scholarly journals Application of Prostate Cancer Models for Preclinical Study: Advantages and Limitations of Cell Lines, Patient-Derived Xenografts, and Three-Dimensional Culture of Patient-Derived Cells

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 74 ◽  
Author(s):  
Takeshi Namekawa ◽  
Kazuhiro Ikeda ◽  
Kuniko Horie-Inoue ◽  
Satoshi Inoue
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Three Dimensional ◽  
Preclinical Study ◽  
Cellular Heterogeneity ◽  
Preclinical Model ◽  
Immunodeficient Mice ◽  
Metastatic Lesions ◽  
Pdx Models

Various preclinical models have been developed to clarify the pathophysiology of prostate cancer (PCa). Traditional PCa cell lines from clinical metastatic lesions, as exemplified by DU-145, PC-3, and LNCaP cells, are useful tools to define mechanisms underlying tumorigenesis and drug resistance. Cell line-based experiments, however, have limitations for preclinical studies because those cells are basically adapted to 2-dimensional monolayer culture conditions, in which the majority of primary PCa cells cannot survive. Recent tissue engineering enables generation of PCa patient-derived xenografts (PDXs) from both primary and metastatic lesions. Compared with fresh PCa tissue transplantation in athymic mice, co-injection of PCa tissues with extracellular matrix in highly immunodeficient mice has remarkably improved the success rate of PDX generation. PDX models have advantages to appropriately recapitulate the molecular diversity, cellular heterogeneity, and histology of original patient tumors. In contrast to PDX models, patient-derived organoid and spheroid PCa models in 3-dimensional culture are more feasible tools for in vitro studies for retaining the characteristics of patient tumors. In this article, we review PCa preclinical model cell lines and their sublines, PDXs, and patient-derived organoid and spheroid models. These PCa models will be applied to the development of new strategies for cancer precision medicine.

Development of novel metastatic prostate cancer cell lines by “organoid” in vitro culture technology.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 33-33
Author(s):  
Ian Vela ◽  
Dong Gao ◽  
Anuradha Gopalan ◽  
Andrea Sboner ◽  
Eva Undvall ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Culture Media ◽  
Three Dimensional ◽  
Genomic Analysis ◽  
Growth Conditions ◽  
In Vitro Models ◽  
Culture Technique

33 Background: The inability to propagate patient-derived prostate cancer cells in vitro is a major impediment in the mechanistic understanding of tumorigenesis and therapeutic response. In order to generate accurate in vitro models that represent the diversity of in situ prostate cancer, we have developed a three-dimensional “organoid” system to culture metastasis samples and integrated it into our precision medicine workflow of attaining and characterizing pre-treatment biopsies. Methods: Biopsy samples of prostate cancer metastases, both soft tissue and bone, acquired at the time of therapeutic or diagnostic interventions following informed consent and institutional review board approval were obtained from two institutions. Samples were digested in Type II Collagenase (Gibco) and re-suspended in growth factor reduced Matrigel (BD), plated on plastic, and overlaid with prostate culture media (PCM). PCM consists of serum free Advanced DMEM/F12 (Gibco) with multiple growth factors optimized to propagate benign primary prostate cells. Cultures were maintained at 37°C in 5% CO2. Results: In the initial 51 samples, 15 continuous organoid cultures (29%) were established from distinct sites (9 of 32 bone, 6 of 19 soft). Tumor content of the biopsy represents a major determinant of organoid growth. Once established, organoids propagate indefinitely with different kinetics (approximately 48 hours to 1 week doubling time), and can be cryopreserved. Histological analysis shows that the organoids recapitulate the structure of the in situ cancer and genomic analysis using array CGH and whole-exome sequencing (WES) shows the presence of typical copy number alterations including TMPRSS2-ERG interstitial deletion, PTEN loss, CHD1 loss, and AR amplification. WES of two organoid/metastasis pairs shows that the growth conditions do not generate additional mutations. Conclusions: This novel tissue culture technique enables the development of new cell lines derived from metastatic deposits. This advance will facilitate research by availing new and varied cell lines, which will hopefully be more closely aligned to the spectrum of behavior of the clinical disease in comparison to the limited and problematic cell line models currently available.

scholarly journals Organoids of the female reproductive tract

2021 ◽  
Vol 99 (4) ◽  
pp. 531-553 ◽  
Author(s):  
Cindrilla Chumduri ◽  
Margherita Y. Turco
Keyword(s):  
Reproductive Tract ◽  
Personalised Medicine ◽  
Three Dimensional ◽  
In Vitro Models ◽  
Experimental Models ◽  
Female Reproductive Tract ◽  
Cellular Heterogeneity ◽  
Dynamic Regulation ◽  
Pregnancy And Childbirth

