LNCaP cells 87 times in a mediumdevoid of androgen. These cells exhibit a greater amount of AR and display an amplifiedproliferation to androgen until passage 75. In nude mice, bicalutamide promoted thegrowth of LNCaP-abl xenografts while testosterone suppressed it [64]. LNCaP-IL6C cellshave a tremendous growth potential in nude mice and this cell line was established afterserial passaging in the absence of IL6 [65]. LNCaP-IL6C cells show an upregulation ofcyclin-dependent kinase 2 and diminished expression of the tumor suppressors pRb andp27. Loberg et al., reported the generation of an androgen-independent PCa cell linethrough subcutaneous implantation and serial passaging of VCaP cells in castrated maleSCID mice [66]. VCaP expresses high levels of PSA, prostatic acid phosphatase (PAP),cytokeratin-18, and wild-type AR [48]. Figure 2 describes the steps involved in cell andpatient-derived xenografts development.Life 2022, 12, 1607 7 of 18Life 2022, 12, 1607 7 of 19 Figure 2. Illustrations of the development of (A) patient-derived and (B) cell-derived xenografts. Although cell derived xenograft models are useful to assess the efficacy and mecha-nisms of drugs, they are devoid of heterogeneity and cannot mimic the complexity of the tumor microenvironment. Hence, PDX models are advantageous that are developed by relocating patient tumor samples into host animals. These models can better replicate tu-mor heterogeneity which is helpful to design more effective therapeutics. In 1976, Schroeder et al. first reported the transplantation of PCa tissues into nude mice [67]. De-spite being a popular PDX model, nude mice can retain some humoral adaptive immunity and an innate immune system, thereby restricting PDX engraftment. SCID mice lack both T- and B-cells, but they are sensitive to radiation-induced DNA damage and can produce T and B cells with increasing age. IL2rg mutations resulted in the development of NSG, NOG, and NRG mice. NSG and NOG mice were reported to demonstrate an escalated sensitivity to drugs [2]. Considering the limitations of different models, orthotopic xeno-grafting of tissue is accepted as the finest model that offers a more physiologically relevant microenvironment and the tumor take rate in this model is approximately 70% [68]. Table 2 illustrates the major features of PCa xenograft models. Table 2. Properties of xenograft models of prostate cancer. Compiled from published literature [31,63,66,69]. Cell Line Source Androgen Dependence PSA AR Metastasis to Organs LNCaP Lymph node + + + Bone PC-3 Bone - - - Bone DU145 Brain - - - No VCaP Spinal cord + + + Bone Figure 2. Illustrations of the development of (A) patient-derived and (B) cell-derived xenografts.Although cell derived xenograft models are useful to assess the efficacy and mecha-nisms of dr gs, they are devoid of heterogeneity an cannot mimic the complexity of thetumor microenvironment. Hence, PDX models are advantageous that are developed byrelocating patient tumor samples into host anim ls. These models can better replicate tumorheterogeneity which is helpful to design mor effective therapeuti s. In 1976, Schroederet al. first reported the transplantation of PCa tissues into nude mice [67]. Despite beinga popular PDX model, nude mice can retain some humoral a aptive immunity and aninnate immune system, thereby restricting PDX engraftment. SCID mice lack both T- andB-cells, but they are sensitive to radiation-induced DNA damage and can produce T and Bcells with increasing age. IL2rg mutations resulted in the develop ent of NSG, NOG, andNRG mice. NSG and NOG mice were reported to demonstrate an escalated sensitivity todrugs [2]. Considering the limitations of different models, orthotopic xenografting of tissueis accepted as the finest model that offers a more physiologically relevant microenviron-ment and the tumor take rate in this model is approximately 70% [68]. Table 2 illustratesthe major features of PCa xenograft models.Table 2. Properties of xenograft models of prostate cancer. Compiled from publishedliterature [31,63,66,69].Cell Line Source AndrogenDependence PSA ARMetastasis toOrgansLNCaP Lymph node + + + BonePC-3 Bone - - - BoneDU145 Brain - - - NoVCaP Spinal cord + + + Bone4. Transgenic Mouse Models (Genetically Engineered Mouse, GEM)4.1. PTENThe deletion of phosphatase, PTEN takes place about in 86% CRPC [70]. While thehomozygous PTEN knockout results in lethality to mouse embryos, the heterozygousPTEN+/− knockout leads to multifarious lesions such as endometrial complex atypicalhyperplasia, dysplastic intestinal polyps, lymphomas, and PIN [71,72]. This PTEN knock-Life 2022, 12, 1607 8 of 18out model is useful to validate the role of the tumor microenvironment in the growth andprogression of PCa. It is worth mentioning that Nkx3.1-PTEN double mutant mice canbetter mimic the early stages of human PCa since these mice have an increased tendency todevelop high-grade prostatic intraepithelial neoplasia (HGPIN) [73].Ding et al. generated PTENpc−/− Smad4pc−/− mice that were later used to study theeffects of combination therapy of a hypoxia-prodrug, TH-302, and checkpoint blocker. Thiscombination therapy markedly extended the survival of PTENpc−/− Smad4pc−/− mice [11].Furthermore, Wang and colleagues reported that polymorphonuclear myeloid-derivedsuppressor cells (MDSCs) are a major source of infiltrating immune cells in PCa and theirreduction can suppress the progression of PCa [74]. Liu et al., reported a novel PTENknockout (PTENadcre+) mouse model where they generated prostate-specific Cre-LoxPgenes through the delivery of adenovirus to the anterior prostate lobes. This model was asignificant milestone to compare the age difference in PCa since the result showed that theold mice group has a greater frequency of PCa development and progression comparedto young mice [75]. Table 3 depicts the genetic alterations and metastatic potential ofgenetically engineered PCa mouse models.Table 3. Mouse model of prostate cancer developed by genetic manipulation. Compiled frompublished literature [70,76].Model Genetic Alteration Metastasis to Organs Time to DevelopPTENCre recombinase-mediatedremoval of PTEN codingsequence between twoloxP sitesLymph nodeand lungPIN: 6 weeksInvasive carcinoma:9–29 weeksTRAMPCombination of prostatespecific promoter PB and APR2to induce SV40 large/smallT antigenBone, lung, lymphnode, adrenal gland,kidneyMild hyperplasia:8–12 weeksMetastatic lesion:18 weeks4.2. TRAMPThe transgenic adenocarcinoma of the mouse prostate (TRAMP) model was developedby Norman Greenberg and his group in 1995 [76]. In this model, the development periodsof PIN and lymphatic metastases were 18 weeks and 28 weeks, respectively, and hence,it is a very useful model to study PCa pathology, prevention, and treatment [77,78]. ThisTRAMP model first presented castration-resistant disease progression [79]. In TRAMPmice, the rat prostate governs the expression of large and small SV40 T antigens through aprostate specific promoter probasin (PB or Rpb) [80]. Chloramphenicol acetyl