61 research outputs found
Novel patient-derived 3D culture models to guide clinical decision-making in prostate cancer
Castration-resistant prostate cancer remains an incurable disease. The unmet clinical need to optimally select individual treatment options, and thereby maximize survival benefit, can be addressed by patient-specific preclinical models. Patient-derived organoids preserve original tumor characteristics and have shown potential for high-throughput assessments and coclinical drug testing, as highlighted for several cancer types in this review. This new patient-derived 3D culture technique and its downstream applications are the subjects of intense investigation in prostate cancer. Although challenges are not trivial, we expect a major impact on prostate cancer research, with a window of opportunities for early bench-to-bedside translation of new drug discoveries and guidance of patient-tailored disease management
Hormonal dependence of human prostate tumors transplantable in nude mice : the importance of low androgen levels in prostate tumor growth
The studies presented in this thesis provide experimental data which could
contribute to the discussion on whether adrenal androgens are, directly or indirectly,
capable of inducing growth stimulation of human prostate tumor tissue. Hormonal
titration experiments were conducted to investigate whether there is a critical
androgen level for growth stimulation of human prostate tumors and whether or not
this threshold level exceeds the androgen levels found in castrated men (Chapters 5
and 7). Since the adrenals of rodents do not secrete androgens (Chapter 6),
castration of the mouse can be regarded as total androgen withdrawal. The effect of
adrenal androgens on human prostate tumor growth was studied in PC-82 tumorbearing
mice supplemented with adrenal androgens, androstenedione and
dehydroepiandrosterone (DHEA) (Chapters 7 and 8).
In the general discussion (Chapter 10) an attempt is made to integrate
experimental data and the derived ideas presented in this thesis with clinical
experience on prostate cancer. Hopefully this thesis will contribute to a better
understanding of the mechanisms of androgen regulated growth of human prostatic
carcinoma which, together with the outcome of the necessary future experiments
with human xenograft models, will result in a more effective treatment of patients
with advanced prostatic cancer
Patient-derived xenograft models in cancer research
This series of 12 articles, consisting of 9 original articles and 3 reviews, is presented by international leaders in translational cancer research [...
Peptide receptor imaging of prostate cancer with radiolabelled bombesin analogues
Prostate Cancer (PC) is a type of cancer that is often diagnosed at very early stages due to improved detection among man in the Western world. Current imaging techniques are not optimal to determine extent of minimal early stage PC even though this is of great clinical importance. Human PC and high-grade PIN have shown high Gastrin-Releasing Peptide Receptor (GRPR) expression, while normal prostate tissue and BPH revealed to be predominantly GRPR-negative. Radiolabelled Gastrin-Releasing Peptide (GRP) or bombesin (BN) analogues targeting the GRPR can be used as non-invasive tools to diagnose, monitor and potentially treat PC. These BN analogues have already proven to be able to image PC in both tumour-bearing mice and clinical patients showing no important side effects. It's desirable that new peptides require fast-track standardised comparative testing in relevant PC models to select the best performing BN analogues for further evaluation in patients. Although knowledge about GRPR expression and development of new BN analogues can be extended, it is time to study performance of BN analogues for peptide receptor based imaging in patients validating results of PC imaging using histopathology as a golden standard
Determination of Ki-67 defined growth fraction by monoclonal antibody MIB- I in formalin-fixed, paraffin-embedded prostatic cancer tissues
The applicability of MIBβ1, a monoclonal antibody directed against the Kiβ67 antigen, was studied in the PCβ82 and LNCaP prostatic tumor models at various levels of proliferative activity. Statistically significant correlations were found in LNCaP cultures between Kiβ67 and MIBβ1 scores (r = 0.84, P < 0.001), and in PCβ82 tumors between MIBβ1 scores and paraffin tissue Kiβ67 (pKiβ67) (r = 0.90, P < 0.001), frozen tissue Kiβ67 (fKiβ67) (r = 0.86, P < 0.001), and BrdU uptake (r = 0.70, P < 0.001), respectively. pKiβ67 scores were double the fKiβ67 scores, which may be due to methodological differences. MIBβ1 scores exceeded both the fKiβ67 and pKiβ67 scores. The affinity of MIBβ1 for the antigen is much higher than the affinity of Kiβ67, which may explain the differences. MIBβ1 is a promising means of evaluating the presence of only minute amounts of the Kiβ67 antigen in paraffinβembedded human tumor material, especially in relatively slowly growing tumors