AbstractHealthy functioning of the female reproductive tract (FRT) depends on balanced and dynamic regulation by hormones during the menstrual cycle, pregnancy and childbirth. The mucosal epithelial lining of different regions of the FRT—ovaries, fallopian tubes, uterus, cervix and vagina—facilitates the selective transport of gametes and successful transfer of the zygote to the uterus where it implants and pregnancy takes place. It also prevents pathogen entry. Recent developments in three-dimensional (3D) organoid systems from the FRT now provide crucial experimental models that recapitulate the cellular heterogeneity and physiological, anatomical and functional properties of the organ in vitro. In this review, we summarise the state of the art on organoids generated from different regions of the FRT. We discuss the potential applications of these powerful in vitro models to study normal physiology, fertility, infections, diseases, drug discovery and personalised medicine.

scholarly journals Synthesis and Evaluation of the Tetracyclic Ring-System of Isocryptolepine and Regioiso-Mers for Antimalarial, Antiproliferative and Antimicrobial Activities

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3268
Author(s):  
Katja S. Håheim ◽  
Emil Lindbäck ◽  
Kah Ni Tan ◽  
Marte Albrigtsen ◽  
Ida T. Urdal Helgeland ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Antimicrobial Activities ◽  
Ring System ◽  
Human Prostate ◽  
The Novel ◽  
Human Prostate Cancer ◽  
Biofilm Inhibition

A series of novel quinoline-based tetracyclic ring-systems were synthesized and evaluated in vitro for their antiplasmodial, antiproliferative and antimicrobial activities. The novel hydroiodide salts 10 and 21 showed the most promising antiplasmodial inhibition, with compound 10 displaying higher selectivity than the employed standards. The antiproliferative assay revealed novel pyridophenanthridine 4b to be significantly more active against human prostate cancer (IC50 = 24 nM) than Puromycin (IC50 = 270 nM) and Doxorubicin (IC50 = 830 nM), which are used for clinical treatment. Pyridocarbazoles 9 was also moderately effective against all the employed cancer cell lines and moreover showed excellent biofilm inhibition (9a: MBIC = 100 µM; 9b: MBIC = 100 µM).

scholarly journals Acetyl-L-Carnitine downregulates invasion (CXCR4/CXCL12, MMP-9) and angiogenesis (VEGF, CXCL8) pathways in prostate cancer cells: rationale for prevention and interception strategies

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Denisa Baci ◽  
Antonino Bruno ◽  
Caterina Cascini ◽  
Matteo Gallazzi ◽  
Lorenzo Mortara ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Dietary Supplements ◽  
Cell Lines ◽  
Angiogenic Factors ◽  
Migration And Invasion ◽  
Prostate Cancer Cells

Abstract Background Prostate cancer (PCa) is a leading cause of cancer-related death in males worldwide. Exacerbated inflammation and angiogenesis have been largely demonstrated to contribute to PCa progression. Diverse naturally occurring compounds and dietary supplements are endowed with anti-oxidant, anti-inflammatory and anti-angiogenic activities, representing valid compounds to target the aberrant cytokine/chemokine production governing PCa progression and angiogenesis, in a chemopreventive setting. Using mass spectrometry analysis on serum samples of prostate cancer patients, we have previously found higher levels of carnitines in non-cancer individuals, suggesting a protective role. Here we investigated the ability of Acetyl-L-carnitine (ALCAR) to interfere with key functional properties of prostate cancer progression and angiogenesis in vitro and in vivo and identified target molecules modulated by ALCAR. Methods The chemopreventive/angiopreventive activities ALCAR were investigated in vitro on four different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCaP, 22Rv1) and a benign prostatic hyperplasia (BPH) cell line. The effects of ALCAR on the induction of apoptosis and cell cycle arrest were investigated by flow cytometry (FC). Functional analysis of cell adhesion, migration and invasion (Boyden chambers) were performed. ALCAR modulation of surface antigen receptor (chemokines) and intracellular cytokine production was assessed by FC. The release of pro-angiogenic factors was detected by a multiplex immunoassay. The effects of ALCAR on PCa cell growth in vivo was investigated using tumour xenografts. Results We found that ALCAR reduces cell proliferation, induces apoptosis, hinders the production of pro inflammatory cytokines (TNF-α and IFN-γ) and of chemokines CCL2, CXCL12 and receptor CXCR4 involved in the chemotactic axis and impairs the adhesion, migration and invasion capabilities of PCa and BPH cells in vitro. ALCAR exerts angiopreventive activities on PCa by reducing production/release of pro angiogenic factors (VEGF, CXCL8, CCL2, angiogenin) and metalloprotease MMP-9. Exposure of endothelial cells to conditioned media from PCa cells, pre-treated with ALCAR, inhibited the expression of CXCR4, CXCR1, CXCR2 and CCR2 compared to those from untreated cells. Oral administration (drinking water) of ALCAR to mice xenografted with two different PCa cell lines, resulted in reduced tumour cell growth in vivo. Conclusions Our results highlight the capability of ALCAR to down-modulate growth, adhesion, migration and invasion of prostate cancer cells, by reducing the production of several crucial chemokines, cytokines and MMP9. ALCAR is a widely diffused dietary supplements and our findings provide a rational for studying ALCAR as a possible molecule for chemoprevention approaches in subjects at high risk to develop prostate cancer. We propose ALCAR as a new possible “repurposed agent’ for cancer prevention and interception, similar to aspirin, metformin or beta-blockers.