transferaseinduced the expression of SV40 large T antigen and luciferase reporter assays confirmedthe presence of two androgen receptor binding sites (ARBS) in the PB promoter [81]. Thehemizygous TRAMP mice result in PCa with metastasis and can show different diseasestates such as mild intraepithelial hyperplasia and large multinodular malignant neoplasia.These mice can result in the formation of PIN and adenocarcinoma at the ages of 12 and24 weeks, respectively in the dorsal and lateral lobes of the prostate. At the age of 12 weeks,the mice were castrated; however, this event did not impact the development of primarytumors or metastasis in most of the TRAMP mice. A major drawback of the TRAMPmodel is the development of neuroendocrine PCa that could be due to the loss of Rb andp53 [82,83]. A major drawback of the TRAMP model is the development of neuroendocrinePCa which could be due to the loss of Rb and p53 [82,83]. Therefore, the TRAMP model ismore appropriate to study PCa of neuroendocrine origin.5. Knockout Models (Androgen Receptor Knockout (ARKO) Mice)Androgen receptor knockout (ARKO) models are outstanding models since they areuseful to study AR physiological roles in selective cell types within reproductive systems.To develop the ARKO mice, C57-B6/129/SvEv loxP-floxed AR mice were first generatedLife 2022, 12, 1607 9 of 18and then they were mated with Cre recombinase expressing mice [84,85]. Floxed AR micewere mated with the transgenic mice that harbored Cre expression driven by the strongβ-actin (ACTB) promoter human cytomegalovirus (CMV) promoter, or phosphoglyceratekinase (PGK) promoter [84–86]. Some other ARKO models are prostate epithelial ARKO(PEARKO) mice, Leydig cell–specific ARKO (L-AR−/y) mice, and germ cell–specific ARKO(G-AR−/y) mice [87–89]. AR signaling is important due to the fact that the global femaleARKO mice exhibited impaired mammary gland development along with subfertility [90].The ARKO male mice displayed reduced levels of testosterone and cancellous bone volumesthan their wild-type counterparts. Moreover, they had a female-like appearance and ARKOfemale mice presented fertility impairment. The floxed AR mice are beneficial since theycould be used to generate tissue-specific ARKO such as liver, breast, and prostate wherethe roles of AR could be determined [85]. Niu et al. (2008) reported that AR exerted distinctattributes in the stromal and epithelial cells of the prostate as evidenced in two modelsnamely, inducible (ind)-AR knockout (ARKO)-TRAMP and prostate epithelial-specificARKO TRAMP (pes-ARKO-TRAMP) models. They found that although AR was missingin both epithelium and stroma, pes-ARKO-TRAMP mice produced bigger tumors with ahigher proliferation index [91]. Overall, the generation of ARKO model is of paramountimportance since this offers a fresh avenue to determine the impact of androgens in thetarget tissues.6. PCa Inflammation ModelsThe PCa inflammation models are heavily impacted by carcinogens, animal genetics,hormonal imbalance, fat-enriched diet, cholesterol, and advanced age. For example, anelevated expression of estrogen receptor-α (ER-α) and a decreased expression of ER-βand androgen receptor (AR) promoted the oncogenic effect of 17β-estradiol on NRP-152cells [92]. Chronic inflammation was evident in 48 weeks old FVB/N mice due to theupregulated expression of estrogens such as 17β-estradiol as well as inflammatory markersnamely, macrophages, neutrophils, and T-lymphocytes that resulted in prostatic intraep-ithelial neoplasias (PINs) [93]. Yatkin et al., showed that androgen replacement therapywas able to prevent the 17β-estradiol-induced inflammatory reaction in the prostates ofcastrated Noble rats [94].The causative factors for prostatic infection are usually bacteria, fungi, uric acid crystalsor urine reflux. All these stimuli result in the activation of proinflammatory cytokines inthe prostate that promote tumor development. Reports suggest that an elevated expressionof inflammasome complex in the prostate of a rat model may mimic an inflammatory statesimilar to BPH in humans [95]. Elkahwaji et al., demonstrated that inflammation triggersprostate carcinogenesis by inducing oxidative stress-mediated DNA damage and injury [96].A high grade PIN developed in humanized mice due to prostate inflammation was theresult of treatment with the carcinogen 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine(PhIP). This was associated with an expression of AR while the expression of PTEN andP63 was diminished. When these mice were fed high-fat diet, they developed carcinoma insitu [97]. Overall, there lies a strong relation between persistent prostatic inflammation andPCa development.7. Clinical Research Models of PCaClinical models of PCa research are primarily limited to human prostate tissues andPCa patients. Though preclinical models offer the advantage of ready availability andflexibility of treatment, clinical models provide the targeted endpoint of the research inquestion.7.1. Human Prostate TissuesProstate tissues from healthy humans or patients represent a unique but challengingopportunity to understand the disease pathogenesis and key players that are involved inthe disease. Higher expression of steroidogenic enzymes in human prostate homogenatesLife 2022, 12, 1607 10 of 18(HPH) compared to cell lines offers significant advantages in terms of experimental easeand clinical relevance. Typically, human prostate tissues are homogenized which aretermed HPH in laboratory terminology. Based on the maturity pattern, histology, andactivity, the human prostate gland can be classified into several zones such as fibromuscular,transition, central, and peripheral [98,99]. Clinical studies have deduced that tumorsfrom the peripheral zone have unfavorable long-term survival compared to tumors fromthe transition zone [100]. Biopsy and prostatectomy provide tissue samples for researchpurposes which are eventually categorized as normal or cancerous based on Gleason scoreand staging by a pathologist [101]. Both types of tissues are useful to understand normalprostatic physiology and pathological conditions that drive cancerous growth. Often,PCa patients are treated with hormonal agents (e.g., LHRH agonists) to shrink the size(neoadjuvant therapy) before radical prostatectomy [102]. These tissues are invaluable asboth the biomarkers driving the disease as well as the effect of neoadjuvant therapy ondisease biomarkers can be determined using these types of tissues.De novo steroidogenesis in the tissues reveals the intratumoral dynamics in CRPC [34,103].Determination of protein expression by Western blot and immunohistochemistry is achiev-able [104]; however, gene expression profiling is not possible due to the flash frozennature of the samples in wax blocks. HPH is one of the most reliable models to evaluatesteroidogenic enzyme inhibition by experimental therapeutic agents [105,106]. Becausesteroidogenic enzyme levels are relatively higher in tissues than in secondary cell lines,the measurement of steroidogenesis is much more robust and measurable in HPH [34].Both the classical and backdoor steroidogenesis pathways are observed in HPH with DHTas the end product [107–109]. SRD5A isoforms and CYP17A1 enzymes are detected inWestern blot and activity studies in HPH [104] which provides mechanistic insight intosteroidogenesis and its inhibitors. Figure 3 shows the steroidogenesis in humans includingboth classical and backdoor pathways.Life 2022, 12, 1607 11 of 19 Figure 3. Human steroidogenesis pathway [34,103,105–107,110,111]. 