Effects of low testosterone levels and of adrenal androgens on growth of prostate tumor models in nude mice
Abstract
Two transplantable, androgen dependent prostate tumor models of human origin, PC-82 and PC-EW, were used to study the effect of low androgen levels and adrenal androgens on prostate tumor cell proliferation. Tumor load of the PC-82 and PC-EW tumors could be maintained constant when plasma testosterone levels were 0.8 and 0.9 nmol/l, respectively, corresponding with an intratissue 5Ξ±-dihydrotestosterone level of 3β4 pmol/g tissue. This critical androgen level for prostate tumor growth stimulation amounted to 2β3 times the castration level and proved to be similar for both tumor models. Relatively high levels of androstenedione resulted in physiological levels of plasma testosterone causing androgen concentrations in PC-82 tumor tissue exceeding the critical level for tumor growth. These results indicate that submaximal suppression of androgens can stop tumor growth in these prostate tumor models
Kinetics of neuroendocrine differentiation in an androgen-dependent human prostate xenograft model
It was previously shown in the PC-295 xenograft that the number of
chromogranin A (CgA)-positive neuroendocrine (NE) cells increased after
androgen withdrawal. NE cells did not proliferate and differentiated from
G0-phase-arrested cells. Here we further characterized NE differentiation,
androgen receptor status, and apoptosis-associated Bcl-2 expression in the
PC-295 model after androgen withdrawal to assess the origin of NE cells.
PC-295 tumor volumes decreased by 50% in 4 days. Intraperitoneal
bromodeoxyuridine (BrdU) incorporation and MIB-1 labeling decreased to 0%,
and the apoptosis was maximal at day 4. Androgen receptor expression and
prostate-specific antigen (PSA) serum levels decreased rapidly within 2
days. The number of NE cells increased 6-fold at day 4 and 30-fold at day
7. Five and ten percent of the CgA-positive cells were BrdU positive after
continuous BrdU labeling for 2 and 4 days, respectively. However, no MIB-1
expression was observed in CgA-positive cells. NE cells expressed the
regulated secretory pathway marker secretogranin III but were negative for
androgen receptor and Bcl-2. Bcl-2 expression did increase in the non-NE
tumor cells. In conclusion, androgen withdrawal leads to a rapid PC-295
tumor regression and a proliferation-independent induction of NE
differentiation. The strictly androgen-independent NE cells that were
still present after 21 days differentiated mainly from G0-phase-arrested
cells
Role of the DNA damage response in prostate cancer formation, progression and treatment
Background: Clinical and preclinical studies have revealed that alterations in DNA damage response (DDR) pathways may play an important role in prostate cancer (PCa) etiology and progression. These alterations can influence PCa responses to radiotherapy and anti-androgen treatment. The identification of DNA repair gene aberrations in PCa has driven the interest for further evaluation whether these genetic changes may serve as biomarkers for patient stratification. Methods: In this review, we summarize the current knowledge on DDR alterations in PCa, their potential impact on clinical interventions and prospects for improved management of PCa. We particularly focus on the influence of DDR gene mutations on PCa initiation and progression and describe the underlying mechanisms. Results and Conclusions: A better understanding of these mechanisms, will contribute to better disease management as treatment strategies can be chosen based on the specific disease properties, since a growing number of treatments are targeting DDR pathway alterations (such as Poly(ADP-ribose) polymerase inhibitors). Furthermore, the recently discovered crosstalk between the DDR and androgen receptor signaling opens a new array of possible strategies to optimize treatment combinations. We discuss how these recent and ongoing studies will help to improve diagnostic, prognostic and therapeutic approaches for PCa management
Characterization of a zinc-finger protein and its association with apoptosis in prostate cancer cells
BACKGROUND: The transition from androgen-dependent to androgen-independent
prostate cancer is not fully understood but appears to involve multiple
genetic changes. We have identified a gene, GC79, that is more highly
expressed in androgen-dependent LNCaP-FGC human prostate cancer cells than
in androgen-independent LNCaP-LNO human prostate cancer cells. Physiologic
levels (0.1 nM:) of androgens repress expression of GC79 messenger RNA
(mRNA) in LNCaP-FGC cells. To determine the role of GC79, we cloned its
complementary DNA (cDNA) and functionally characterized its product.