TMOD-31. AN ORGANOTYPIC TISSUE PLATFORM TO BRIDGE IN VITRO AND IN VIVO ASSAYS FOR BRAIN CANCER TREATMENT

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi222-vi222
Author(s):  
Breanna Mann ◽  
Noah Bell ◽  
Denise Dunn ◽  
Scott Floyd ◽  
Shawn Hingtgen ◽  
...  
Keyword(s):  
Cell Lines ◽  
Brain Cancer ◽  
Brain Slice ◽  
Brain Slices ◽  
In Vitro Assays ◽  
Preclinical Model ◽  
Short Period ◽  
The Brain

Abstract Brain cancers remain one of the greatest medical challenges. The lack of experimentally tractable models that recapitulate brain structure/function represents a major impediment. Platforms that enable functional testing in high-fidelity models are urgently needed to accelerate the identification and translation of therapies to improve outcomes for patients suffering from brain cancer. In vitro assays are often too simple and artificial while in vivo studies can be time-intensive and complicated. Our live, organotypic brain slice platform can be used to seed and grow brain cancer cell lines, allowing us to bridge the existing gap in models. These tumors can rapidly establish within the brain slice microenvironment, and morphologic features of the tumor can be seen within a short period of time. The growth, migration, and treatment dynamics of tumors seen on the slices recapitulate what is observed in vivo yet is missed by in vitro models. Additionally, the brain slice platform allows for the dual seeding of different cell lines to simulate characteristics of heterogeneous tumors. Furthermore, live brain slices with embedded tumor can be generated from tumor-bearing mice. This method allows us to quantify tumor burden more effectively and allows for treatment and retreatment of the slices to understand treatment response and resistance that may occur in vivo. This brain slice platform lays the groundwork for a new clinically relevant preclinical model which provides physiologically relevant answers in a short amount of time leading to an acceleration of therapeutic translation.

scholarly journals In vitro engineering of a bone metastases model allows for study of the effects of antiandrogen therapies in advanced prostate cancer

2021 ◽  
Vol 7 (27) ◽  
pp. eabg2564
Author(s):  
Nathalie Bock ◽  
Thomas Kryza ◽  
Ali Shokoohmand ◽  
Joan Röhl ◽  
Akhilandeshwari Ravichandran ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Advanced Prostate Cancer ◽  
Adaptive Responses ◽  
Metastatic Tissue ◽  
Metastatic Lesions ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

While androgen-targeted therapies are routinely used in advanced prostate cancer (PCa), their effect is poorly understood in treating bone metastatic lesions and ultimately results in the development of metastatic castrate resistant prostate cancer (mCRPC). Here, we used an all-human microtissue-engineered model of mineralized metastatic tissue combining human osteoprogenitor cells, 3D printing and prostate cancer cells, to assess the effects of the antiandrogens, bicalutamide, and enzalutamide in this microenvironment. We demonstrate that cancer/bone stroma interactions and antiandrogens drive cancer progression in a mineralized microenvironment. Probing the bone microenvironment with enzalutamide led to stronger cancer cell adaptive responses and osteomimicry than bicalutamide. Enzalutamide presented with better treatment response, in line with enzalutamide delaying time to bone-related events and enzalutamide extending survival in mCRPC. The all-human microtissue-engineered model of mineralized metastatic tissue presented here represents a substantial advance to dissect the role of the bone tumor microenvironment and responses to therapies for mCPRC.

scholarly journals Tumor- and Osteoblast-Derived Periostin in Prostate Cancer bone Metastases

2022 ◽  
Vol 11 ◽  
Author(s):  
Chuan-Yu Sun ◽  
Yuan-Yuan Mi ◽  
Sheng-Yang Ge ◽  
Qing-Feng Hu ◽  
Ke Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Integrin Αvβ3 ◽  
Integrin Receptors ◽  
Secreted Expression ◽  
Metastatic Lesions ◽  
Promising Therapeutic Target ◽  
Pet Ct