7.2. Prostate Cancer Patients It is undebatable that PCa patients in clinical studies are the gold standard of research in this area. The species differences in metabolic landscape and tumor microenvironment between rodents and humans can pose a discrepancy in outcome [112]. While it is recog-nizable that humans should not be involved in research on PCa, or as a matter a fact for any disease, until the safety and efficacy of the compounds have been established with reasonable confidence, the pharmacokinetics, DDI, and other drug deposition-related studies face lesser regulatory stringency than during drug development stage. Identifica-tion of resistant treatment regimen is primarily derivative of post-approval clinical studies where lower treatment efficacy provide the impetus for research at the preclinical level to develop drug-resistant cell lines and research design [113,114]. 8. Utility of Prostate Cancer Models in Drug Development Till today, a perfect model for PCa does not exist and this makes the research some-how ineffectual on a lot of occasions. Since there are legitimate ethical issues in relation to research on humans, the use of a mouse is still the choice of model. It is, indeed, imperative to find out the underlying cellular and molecular mechanisms of PCa development, pro-gression, metastasis, and drug resistance to devise more effective therapeutic strategies. Despite being powerful, GEMMs are barely used to determine the effects of drugs. This is primarily due to their lengthy time course [115]. Similar to GEMMs, PDX is also used less frequently for drug studies [116]. Another reason is that metastatic lesions are uncommon in GEMMs. Extrapolatory evidence shows the absence of metastases in most of the cases where the mice have to be euthanized due to excessive tumor burden or sometimes due to immunosurveillance mechanisms [117]. The xenograft models that are developed by injecting human cell lines are most commonly used to investigate the effects of drugs. This is accomplished by subcutaneously injecting PCa cells, allowing the tumor to be palpable, treating it with drugs, and then determining the difference in tumor volume as per the study protocol. Some subcutaneous xenograft models can be beneficial to study metastasis Figure 3. Human steroidogenesis pathway [34,103,105–107,110,111].7.2. Prostate Cancer PatientsIt is undebatable that PCa patients in clinical studies are the gold standard of researchin this area. The species differences in metabolic landscape and tumor microenvironmentbetween rodents and humans can pose a discrepancy in outcome [112]. While it is recog-Life 2022, 12, 1607 11 of 18nizable that humans should not be involved in research on PCa, or as a matter a fact forany disease, until the safety and efficacy of the compounds have been established with rea-sonable confidence, the pharmacokinetics, DDI, and other drug deposition-related studiesface lesser regulatory stringency than during drug development stage. Identification ofresistant treatment regimen is primarily derivative of post-approval clinical studies wherelower treatment efficacy provide the impetus for research at the preclinical level to developdrug-resistant cell lines and research design [113,114].8. Utility of Prostate Cancer Models in Drug DevelopmentTill today, a perfect model for PCa does not exist and this makes the research somehowineffectual on a lot of occasions. Since there are legitimate ethical issues in relation toresearch on humans, the use of a mouse is still the choice of model. It is, indeed, impera-tive to find out the underlying cellular and molecular mechanisms of PCa development,progression, metastasis, and drug resistance to devise more effective therapeutic strategies.Despite being powerful, GEMMs are barely used to determine the effects of drugs. This isprimarily due to their lengthy time course [115]. Similar to GEMMs, PDX is also used lessfrequently for drug studies [116]. Another reason is that metastatic lesions are uncommonin GEMMs. Extrapolatory evidence shows the absence of metastases in most of the caseswhere the mice have to be euthanized due to excessive tumor burden or sometimes dueto immunosurveillance mechanisms [117]. The xenograft models that are developed byinjecting human cell lines are most commonly used to investigate the effects of drugs. Thisis accomplished by subcutaneously injecting PCa cells, allowing the tumor to be palpable,treating it with drugs, and then determining the difference in tumor volume as per thestudy protocol. Some subcutaneous xenograft models can be beneficial to study metastasisand a drug’s effect based on the cell lines involved [118]. Orthotopic injection modelsthat offer more patient-relevant tumor microenvironments are developed by seeding PCacells directly into the murine prostate [119]. Nevertheless, this model is not devoid ofdisadvantages. For example, the establishment of the orthotopic model requires delicatesurgical skills. Moreover, the measurement of tumor volume is complicated since the tumorin this model is not always visible. PDX models are useful as they have the advantagesof cellular heterogeneity, molecular diversity, and histology of primary patient tumors.One disadvantage of this model is that reproducibility is comparatively low because of theheterogeneity of PCa [24]. Clinical models such as human prostate tissues and patientsare obviously most desirable research models of PCa as the results are either directly ormost closely translatable in understanding the disease, identifying drug targets, and/ordeveloping treatment strategies.The use of PCa cells in cancer stem cell (CSC) research has also been reported thatintroduced a new horizon in PCa research. PCa stem cells were identified by Collins et al.from primary human PCa [120]. These CSCs can self-renew, differentiate, and result intumor development. While currently available agents are effective against proliferatingcells, CSCs are quite invulnerable that can render metastasis and drug resistance [121].A very recent study by Li et al. demonstrated the use of PCa cells in CSC research wherethey showed that angiogenin and plexin-B2 regulate the stemness of prostate CSCs. In thisstudy, they employed the CSCs that were cloned from PC-3, DU145, and LNCaP cells [122].Similarly, Miolo et al. demonstrated that photoactivated 4,6,4′-trimethylangelicin (TMA)can reduce the expression CD44 when they conducted the study using DU145 cells [123].Expression of CD44 serves as a viable marker of CSC and overexpression