METHODS: The differentially expressed GC79 gene was cloned from human
prostate cDNA libraries, sequenced, and transfected into mammalian cells
to study its function. Expression of GC79 was analyzed in various adult
and fetal human tissues and in prostate glands of castrated rats. The
association of GC79 expression and apoptosis was investigated in COS-1 and
LNCaP cells transfected with GC79 cDNA. All statistical tests are
two-sided. RESULTS: Sequence analysis indicates that GC79 encodes a large,
complex, multitype zinc-finger protein, containing nine C(2)H(2)-type
zinc-finger domains, a cysteine-rich region, and a GATA C(4)-type
zinc-finger domain. Castration-induced androgen withdrawal increased the
expression of GC79 mRNA in the regressing rat ventral prostate, suggesting
that the expression of GC79 mRNA is associated with the process of
apoptotic cell death in the rat ventral prostate. Transfection and
induction of GC79 cDNA in both COS-1 and LNCaP prostate cancer cells led
to an apoptotic index that was eightfold higher (P:<.001, two-sided
Student's t test) than that observed in uninduced transfected cells.
CONCLUSIONS: We have cloned an androgen-repressible gene, GC79, that is
potentially involved in apoptosis. This finding may have implications for
the development of androgen-independent prostate cancer and, ultimately,
for the treatment of prostate cancer
Π Π°Π·ΡΠ°Π±ΠΎΡΠΊΠ° ΡΡΠ°Π½ΡΠΈΠΉ ΠΈ ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ΠΈΠ΅ Π½Π° Π½ΠΈΡ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠΉ ΠΏΠΎ ΠΎΠ±Π»ΡΡΠ΅Π½ΠΈΡ ΠΌΠΈΠΊΡΠΎΡΡ Π΅ΠΌ ΠΈ ΡΠ°Π΄ΠΈΠΎΠ±ΠΈΠΎΠ»ΠΎΠ³ΠΈΠΈ ΠΏΡΡΠΊΠ°ΠΌΠΈ ΠΈΠΎΠ½ΠΎΠ² Π½ΠΈΠ·ΠΊΠΈΡ ΠΈ Π²ΡΡΠΎΠΊΠΈΡ ΡΠ½Π΅ΡΠ³ΠΈΠΉ ΡΡΠΊΠΎΡΠΈΡΠ΅Π»ΡΠ½ΠΎΠ³ΠΎ ΠΊΠΎΠΌΠΏΠ»Π΅ΠΊΡΠ° NICA
The aim of this study was to evaluate the impact of androgen ablation therapy in different prostate cancer (PCa) cell lines-reflecting different stages of the disease-on (18)F-fluorodeoxyglucose (FDG), (11)C-choline and (11)C-acetate uptake. Uptake experiments were performed in androgen-sensitive (LNCaP, PC346C) and independent cell lines (22Rv1, PC346DCC, PC-3) as well as in a benign prostatic hyperplasia (BPH-1) cell line. Tracer uptake was assessed under androgen ablation. Results of the cancer cell lines were normalized to those of BPH-1. To evaluate the effect of androgen on the uptake of (18)F-FDG, (11)C-choline and (11)C-acetate in PCa cell lines, 10(-8)M R1881, 10(-10)M R1881, the combination of 10(-10)M R1881 plus 10(-6)M Casodex or 10(-6)M Casodex alone were added in parallel cell cultures 1 day before uptake experiments. Uptake in androgen-supplemented cell cultures was compared to the uptake under androgen deprivation. Uptake was corrected for cell number using protein content. Compared to BPH-1, a higher (18)F-FDG uptake was observed only in PC346C cells, whereas a higher (11)C-choline and markedly increased (11)C-acetate uptake was seen in all cancer cell lines. Androgens significantly modulated the uptake of (18)F-FDG in LNCaP, PC346C and 22Rv1 cells, and of (11)C-choline in the PC346C and 22Rv1 cell line. No androgenic effect on (11)C-choline and (18)F-FDG uptake was observed in PC-3 and PC346DCC cells. (11)C-Acetate uptake was independent of androgen status in all PCa cell lines studied. (18)F-FDG uptake in PCa cell lines showed the highest variability and strongest androgen effect, suggesting its poor potential for metabolic imaging of advanced PCa. In contrast to (18)F-FDG and (11)C-choline, (11)C-acetate uptake was unaffected by androgens and thus (11)C-acetate seems best for monitoring PCa progression
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