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Eva Corey

Publications and source records attributed to Eva Corey.

At least 19 recordsLinked to original sources
PubMed2026

Evolution and heterogeneity of lethal metastatic bladder cancer subtypes.

Histological variation is a prognostic feature of metastatic urothelial cancer1-3, but its evolutionary trajectory remains poorly defined. We developed a metastatic bladder cancer rapid autopsy programme enriched in histological subtypes4 to profile individuals with terminal disease. Here by reconstructing the evolutionary histories of patient tumours, we show that metastasis-to-metastasis seeding is the dominant pattern of cancer spread and that increased polyclonal migration predicts poor prognosis. The burden, heterogeneity and timing of genomic alterations differ markedly among histological subtypes. Plasmacytoid and neuroendocrine variants develop early driver alterations associated with shorter survival. Mutational signature analyses and experimental models demonstrated that plasmacytoid tumours uniquely use the Fanconi anaemia pathway to mitigate chemotherapy-induced genomic scarring. Single-nucleus profiling revealed mixed cell states in histological subtypes and an association between transcriptional heterogeneity and patient survival. Characterization of the tumour microenvironment uncovered distinct immune states across subtypes, with plasmacytoid tumours exhibiting immune-inflamed profiles, whereas squamous tumours are predominantly immunosuppressive. Last, we demonstrate that post-mortem cell-free DNA captures genomic and transcriptional heterogeneity of the subtypes, which provides a potential strategy for noninvasive assessment of tumour identity and aggressiveness. Our results provide new insights into how tumour heterogeneity shapes the evolutionary history of disease progression in bladder cancer histological subtypes.

Journal Article↗
PubMed2026

Patient-derived models of prostate cancer: Capturing tumour complexity from initiation to metastasis.

Prostate cancer is a growing global health challenge. To identify new ways to improve patient care, researchers need a variety of preclinical models that faithfully recapitulate human tumours across the disease continuum, from initiation to metastasis. These complementary models include primary cultures of prostate epithelial cells (PrECs), co-cultures, patient-derived explants (PDEs), patient-derived organoids (PDOs) and patient-derived xenografts (PDXs). Collectively, these models enable researchers to study tumour biology and therapeutic responses in clinically relevant contexts. Yet, there is still a need to improve the fidelity of preclinical models to human tumours by integrating diverse cell types from the tumour microenvironment and mimicking biomechanical features. By improving culture methods with matrix components that resemble the tumour microenvironment and new formulations of media that imitate human plasma, in vitro models will more accurately reflect human physiology, nutrient availability, and metabolism. In time this may reduce the reliance on animal testing through organ-on-chip and related techniques. These more complex models are suited to more detailed experimental readouts, including single-cell and spatial analyses. Intravital imaging also enables dynamic visualisation of cell-cell interactions and treatment responses in vivo. Collectively, these approaches are facilitating a shift towards sophisticated models that capture patients' tumour heterogeneity, different cellular niches, and provide opportunities to carefully study tumorigenesis, metastasis, lineage plasticity, and therapy resistance. In this review, we discuss the current progress and future directions for patient-derived models of prostate cancer, highlighting how they can be generated, refined, characterised and shared to accelerate the worldwide effort in translational research.

Humans↗
PubMed2006

Targeting factors involved in bone remodeling as treatment strategies in prostate cancer bone metastasis.

Prostate cancer is the most commonly diagnosed cancer in men within the western world and the third leading cause of cancer-related deaths. Even if the cancer is considered localized to the prostate, there is a 15% to 20% incidence of subsequent metastatic disease. Prostate cancer has a very high proclivity for metastasizing to bone, with approximately 90% of men with advanced disease having skeletal lesions. The prostate cancer metastases are characteristically osteoblastic, with extensive new bone deposition, unlike other tumors that metastasize to bone and cause an osteolytic response reflective of bone degradation. There are a considerable number of studies relating to inhibition of the osteoblastic response, including interference with endothelin-1, bone morphogenetic proteins, and Wnt signaling pathways. Within the past few years, several studies showed that increased osteolytic activity also occurs in the background of the prostate cancer skeletal metastases. Because growth factors are being released from the bone matrix during degradation, it suggests that inhibition of osteolysis might be effective in slowing tumor growth. Several strategies are being developed and applied to affect directly the osteolytic events, including use of bisphosphonates and targeting the critical biological regulators of osteoclastogenesis, receptor activator of nuclear factor-kappaB and receptor activator of nuclear factor-kappaB ligand. This review focuses on several of the clinical and preclinical strategies to inhibit the growth of prostate cancer cells in bone and to alleviate the multitude of associated skeletal-related events.