of CD44 is linkedto PCa staging and response to therapy [124,125]. Silencing of CD44 results in inhibitionof nuclear translocation of β-catenin in PCa [126]. Moreover, Assoun et al. characterizediPS87 PCa cell line and reported its stem cell-like properties [127]. These studies show thatPCa cells possess enormous potential to be used in the development of novel treatmentstrategies involving CSC.Life 2022, 12, 1607 12 of 189. Limitations of Prostate Cancer Models and Future DirectionThe currently available PCa cell line models have several limitations. For example,these cell lines are devoid of heterogeneity that is frequently detected in patient-derivedtumor samples [22]. Indeed, growing these cells in monolayer cultures is the reason behindthis lack of heterogeneity. Moreover, these cell lines are grown under in vitro cultureconditions that do not properly represent the human tumor microenvironment [128].Compared to cell line models, patient-derived xenografts (PDXs) are preferred sincethey are grown in immunocompromised mice that can more precisely mimic the hetero-geneity of human PCa cells. Additionally, they have their endocrine system unaffected, andthey can be used in metastatic conditions. In the earlier days, the success with PDX was verylimited; however, presently a good number of PDX models are being employed globally forevaluating the effects of different chemotherapeutics with enhanced success [129]. How-ever, PDX models also entail some limitations. First, time constraint is a major drawback inthese models since PDX engraftment and drug testing may take several months. Second,these models are beneficial for testing the effects of few drugs only and are not a goodcandidate for high-throughput screening. Third, metastatic characteristics of tumor cellsmay be variable due to the variation in clinical conditions. In addition, human prostatetissue models are difficult to obtain with access in research centers attached to a major PCahospital. Furthermore, the swiftness of freezing the samples and method of freezing thesamples after radical prostatectomy can have implications on the stability of proteins inthose samples. Availability of pathologists to carry out the staging may restrict the properinterpretation of the PCa tissues and related biomarkers.Considering all these downsides, three-dimensional (3-D) cultures have emerged asa novel and suitable alternative to patient-derived cancer models. For example, spheroidculture model is created by using culture plates with low attachment properties and theyoffer substantial success rates [130]. Another model namely, 3-D organoid culture modelscan better imitate the morphological and genetic characteristics of actual tumors by virtueof retaining tumor heterogeneity [131].10. ConclusionsThe availability of a number of models has remarkably advanced the field of PCaresearch. Although the in vitro models offer convenience to study cancer-related pathways,in vivo models are useful to better understand the different steps of tumor progression.Nevertheless, the cell line models have a significant drawback of not producing the precisehuman tumor microenvironment and that is why in vivo models are of paramount impor-tance since PDX in mice can better mimic the human tumor environment. Moreover, GEMsprovide with a huge advantage of developing different types of PCa tumors. However,a model that can represent PCa of multifarious ethnicity is still lacking and hence, furtherinvestigation is unquestionably necessary to better understand the oncological drivers ofPCa as well as to devise more effective therapeutic strategies.Author Contributions: Conceptualization, S.D.; methodology, S.D. and D.B.; software, S.D.; re-sources, S.D. and D.B.; data curation, D.B., L.G. and F.J.; writing—original draft preparation, D.B.,S.D., L.G. and F.J.; writing—review and editing, S.D. and D.B.; supervision, S.D.; project administra-tion, S.D. All authors have read and agreed to the published version of the manuscript.Funding: No funding was received for this manuscript.Institutional Review Board Statement: Not applicable.Informed Consent Statement: Not applicable.Data Availability Statement: Not applicable.Conflicts of Interest: The authors declare no conflict of interest.Life 2022, 12, 1607 13 of 18References1. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates ofincidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [CrossRef] [PubMed]2. Teo, M.Y.; Rathkopf, D.E.; Kantoff, P. Treatment of Advanced Prostate Cancer. Annu. Rev. Med. 2019, 70, 479–499. [CrossRef][PubMed]3. Crawford, E.D.; Higano, C.S.; Shore, N.D.; Hussain, M.; Petrylak, D.P. Treating Patients with Metastatic Castration ResistantProstate Cancer: A Comprehensive Review of Available Therapies. J. Urol. 2015, 194, 1537–1547. [CrossRef] [PubMed]4. Gurel, B.; Iwata, T.; Koh, C.M.; Jenkins, R.B.; Lan, F.; Van Dang, C.; Hicks, J.L.; Morgan, J.; Cornish, T.C.; Sutcliffe, S.; et al. NuclearMYC protein overexpression is an early alteration in human prostate carcinogenesis. Mod. Pathol. 2008, 21, 1156–1167. [CrossRef]5. Krajewska, M.; Krajewski, S.; Epstein, J.I.; Shabaik, A.; Sauvageot, J.; Song, K.; Kitada, S.; Reed, J.C. Immunohistochemicalanalysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers. Am. J. Pathol. 1996, 148, 1567–1576.6. Martignano, F.; Gurioli, G.; Salvi, S.; Calistri, D.; Costantini, M.; Gunelli, R.; De Giorgi, U.; Foca, F.; Casadio, V. GSTP1 Methylationand Protein Expression in Prostate Cancer: Diagnostic Implications. Dis. Markers 2016, 2016, 4358292. [CrossRef]7. Chen, W.S.; Alshalalfa, M.; Zhao, S.G.; Liu, Y.; Mahal, B.A.; Quigley, D.A.; Wei, T.; Davicioni, E.; Rebbeck, T.R.; Kantoff, P.W.; et al.Novel RB1-Loss Transcriptomic Signature Is Associated with Poor Clinical Outcomes across Cancer Types. Clin. Cancer Res. 2019,25, 4290–4299. [CrossRef]8. Gurel, B.; Ali, T.Z.; Montgomery, E.A.; Begum, S.; Hicks, J.; Goggins, M.; Eberhart, C.G.; Clark, D.P.; Bieberich, C.J.; Epstein, J.I.;et al. NKX3.1 as a marker of prostatic origin in metastatic tumors. Am. J. Surg. Pathol. 2010, 34, 1097–1105. [CrossRef]9. McMenamin, M.E.; Soung, P.; Perera, S.; Kaplan, I.; Loda, M.; Sellers, W.R. Loss of PTEN expression in paraffin-embeddedprimary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res. 1999, 59, 4291–4296.10. Augello, M.A.; Den, R.B.; Knudsen, K.E. AR function in promoting metastatic prostate cancer. Cancer Metastasis Rev. 2014, 33,399–411. [CrossRef]11. Ding, Z.; Wu, C.J.; Chu, G.C.; Xiao, Y.; Ho, D.; Zhang, J.; Perry, S.R.; Labrot, E.S.; Wu, X.; Lis, R.; et al. SMAD4-dependent barrierconstrains prostate cancer growth and metastatic progression. Nature 2011, 470, 269–273. [CrossRef]12. Sullivan, W.P.; Vroman, B.T.; Bauer, V.J.; Puri, R.K.; Riehl, R.M.; Pearson, G.R.; Toft, D.O. Isolation of steroid receptor bindingprotein from chicken oviduct and production of monoclonal antibodies. Biochemistry 1985, 24, 4214–4222. [CrossRef]13. Sarker, D.; Reid, A.H.; Yap, T.A.; de Bono, J.S. Targeting the PI3K/AKT pathway for the treatment of prostate cancer. Clin. CancerRes. 