Exploring the biological function of periostin (POSTN) in prostate cancer (PCa) bone metastasis is of importance. It was observed that the expression of POSTN was high in PCa, especially highest in PCa metastasized to bone. In this study, we found that inhibiting POSTN in PCa cells could significantly alleviate PCa bone metastasis in vivo, suggesting POSTN is a promising therapeutic target. Since, due to the secreted expression of POSTN in osteoblasts and PCa, we hypothesized the positive feedback loop between osteoblasts and PCa mediated by POSTN in PCa bone metastasis. The in vitro experiments demonstrated that osteoblast-derived POSTN promoted PCa cell proliferation and invasion and PCa cell-derived POSTN promotes proliferation of osteoblasts. Furthermore, we found that POSTN regulated PCa and osteoblast function through integrin receptors. Finally, 18F-Alfatide II was used as the molecule probe of integrin αvβ3 in PET-CT, revealing high intake in metastatic lesions. Our findings together indicate that targeting POSTN in PCa cells as well as in the osteoblastic may be an effective treatment for PCa bone metastasis.

scholarly journals Effects of the Latex of Synadenium grantii Hook F. (Euphorbiaceae) on a Preclinical Model of Canine Prostate Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Eric Saymom Andrade Brito ◽  
Laís Di Paulie Taborda Prado ◽  
Liana Késia Costa Araújo ◽  
Emmanuel Arnhold ◽  
Moema Pacheco Chediak Matos ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bioactive Compounds ◽  
Phorbol Esters ◽  
Scientific Evidence ◽  
Preclinical Model ◽  
Antitumor Effects ◽  
Carcinoma Cell Lines ◽  
Diphenyltetrazolium Bromide ◽  
Natural Drugs

Prostatic cancer (PC) stands out in terms of its occurrence, pathophysiology, and unfavorable prognostics in humans and dogs. Natural drugs bear an integrative potential for conventional antineoplastic treatments. In this context, the bioproducts of Synadenium grantii have been empirically used in different parts of Brazil for the integrative treatment of prostate cancer in humans. However, there is no availability of scientific evidence of the antitumor effects of S. grantii. Therefore, this study aimed to investigate the bioactive compounds in the latex of S. grantii using the high-resolution mass spectrophotometry (HRMS) and to evaluate its cytotoxic effects on primary canine PC cell cultures. Four fragments of phorbol ester were identified as potential bioactive compounds using the HRMS. With the help of an MTT ([3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyltetrazolium bromide]) assay, two canine prostatic carcinoma cell lines (PC 1 and PC2) showed a decrease in the tumor cell count, with an Inhibitory concentration 50 (IC50)of 0.8469 and 0.6068 mg/ml, respectively, for PC1 and PC2. In conclusion, the latex of S. grantii contains phorbol esters in its composition, and its aqueous solution has a cytotoxic effect on canine metastatic PC cells in vitro.

Refining In Vitro Neurotoxicity Testing — The Development of Blood–Brain Barrier Models

2003 ◽  
Vol 31 (3) ◽  
pp. 273-276 ◽  
Author(s):  
Hanna Tähti ◽  
Heidi Nevala ◽  
Tarja Toimela
Keyword(s):  
Blood Brain Barrier ◽  
Cell Lines ◽  
Three Dimensional ◽  
Brain Barrier ◽  
Culture Methods ◽  
Blood Brain ◽  
Capillary Endothelial Cells ◽  
In Vitro Bbb Model

The purpose of this paper is to review the current state of development of advanced in vitro blood–brain barrier (BBB) models. The BBB is a special capillary bed that separates the blood from the central nervous system (CNS) parenchyma. Astrocytes maintain the integrity of the BBB, and, without astrocytic contacts, isolated brain capillary endothelial cells in culture lose their barrier characteristics. Therefore, when developing in vitro BBB models, it is important to add astrocytic factors into the culture system. Recently, novel filter techniques and co-culture methods have made it possible to develop models which resemble the in vivo functions of the BBB in an effective way. With a BBB model, kinetic factors can be added into the in vitro batteries used for evaluating the neurotoxic potential of chemicals. The in vitro BBB model also represents a useful tool for the in vitro prediction of the BBB permeability of drugs, and offers the possibility to scan a large number of drugs for their potential to enter the CNS. Cultured monolayers of brain endothelial cell lines or selected epithelial cell lines, combined with astrocyte and neuron cultures, form a novel three-dimensional technique for the screening of neurotoxic compounds.

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