Animals↗
PubMed2006

Basic mechanisms responsible for osteolytic and osteoblastic bone metastases.

Certain solid tumors metastasize to bone and cause osteolysis and abnormal new bone formation. The respective phenotypes of dysregulated bone destruction and bone formation represent two ends of a spectrum, and most patients will have evidence of both. The mechanisms responsible for tumor growth in bone are complex and involve tumor stimulation of the osteoclast and the osteoblast as well as the response of the bone microenvironment. Furthermore, factors that increase bone resorption, independent of tumor, such as sex steroid deficiency, may contribute to this vicious cycle of tumor growth in bone. This article discusses mechanisms and therapeutic implications of osteolytic and osteoblastic bone metastases.

Bone Neoplasms↗
PubMed2006

Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment.

BACKGROUND: After development of hormone-refractory metastatic disease, prostate cancer is incurable. The recent history of chemotherapy has shown that with difficult disease targets, combinatorial therapy frequently offers the best chance of a cure. In this study we have examined the effects of a combination of zoledronic acid (ZOL), a new-generation bisphosphonate, and docetaxel on LuCaP 23.1, a prostate cancer xenograft that stimulates the osteoblastic reaction when grown in the bone environment. METHODS: Intra-tibial injections of LuCaP 23.1 cells were used to generate tumors in the bone environment, and animals were treated with ZOL, docetaxel, or a combination of these. Effects on bone and tumor were evaluated by measurements of bone mineral density and histomorphometrical analysis. RESULTS: ZOL decreased proliferation of LuCaP 23.1 in the bone environment, while docetaxel at a dose that effectively inhibited growth of subcutaneous tumors did not show any effects in the bone environment. The combination of the drugs significantly inhibited the growth of LuCaP 23.1 tumors in the bone. CONCLUSION: In conclusion, the use of the osteolysis-inhibitory agent ZOL in combination with docetaxel inhibits growth of prostate tumors in bone and represents a potential treatment option.

Animals↗
PubMed2006

Targeted chemotherapy with cytotoxic bombesin analogue AN-215 inhibits growth of experimental human prostate cancers.

We developed a powerful cytotoxic analogue of bombesin AN-215, in which the bombesin (BN)-like carrier peptide is conjugated to 2-pyrrolino doxorubicin (AN-201). Human prostate cancers express high levels of receptors for BN/gastrin releasing peptide (GRP) that can be used for targeted chemotherapy. The effects of targeted chemotherapy with cytotoxic BN analogue AN-215 were evaluated in nude mice bearing subcutaneous xenografts of DU-145, LuCaP-35, MDA-PCa-2b and intraosseous implants of C4-2 human prostate cancers. Intraosseous growth of C4-2 tumors was monitored by serum PSA. BN/GRP receptors were evaluated by 125I-[Tyr4]BN binding assays and RT-PCR. The effects of AN-215 on apoptosis and cell proliferation were followed by histology, and the expression of Bcl-2 and Bax protein was determined by Western blot analysis. Targeted analog AN-215 significantly inhibited growth of subcutaneously implanted DU-145, LuCaP-35 and MDA-PCa-2b prostate cancers by 81% to 91% compared to controls, while cytotoxic radical AN-201 was less effective and more toxic. Serum PSA levels of mice bearing intraosseous C4-2 prostate tumors were significantly reduced. In LuCaP-35 tumors administration of BN antagonist RC-3095 prior to AN-215 blocked the receptors for BN/GRP and inhibited the effects of AN-215. High affinity receptors for BN/GRP and their m-RNA were detected on membranes of all 4 tumor models. Therapy with AN-215, but not with AN-201, decreased the ratio of Bcl-2/Bax in DU-145 and the expression of antiapoptotic Bcl-2 in LuCaP-35 tumors. The presence of BN/GRP receptors on primary and metastatic prostate cancers makes possible targeted chemotherapy with AN-215 for the treatment of this malignancy.