2009, 15, 4799–4805. [CrossRef]14. Stanbrough, M.; Bubley, G.J.; Ross, K.; Golub, T.R.; Rubin, M.A.; Penning, T.M.; Febbo, P.G.; Balk, S.P. Increased expression ofgenes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006, 66, 2815–2825.[CrossRef]15. Russell, D.W.; Wilson, J.D. Steroid 5 alpha-reductase: Two genes/two enzymes. Annu. Rev. Biochem. 1994, 63, 25–61. [CrossRef]16. Penning, T.M.; Steckelbroeck, S.; Bauman, D.R.; Miller, M.W.; Jin, Y.; Peehl, D.M.; Fung, K.M.; Lin, H.K. Aldo-keto reductase (AKR)1C3: Role in prostate disease and the development of specific inhibitors. Mol. Cell. Endocrinol. 2006, 248, 182–191. [CrossRef]17. Bauman, D.R.; Steckelbroeck, S.; Williams, M.V.; Peehl, D.M.; Penning, T.M. Identification of the major oxidative 3alphahydrox-ysteroid dehydrogenase in human prostate that converts 5alpha-androstane-3alpha,17beta-diol to 5alpha-dihydrotestosterone:A potential therapeutic target for androgen-dependent disease. Mol. Endocrinol. 2006, 20, 444–458. [CrossRef]18. Fujimoto, N.; Miyamoto, H.; Mizokami, A.; Harada, S.; Nomura, M.; Ueta, Y.; Sasaguri, T.; Matsumoto, T. Prostate cancer cellsincrease androgen sensitivity by increase in nuclear androgen receptor and androgen receptor coactivators; a possible mechanismof hormone-resistance of prostate cancer cells. Cancer Invest. 2007, 25, 32–37. [CrossRef]19. Horoszewicz, J.S.; Leong, S.S.; Chu, T.M.; Wajsman, Z.L.; Friedman, M.; Papsidero, L.; Kim, U.; Chai, L.S.; Kakati, S.; Arya, S.K.;et al. The LNCaP cell line–a new model for studies on human prostatic carcinoma. Prog. Clin. Biol. Res. 1980, 37, 115–132.20. Mickey, D.D.; Stone, K.R.; Wunderli, H.; Mickey, G.H.; Vollmer, R.T.; Paulson, D.F. Heterotransplantation of a human prostaticadenocarcinoma cell line in nude mice. Cancer Res. 1977, 37, 4049–4058.21. Kaighn, M.E.; Narayan, K.S.; Ohnuki, Y.; Lechner, J.F.; Jones, L.W. Establishment and characterization of a human prostaticcarcinoma cell line (PC-3). Invest. Urol. 1979, 17, 16–23.22. Wilding, J.L.; Bodmer, W.F. Cancer cell lines for drug discovery and development. Cancer Res. 2014, 74, 2377–2384. [CrossRef]23. Nguyen, H.M.; Vessella, R.L.; Morrissey, C.; Brown, L.G.; Coleman, I.M.; Higano, C.S.; Mostaghel, E.A.; Zhang, X.; True, L.D.;Lam, H.M.; et al. LuCaP Prostate Cancer Patient-Derived Xenografts Reflect the Molecular Heterogeneity of Advanced Diseasean–d Serve as Models for Evaluating Cancer Therapeutics. Prostate 2017, 77, 654–671. [CrossRef]24. Navone, N.M.; van Weerden, W.M.; Vessella, R.L.; Williams, E.D.; Wang, Y.; Isaacs, J.T.; Nguyen, H.M.; Culig, Z.; van der Pluijm,G.; Rentsch, C.A.; et al. Movember GAP1 PDX project: An international collection of serially transplantable prostate cancerpatient-derived xenograft (PDX) models. Prostate 2018, 78, 1262–1282. [CrossRef]25. Veldscholte, J.; Ris-Stalpers, C.; Kuiper, G.G.; Jenster, G.; Berrevoets, C.; Claassen, E.; van Rooij, H.C.; Trapman, J.; Brinkmann,A.O.; Mulder, E. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid bindingcharacteristics and response to anti-androgens. Biochem. Biophys. Res. Commun. 1990, 173, 534–540. [CrossRef]26. Connolly, J.M.; Rose, D.P. Production of epidermal growth factor and transforming growth factor-alpha by the androgen-responsive LNCaP human prostate cancer cell line. Prostate 1990, 16, 209–218. [CrossRef]Life 2022, 12, 1607 14 of 1827. Nakamoto, T.; Chang, C.S.; Li, A.K.; Chodak, G.W. Basic fibroblast growth factor in human prostate cancer cells. Cancer Res. 1992,52, 571–577.28. Carroll, A.G.; Voeller, H.J.; Sugars, L.; Gelmann, E.P. p53 oncogene mutations in three human prostate cancer cell lines. Prostate1993, 23, 123–134. [CrossRef]29. Carson, J.P.; Kulik, G.; Weber, M.J. Antiapoptotic signaling in LNCaP prostate cancer cells: A survival signaling pathwayindependent of phosphatidylinositol 3′-kinase and Akt/protein kinase B. Cancer Res. 1999, 59, 1449–1453.30. Isaacs, W.B.; Carter, B.S.; Ewing, C.M. Wild-type p53 suppresses growth of human prostate cancer cells containing mutant p53alleles. Cancer Res. 1991, 51, 4716–4720.31. Lim, D.J.; Liu, X.L.; Sutkowski, D.M.; Braun, E.J.; Lee, C.; Kozlowski, J.M. Growth of an androgen-sensitive human prostatecancer cell line, LNCaP, in nude mice. Prostate 1993, 22, 109–118. [CrossRef] [PubMed]32. Pettaway, C.A.; Pathak, S.; Greene, G.; Ramirez, E.; Wilson, M.R.; Killion, J.J.; Fidler, I.J. Selection of highly metastatic variants ofdifferent human prostatic carcinomas using orthotopic implantation in nude mice. Clin. Cancer Res. 1996, 2, 1627–1636. [PubMed]33. Das, K.; Lorena, P.D.; Ng, L.K.; Lim, D.; Shen, L.; Siow, W.Y.; Teh, M.; Reichardt, J.K.; Salto-Tellez, M. Differential expression ofsteroid 5alpha-reductase isozymes and association with disease severity and angiogenic genes predict their biological role inprostate cancer. Endocr. Relat. Cancer 2010, 17, 757–770. [CrossRef] [PubMed]34. Deb, S.; Pham, S.; Ming, D.S.; Chin, M.Y.; Adomat, H.; Hurtado-Coll, A.; Gleave, M.E.; Guns, E.S.T. Characterization ofPrecursor-Dependent Steroidogenesis in Human Prostate Cancer Models. Cancers 2018, 10, 343. [CrossRef] [PubMed]35. van Bokhoven, A.; Varella-Garcia, M.; Korch, C.; Hessels, D.; Miller, G.J. Widely used prostate carcinoma cell lines share commonorigins. Prostate 2001, 47, 36–51. [CrossRef] [PubMed]36. Barlaam, B.; Cosulich, S.; Degorce, S.; Fitzek, M.; Green, S.; Hancox, U.; Lambert-van der Brempt, C.; Lohmann, J.J.; Maudet,M.; Morgentin, R.; et al. Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (AZD8186): A potent and selective inhibitor of PI3Kbeta and PI3Kdelta for the treatment of PTEN-deficientcancers. J. Med. Chem. 2015, 58, 943–962. [CrossRef] [PubMed]37. Keer, H.N.; Kozlowski, J.M.; Tsai, Y.C.; Lee, C.; McEwan, R.N.; Grayhack, J.T. Elevated transferrin receptor content in humanprostate cancer cell lines assessed in vitro and in vivo. J. Urol. 1990, 143, 381–385. [CrossRef]38. Rossi, M.C.; Zetter, B.R. Selective stimulation of prostatic carcinoma cell proliferation by transferrin. Proc. Natl. Acad. Sci. USA1992, 89, 6197–6201. [CrossRef]39. Ching, K.Z.; Ramsey, E.; Pettigrew, N.; D’Cunha, R.; Jason, M.; Dodd, J.G. Expression of mRNA for epidermal growth factor,transforming growth factor-alpha and their receptor in human prostate tissue and cell lines. Mol. Cell. Biochem. 1993, 126, 151–158.[CrossRef]40. Berish, R.B.; Ali, A.N.; Telmer, P.G.; Ronald, J.A.; Leong, H.S. Translational models of prostate cancer bone metastasis. Nat. Rev.Urol. 2018, 15, 403–421. [CrossRef]41. Tai, S.; Sun, Y.; Squires, J.M.; Zhang, H.; Oh, W.K.; Liang, C.Z.; Huang, J. PC3 is a cell line characteristic of prostatic small cellcarcinoma. Prostate 2011, 71, 1668–1679. [CrossRef]42. Giatromanolaki, A.; Fasoulaki, V.; Kalamida, D.; Mitrakas, A.; Kakouratos, C.; Lialiaris, T.; Koukourakis, M.I. CYP17A1 andAndrogen-Receptor Expression in Prostate Carcinoma Tissues and Cancer Cell Lines. Curr. Urol. 2019, 13, 157–165. [CrossRef]43. Thalmann, G.N.; Anezinis, P.E.; Chang, S.M.; Zhau, H.E.; Kim, E.E.; Hopwood, V.L.; Pathak, S.; von Eschenbach, A.C.; Chung,L.W. Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res.1994, 54, 2577–2581.44. Klein, K.A.; Reiter, R.E.; Redula, J.; Moradi, H.; Zhu, X.L.; Brothman, A.R.; Lamb, D.J.; Marcelli, M.; Belldegrun, A.; Witte, O.N.;et al. Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice. Nat. Med. 1997,3, 402–408. [CrossRef]45. Sawyers, S.C. Xenograft Models and the Molecular Biology of Human Prostate Cancer. In Xenograft Models and the MolecularBiology of Human Prostate Cancer; Chung, L., Isaacs, W.B., Simons, J.W., Eds.; Humana Press: New York, NY, USA, 2001; pp. 163–174.46. Neshat, M.S.; Mellinghoff, I.K.; Tran, C.; Stiles, B.; Thomas, G.; Petersen, R.; Frost, P.; Gibbons, J.J.; Wu, H.; Sawyers, C.L. Enhancedsensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl. Acad. Sci. USA 2001, 98, 10314–10319. [CrossRef]47. Chang, K.H.; Li, R.; Papari-Zareei, M.; Watumull, L.; Zhao, Y.D.; Auchus, R.J.; Sharifi, N. Dihydrotestosterone synthesis bypassestestosterone to drive castration-resistant prostate cancer. Proc. Natl. Acad. Sci. USA 2011, 108, 13728–13733. [CrossRef]48. Korenchuk, S.; Lehr, J.E.; MClean, L.; Lee, Y.G.; Whitney, S.; Vessella, R.; Lin, D.L.; Pienta, K.J. VCaP, a cell-based model system ofhuman prostate cancer. In Vivo 2001, 15, 163–168.49. Sobel, R.E.; Sadar, M.D. Cell lines used in prostate Cancer Res.earch: A compendium of old and new lines—Part 1. J. Urol. 2005,173, 342–359. [CrossRef]50. Wang, J.; Cai, Y.; Yu, W.; Ren, C.; Spencer, D.M.; Ittmann, M. Pleiotropic biological activities of alternatively spliced TMPRSS2/ERGfusion gene transcripts. Cancer Res. 2008, 68, 8516–8524. [CrossRef]51. Linxweiler, J.; Korbel, C.; Muller, A.; Hammer, M.; Veith, C.; Bohle, R.M.; Stockle, M.; Junker, K.; Menger, M.D.; Saar, M. A novelmouse model of human prostate cancer to study intraprostatic tumor growth and the development of lymph node metastases.Prostate 2018, 78, 664–675. [CrossRef]Life 2022, 12, 1607 15 of 1852. Cai, C.; Chen, S.; Ng, P.; Bubley, G.J.; Nelson, P.S.; Mostaghel, E.A.; Marck, B.; Matsumoto, A.M.; Simon, N.I.; Wang, H.; et al.Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated bytreatment with CYP17A1 inhibitors. Cancer Res. 2011, 71, 6503–6513. [CrossRef]53. Webber, M.M.; Trakul, N.; Thraves, P.S.; Bello-DeOcampo, D.; Chu, W.W.; Storto, P.D.; Huard, T.K.; Rhim, J.S.; Williams, D.E.A human prostatic stromal myofibroblast cell line WPMY-1: A model for stromal-epithelial interactions in prostatic neoplasia.Carcinogenesis 1999, 20, 1185–1192. [CrossRef]54. Bello, D.; Webber, M.M.; Kleinman, H.K.; Wartinger, D.D.; Rhim, J.S. Androgen responsive adult human prostatic epithelial celllines immortalized by human papillomavirus 18. Carcinogenesis 1997, 18, 1215–1223. [CrossRef]55. Millena, A.C.; Vo, B.T.; Khan, S.A. JunD Is Required for Proliferation of Prostate Cancer Cells and Plays a Role in TransformingGrowth Factor-beta (TGF-beta)-induced Inhibition of Cell Proliferation. J. Biol. Chem. 2016, 291, 17964–17976. [CrossRef]56. Sun, Y.; Schaar, A.; Sukumaran, P.; Dhasarathy, A.; Singh, B.B. TGFbeta-induced epithelial-to-mesenchymal transition in prostatecancer cells is mediated via TRPM7 expression. Mol. Carcinog 2018, 57, 752–761. [CrossRef]57. Mohr, L.; Carceles-Cordon, M.; Woo, J.; Cordon-Cardo, C.; Domingo-Domenech, J.; Rodriguez-Bravo, V. Generation of ProstateCancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel. J. Vis. Exp. 2017, 127, e56327. [CrossRef]58. Hongo, H.; Kosaka, T.; Oya, M. Analysis of cabazitaxel-resistant mechanism in human castration-resistant prostate cancer. CancerSci. 2018, 109, 2937–2945. [CrossRef]59. Hongo, H.; Kosaka, T.; Suzuki, Y.; Oya, M. Discovery of a new candidate drug to overcome cabazitaxel-resistant gene signature incastration-resistant prostate cancer by in silico screening. Prostate Cancer Prostatic Dis. 2021. [CrossRef]60. Kregel, S.; Chen, J.L.; Tom, W.; Krishnan, V.; Kach, J.; Brechka, H.; Fessenden, T.B.; Isikbay, M.; Paner, G.P.; Szmulewitz, R.Z.; et al.Acquired resistance to the second-generation androgen receptor antagonist enzalutamide in castration-resistant prostate cancer.Oncotarget 2016, 7, 26259–26274. [CrossRef]61. Liu, C.; Armstrong, C.; Zhu, Y.; Lou, W.; Gao, A.C. Niclosamide enhances abiraterone treatment via inhibition of androgenreceptor variants in castration resistant prostate cancer. Oncotarget 2016, 7, 32210–32220. [CrossRef]62. Horoszewicz, J.S.; Leong, S.S.; Kawinski, E.; Karr, J.P.; Rosenthal, H.; Chu, T.M.; Mirand, E.A.; Murphy, G.P. LNCaP model ofhuman prostatic carcinoma. Cancer Res. 1983, 43, 1809–1818. [PubMed]63. Stephenson, R.A.; Dinney, C.P.; Gohji, K.; Ordonez, N.G.; Killion, J.J.; Fidler, I.J. Metastatic model for human prostate cancer usingorthotopic implantation in nude mice. J. Natl. Cancer Inst. 1992, 84, 951–957. [CrossRef] [PubMed]64. Culig, Z.; Hoffmann, J.; Erdel, M.; Eder, I.E.; Hobisch, A.; Hittmair, A.; Bartsch, G.; Utermann, G.; Schneider, M.R.; Parczyk, K.;et al. Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression ina new model system. Br. J. Cancer 1999, 81, 242–251. [CrossRef] [PubMed]65. Steiner, H.; Godoy-Tundidor, S.; Rogatsch, H.; Berger, A.P.; Fuchs, D.; Comuzzi, B.; Bartsch, G.; Hobisch, A.; Culig, Z. Acceleratedin vivo growth of prostate tumors that up-regulate interleukin-6 is associated with reduced retinoblastoma protein expressionand activation of the mitogen-activated protein kinase pathway. Am. J. Pathol. 2003, 162, 655–663. [CrossRef]66. Loberg, R.D.; St John, L.N.; Day, L.L.; Neeley, C.K.; Pienta, K.J. Development of the VCaP androgen-independent model ofprostate cancer. Urol Oncol 2006, 24, 161–168. [CrossRef]67. Schroeder, F.H.; Okada, K.; Jellinghaus, W.; Wullstein, H.K.; Heinemeyer, H.M. Human prostatic adenoma and carcinoma.Transplantation of cultured cells and primary tissue fragments in “nude” mice. Invest. Urol. 1976, 13, 395–403.68. Wang, Y.; Revelo, M.P.; Sudilovsky, D.; Cao, M.; Chen, W.G.; Goetz, L.; Xue, H.; Sadar, M.; Shappell, S.B.; Cunha, G.R.; et al.Development and characterization of efficient xenograft models for benign and malignant human prostate tissue. Prostate 2005,64, 149–159. [CrossRef]69. Mabuchi, M.; Ueda, M.; Yoshida, Y.; Horiike, K.; Yamaoka, K.; Nakao, S.; Shimizu, T.; Ueda, Y.; Tsujikawa, K.; Tanaka, A.Systematic Trial for Evaluating Docetaxel in a Human Prostate Cancer Cell DU145 Xenograft Model. AntiCancer Res. 2017, 37,1665–1676. [CrossRef]70. Holcomb, I.N.; Young, J.M.; Coleman, I.M.; Salari, K.; Grove, D.I.; Hsu, L.; True, L.D.; Roudier, M.P.; Morrissey, C.M.; Higano,C.S.; et al. Comparative analyses of chromosome alterations in soft-tissue metastases within and across patients with castration-resistant prostate cancer. Cancer Res. 2009, 69, 7793–7802. [CrossRef]71. Di Cristofano, A.; Pesce, B.; Cordon-Cardo, C.; Pandolfi, P.P. Pten is essential for embryonic development and tumour suppression.Nat. Genet. 1998, 19, 348–355. [CrossRef]72. Podsypanina, K.; Ellenson, L.H.; Nemes, A.; Gu, J.; Tamura, M.; Yamada, K.M.; Cordon-Cardo, C.; Catoretti, G.; Fisher, P.E.;Parsons, R. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc. Natl. Acad. Sci. USA 1999, 96,1563–1568. [CrossRef]73. Kim, M.J.; Cardiff, R.D.; Desai, N.; Banach-Petrosky, W.A.; Parsons, R.; Shen, M.M.; Abate-Shen, C. Cooperativity of Nkx3.1 andPten loss of function in a mouse model of prostate carcinogenesis. Proc. Natl. Acad. Sci. USA 2002, 99, 2884–2889. [CrossRef]74. Wang, G.; Lu, X.; Dey, P.; Deng, P.; Wu, C.C.; Jiang, S.; Fang, Z.; Zhao, K.; Konaparthi, R.; Hua, S.; et al. Targeting YAP-DependentMDSC Infiltration Impairs Tumor Progression. Cancer Discov. 2016, 6, 80–95. [CrossRef]75. Liu, S.; Zhang, B.; Rowan, B.G.; Jazwinski, S.M.; Abdel-Mageed, A.B.; Steele, C.; Wang, A.R.; Sartor, O.; Niu, T.; Zhang, Q. A NovelControlled PTEN-Knockout Mouse Model for Prostate Cancer Study. Front. Mol. Biosci. 2021, 8, 696537. [CrossRef]76. Greenberg, N.M.; DeMayo, F.; Finegold, M.J.; Medina, D.; Tilley, W.D.; Aspinall, J.O.; Cunha, G.R.; Donjacour, A.A.; Matusik, R.J.;Rosen, J.M. Prostate cancer in a transgenic mouse. Proc. Natl. Acad. Sci. USA 1995, 92, 3439–3443. [CrossRef]Life 2022, 12, 1607 16 of 1877. Gupta, S.; Hastak, K.; Ahmad, N.; Lewin, J.S.; Mukhtar, H. Inhibition of prostate carcinogenesis in TRAMP mice by oral infusionof green tea polyphenols. Proc. Natl. Acad. Sci. USA 2001, 98, 10350–10355. [CrossRef]78. Maroulakou, I.G.; Anver, M.; Garrett, L.; Green, J.E. Prostate and mammary adenocarcinoma in transgenic mice carrying a ratC3(1) simian virus 40 large tumor antigen fusion gene. Proc. Natl. Acad. Sci. USA 1994, 91, 11236–11240. [CrossRef]79. Gingrich, J.R.; Barrios, R.J.; Kattan, M.W.; Nahm, H.S.; Finegold, M.J.; Greenberg, N.M. Androgen-independent prostate cancerprogression in the TRAMP model. Cancer Res. 1997, 57, 4687–4691.80. Gingrich, J.R.; Barrios, R.J.; Morton, R.A.; Boyce, B.F.; DeMayo, F.J.; Finegold, M.J.; Angelopoulou, R.; Rosen, J.M.; Greenberg,N.M. Metastatic prostate cancer in a transgenic mouse. Cancer Res. 1996, 56, 4096–4102.81. Rennie, P.S.; Bruchovsky, N.; Leco, K.J.; Sheppard, P.C.; McQueen, S.A.; Cheng, H.; Snoek, R.; Hamel, A.; Bock, M.E.; MacDonald,B.S.; et al. Characterization of two cis-acting DNA elements involved in the androgen regulation of the probasin gene. Mol.Endocrinol. 1993, 7, 23–36. [CrossRef]82. Chiaverotti, T.; Couto, S.S.; Donjacour, A.; Mao, J.H.; Nagase, H.; Cardiff, R.D.; Cunha, G.R.; Balmain, A. Dissociation of epithelialand neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer. Am. J.Pathol. 2008, 172, 236–246. [CrossRef]83. Rickman, D.S.; Beltran, H.; Demichelis, F.; Rubin, M.A. Biology and evolution of poorly differentiated neuroendocrine tumors.Nat. Med. 2017, 23, 664–673. [CrossRef]84. Matsumoto, T.; Takeyama, K.; Sato, T.; Kato, S. Androgen receptor functions from reverse genetic models. J. Steroid Biochem. Mol.Biol. 2003, 85, 95–99. [CrossRef]85. Yeh, S.; Tsai, M.Y.; Xu, Q.; Mu, X.M.; Lardy, H.; Huang, K.E.; Lin, H.; Yeh, S.D.; Altuwaijri, S.; Zhou, X.; et al. Generation andcharacterization of androgen receptor knockout (ARKO) mice: An in vivo model for the study of androgen functions in selectivetissues. Proc. Natl. Acad. Sci. USA 2002, 99, 13498–13503. [CrossRef]86. Ophoff, J.; Van Proeyen, K.; Callewaert, F.; De Gendt, K.; De Bock, K.; Vanden Bosch, A.; Verhoeven, G.; Hespel, P.; Vanderschueren,D. Androgen signaling in myocytes contributes to the maintenance of muscle mass and fiber type regulation but not to musclestrength or fatigue. Endocrinology 2009, 150, 3558–3566. [CrossRef]87. Simanainen, U.; Allan, C.M.; Lim, P.; McPherson, S.; Jimenez, M.; Zajac, J.D.; Davey, R.A.; Handelsman, D.J. Disruption of prostateepithelial androgen receptor impedes prostate lobe-specific growth and function. Endocrinology 2007, 148, 2264–2272. [CrossRef]88. Tsai, M.Y.; Yeh, S.D.; Wang, R.S.; Yeh, S.; Zhang, C.; Lin, H.Y.; Tzeng, C.R.; Chang, C. Differential effects of spermatogenesis andfertility in mice lacking androgen receptor in individual testis cells. Proc. Natl. Acad. Sci. USA 2006, 103, 18975–18980. [CrossRef]89. Xu, Q.; Lin, H.Y.; Yeh, S.D.; Yu, I.C.; Wang, R.S.; Chen, Y.T.; Zhang, C.; Altuwaijri, S.; Chen, L.M.; Chuang, K.H.; et al. Infertilitywith defective spermatogenesis and steroidogenesis in male mice lacking androgen receptor in Leydig cells. Endocrine 2007, 32,96–106. [CrossRef]90. Hu, Y.C.; Wang, P.H.; Yeh, S.; Wang, R.S.; Xie, C.; Xu, Q.; Zhou, X.; Chao, H.T.; Tsai, M.Y.; Chang, C. Subfertility and defectivefolliculogenesis in female mice lacking androgen receptor. Proc. Natl. Acad. Sci. USA 2004, 101, 11209–11214. [CrossRef] [PubMed]91. Niu, Y.; Altuwaijri, S.; Yeh, S.; Lai, K.P.; Yu, S.; Chuang, K.H.; Huang, S.P.; Lardy, H.; Chang, C. Targeting the stromal androgenreceptor in primary prostate tumors at earlier stages. Proc. Natl. Acad. Sci. USA 2008, 105, 12188–12193. [CrossRef] [PubMed]92. Dwarakanath, A.D.; Michael, J.; Allan, R.N. Sulphasalazine induced renal failure. Gut 1992, 33, 1006–1007. [CrossRef] [PubMed]93. Ellem, S.J.; Wang, H.; Poutanen, M.; Risbridger, G.P. Increased endogenous estrogen synthesis leads to the sequential induction ofprostatic inflammation (prostatitis) and prostatic pre-malignancy. Am. J. Pathol. 2009, 175, 1187–1199. [CrossRef] [PubMed]94. Yatkin, E.; Bernoulli, J.; Talvitie, E.M.; Santti, R. Inflammation and epithelial alterations in rat prostate: Impact of the androgen tooestrogen ratio. Int. J. Androl. 2009, 32, 399–410. [CrossRef] [PubMed]95. Kashyap, M.; Pore, S.; Wang, Z.; Gingrich, J.; Yoshimura, N.; Tyagi, P. Inflammasomes are important mediators of prostaticinflammation associated with BPH. J. Inflamm. 2015, 12, 37. [CrossRef]96. Elkahwaji, J.E.; Zhong, W.; Hopkins, W.J.; Bushman, W. Chronic bacterial infection and inflammation incite reactive hyperplasiain a mouse model of chronic prostatitis. Prostate 2007, 67, 14–21. [CrossRef]97. Gong, Y.G.; He, D.L.; Wang, M.Z.; Li, X.D.; Zhu, G.D.; Zheng, Z.H.; Du, Y.F.; Chang, L.S.; Nan, X.Y. Holmium laser enucleation ofthe prostate: A modified enucleation technique and initial results. J. Urol. 2012, 187, 1336–1340. [CrossRef]98. Dunn, M.W.; Kazer, M.W. Prostate Cancer Overview. Semin. Oncol. Nurs. 2011, 27, 241–250. [CrossRef]99. Lee, C.H.; Akin-Olugbade, O.; Kirschenbaum, A. Overview of Prostate Anatomy, Histology, and Pathology. Endocrinol. Metab.Clin. N. Am. 2011, 40, 565–575. [CrossRef]100. Lee, J.J.; Thomas, I.C.; Nolley, R.; Ferrari, M.; Brooks, J.D.; Leppert, J.T. Biologic differences between peripheral and transitionzone prostate cancer. Prostate 2015, 75, 183–190. [CrossRef]101. Siedow, M.; Eisner, M.; Yaney, A.; Washington, I.; Zynger, D.; Martin, D.; Mo, X.; Diconstanzo, D.; Diaz, D.A. Impact of prostatebiopsy secondary pathology review on radiotherapy management. Prostate 2022, 82, 210–215. [CrossRef]102. McKay, R.R.; Choueiri, T.K.; Taplin, M.E. Rationale for and review of neoadjuvant therapy prior to radical prostatectomy forpatients with high-risk prostate cancer. Drugs 2013, 73, 1417–1430. [CrossRef]103. Deb, S.; Chin, M.Y.; Pham, S.; Adomat, H.; Hurtado-Coll, A.; Gleave, M.E.; Tomlinson Guns, E.S. Steroidogenesis in Peripheraland Transition Zones of Human Prostate Cancer Tissue. Int. J. Mol. Sci. 2021, 22, 487. [CrossRef]Life 2022, 12, 1607 17 of 18104. Godoy, A.; Kawinski, E.; Li, Y.; Oka, D.; Alexiev, B.; Azzouni, F.; Titus, M.A.; Mohler, J.L. 5alpha-reductase type 3 expression inhuman benign and malignant tissues: A comparative analysis during prostate cancer progression. Prostate 2011, 71, 1033–1046.[CrossRef]105. Pham, S.; Deb, S.; Ming, D.S.; Adomat, H.; Hosseini-Beheshti, E.; Zoubeidi, A.; Gleave, M.; Guns, E.S. Next-generationsteroidogenesis inhibitors, dutasteride and abiraterone, attenuate but still do not eliminate androgen biosynthesis in 22RV1 cellsin vitro. J. Steroid Biochem. Mol. Biol. 2014, 144 Pt B, 436–444. [CrossRef]106. Ming, D.-S.; Pham, S.; Deb, S.; Chin, M.Y.; Kharmate, G.; Adomat, H.; Beheshti, E.H.; Locke, J.; Guns, E.T. Pomegranate extractsimpact the androgen biosynthesis pathways in prostate cancer models in vitro and in vivo. J. Steroid Biochem. Mol. Biol. 2014, 143,19–28. [CrossRef]107. Locke, J.A.; Guns, E.S.; Lubik, A.A.; Adomat, H.H.; Hendy, S.C.; Wood, C.A.; Ettinger, S.L.; Gleave, M.E.; Nelson, C.C. AndrogenLevels Increase by Intratumoral De novo Steroidogenesis during Progression of Castration-Resistant Prostate Cancer. Cancer Res.2008, 68, 6407–6415. [CrossRef]108. Ben-Eltriki, M.; Deb, S.; Hassona, M.; Meckling, G.; Fazli, L.; Chin, M.Y.; Lallous, N.; Yamazaki, T.; Jia, W.; Rennie, P.S.; et al.20(S)-protopanaxadiol regio-selectively targets androgen receptor: Anticancer effects in castration-resistant prostate tumors.Oncotarget 2018, 9, 20965–20978. [CrossRef]109. Adomat, H.H.; Bains, O.S.; Lubieniecka, J.M.; Gleave, M.E.; Guns, E.S.; Grigliatti, T.A.; Reid, R.E.; Riggs, K.W. Validation of asequential extraction and liquid chromatography-tandem mass spectrometric method for determination of dihydrotestosterone,androstanediol and androstanediol-glucuronide in prostate tissues. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2012, 902,84–95. [CrossRef]110. Auchus, R.J. The backdoor pathway to dihydrotestosterone. Trends Endocrinol. Metab. 2004, 15, 432–438. [CrossRef]111. Penning, T.M.; Jin, Y.; Rizner, T.L.; Bauman, D.R. Pre-receptor regulation of the androgen receptor. Mol. Cell. Endocrinol. 2008, 281,1–8. [CrossRef]112. Ge, R.; Wang, Z.; Cheng, L. Tumor microenvironment heterogeneity an important mediator of prostate cancer progression andtherapeutic resistance. NPJ Precis Oncol. 2022, 6, 31. [CrossRef] [PubMed]113. Mori, J.O.; Shafran, J.S.; Stojanova, M.; Katz, M.H.; Gignac, G.A.; Wisco, J.J.; Heaphy, C.M.; Denis, G.V. Novel forms of prostatecancer chemoresistance to successful androgen deprivation therapy demand new approaches: Rationale for targeting BETproteins. Prostate 2022, 82, 1005–1015. [CrossRef] [PubMed]114. Pal, S.K.; Patel, J.; He, M.; Foulk, B.; Kraft, K.; Smirnov, D.A.; Twardowski, P.; Kortylewski, M.; Bhargava, V.; Jones, J.O.Identification of mechanisms of resistance to treatment with abiraterone acetate or enzalutamide in patients with castration-resistant prostate cancer (CRPC). Cancer 2018, 124, 1216–1224. [CrossRef]115. Ahmad, I.; Sansom, O.J.; Leung, H.Y. The role of murine models of prostate cancer in drug target discovery and validation. ExpertOpin. Drug Discov. 2009, 4, 879–888. [CrossRef]116. Tse, B.W.; Russell, P.J.; Lochner, M.; Forster, I.; Power, C.A. IL-18 inhibits growth of murine orthotopic prostate carcinomas viaboth adaptive and innate immune mechanisms. PLoS ONE 2011, 6, e24241. [CrossRef]117. Park, S.I.; Kim, S.J.; McCauley, L.K.; Gallick, G.E. Pre-clinical mouse models of human prostate cancer and their utility in drugdiscovery. Curr. Protoc. Pharmacol. 2010, 51, 14–15. [CrossRef] [PubMed]118. Havens, A.M.; Pedersen, E.A.; Shiozawa, Y.; Ying, C.; Jung, Y.; Sun, Y.; Neeley, C.; Wang, J.; Mehra, R.; Keller, E.T.; et al. An in vivomouse model for human prostate cancer metastasis. Neoplasia 2008, 10, 371–380. [CrossRef]119. An, Z.; Wang, X.; Geller, J.; Moossa, A.R.; Hoffman, R.M. Surgical orthotopic implantation allows high lung and lymph nodemetastatic expression of human prostate carcinoma cell line PC-3 in nude mice. Prostate 1998, 34, 169–174. [CrossRef]120. Collins, A.T.; Berry, P.A.; Hyde, C.; Stower, M.J.; Maitland, N.J. Prospective identification of tumorigenic prostate cancer stemcells. Cancer Res. 2005, 65, 10946–10951. [CrossRef]121. Mei, W.; Lin, X.; Kapoor, A.; Gu, Y.; Zhao, K.; Tang, D. The Contributions of Prostate Cancer Stem Cells in Prostate CancerInitiation and Metastasis. Cancers 2019, 11, 434. [CrossRef]122. Li, S.; Goncalves, K.A.; Lyu, B.; Yuan, L.; Hu, G.F. Chemosensitization of prostate cancer stem cells in mice by angiogenin andplexin-B2 inhibitors. Commun. Biol. 2020, 3, 26. [CrossRef]123. Miolo, G.; Sturaro, G.; Cigolini, G.; Menilli, L.; Tasso, A.; Zago, I.; Conconi, M.T. 4,6,4′-trimethylangelicin shows high anti-proliferative activity on DU145 cells under both UVA and blue light. Cell Prolif. 2018, 51, e12430. [CrossRef]124. Yan, Y.; Zuo, X.; Wei, D. Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and TherapeuticTarget. Stem Cells Transl. Med. 2015, 4, 1033–1043. [CrossRef]125. Korski, K.; Malicka-Durczak, A.; Breborowicz, J. Expression of stem cell marker CD44 in prostate cancer biopsies predicts cancergrade in radical prostatectomy specimens. Pol. J. Pathol. 2014, 65, 291–295. [CrossRef]126. Han, J.; Gao, B.; Jin, X.; Xu, Z.; Li, Z.; Sun, Y.; Song, B. Small interfering RNA-mediated downregulation of beta-catenin inhibitsinvasion and migration of colon cancer cells in vitro. Med. Sci. Monit. 2012, 18, BR273–BR280. [CrossRef]127. Assoun, E.N.; Meyer, A.N.; Jiang, M.Y.; Baird, S.M.; Haas, M.; Donoghue, D.J. Characterization of iPS87, a prostate cancer stemcell-like cell line. Oncotarget 2020, 11, 1075–1084. [CrossRef]128. Gao, D.; Chen, Y. Organoid development in cancer genome discovery. Curr. Opin. Genet. Dev. 2015, 30, 42–48. [CrossRef]129. van Weerden, W.M.; Bangma, C.; de Wit, R. Human xenograft models as useful tools to assess the potential of novel therapeuticsin prostate cancer. Br. J. Cancer 2009, 100, 13–18. [CrossRef]Life 2022, 12, 1607 18 of 18130. Linxweiler, J.; Hammer, M.; Muhs, S.; Kohn, M.; Pryalukhin, A.; Veith, C.; Bohle, R.M.; Stockle, M.; Junker, K.; Saar, M. Patient-derived, three-dimensional spheroid cultures provide a versatile translational model for the study of organ-confined prostatecancer. J. Cancer Res. Clin. Oncol. 2019, 145, 551–559. [CrossRef]131. Drost, J.; Karthaus, W.R.; Gao, D.; Driehuis, E.; Sawyers, C.L.; Chen, Y.; Clevers, H. Organoid culture systems for prostateepithelial and cancer tissue. Nat. Protoc. 2016, 11, 347–358. [CrossRef]
Article
eng
Reviewed
Vancouver : University of British Columbia Library
Multidisciplinary Digital Publishing Institute
CC BY 4.0
Faculty
prostate cancer
research models
preclinical
clinical
androgens
steroidogenesis
Preclinical and Clinical Research Models of Prostate Cancer: A Brief Overview
Text