Animals↗
PubMed2006

Inhibition of androgen-independent prostate cancer by estrogenic compounds is associated with increased expression of immune-related genes.

The clinical utility of estrogens for treating prostate cancer (CaP) was established in the 1940s by Huggins. The classic model of the anti-CaP activity of estrogens postulates an indirect mechanism involving the suppression of androgen production. However, clinical and preclinical studies have shown that estrogens exert growth-inhibitory effects on CaP under low-androgen conditions, suggesting additional modes whereby estrogens affect CaP cells and/or the microenvironment. Here we have investigated the activity of 17beta estradiol (E2) against androgen-independent CaP and identified molecular alterations in tumors exposed to E2. E2 treatment inhibited the growth of all four androgen-independent CaP xenografts studied (LuCaP 35V, LuCaP 23.1AI, LuCaP 49, and LuCaP 58) in castrated male mice. The molecular basis of growth suppression was studied by cDNA microarray analysis, which indicated that multiple pathways are altered by E2 treatment. Of particular interest are changes in transcripts encoding proteins that mediate immune responses and regulate androgen receptor signaling. In conclusion, our data show that estrogens have powerful inhibitory effects on CaP in vivo in androgen-depleted environments and suggest novel mechanisms of estrogen-mediated antitumor activity. These results indicate that incorporating estrogens into CaP treatment protocols could enhance therapeutic efficacy even in cases of advanced disease.

Animals↗
PubMed2005

Osteoprotegerin in prostate cancer bone metastasis.

Osteoprotegerin (OPG), a critical regulator of osteoclastogenesis, is expressed by prostate cancer cells, and OPG levels are increased in patients with prostate cancer bone metastases. The objective of this study was to investigate the effects of OPG overexpression on prostate cancer cells and prostate cancer/bone cell interactions in vitro and in vivo. OPG-transfected C4-2 cells expressed 8.0 ng OPG per mL per 10(6) cells, whereas no OPG was detected in the media of C4-2 cells transfected with a control plasmid. OPG overexpressed by C4-2 cells protected these cells from tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis and decreased osteoclast formation. Subcutaneous OPG-C4-2 and pcDNA-C4-2 tumors exhibited similar growth and take-rate characteristics. However, when grown in bone, tumor volume was decreased in OPG-C4-2 versus pcDNA-C4-2 (P=0.0017). OPG expressed by C4-2 cells caused increases in bone mineral density (P=0.0074) and percentage of trabecular bone volume (P=0.007), and decreases in numbers of osteoblasts and osteoclasts when compared with intratibial pcDNA-C4-2 tumors (P=0.003 and P=0.019, respectively). In summary, our data show that increased expression of OPG in C4-2 cells does not directly affect proliferation of prostate cancer cells but indirectly decreases growth of C4-2 tumors in the bone environment. Our data also show that OPG expressed by C4-2 cells inhibits bone lysis associated with C4-2 bone metastasis, which results in net increases in bone volume. We therefore hypothesize that OPG expressed in prostate cancer patient bone metastases may be at least partially responsible for the osteoblastic character of most prostate cancer bone lesions.

Animals↗
PubMed2004

Metastases of prostate cancer express estrogen receptor-beta.

OBJECTIVES: To examine estrogen receptor-beta (ERbeta) expression in prostate cancer (CaP) metastases, thereby providing a basis for conducting estrogen therapy studies in patients with metastatic CaP. Advanced androgen-independent CaP is a serious health problem with no effective treatment at present. Estrogens have been reported to inhibit the growth of CaP cells in androgen-free environments. Recent reports have shown that the prostatic epithelium and primary CaP cells express ERbeta, with decreased expression of ERbeta accompanying CaP progression. It has been proposed that ERbeta may play a role in the growth regulation of prostate cells. The targeting of ERs by selective ER modulators might be an effective method of treating advanced CaP. METHODS: The anti-ERbeta antibody GC17 was used in immunohistochemistry to characterize the expression of ERbeta in CaP metastasis specimens (n = 60) obtained from 20 patients who had died of CaP. Statistical analyses were performed to evaluate the association of ERbeta expression with clinical parameters, including prostate-specific antigen levels, radiotherapy, and estrogen exposure. RESULTS: Nuclear ERbeta staining was detected in all bone CaP metastases (33 of 33) and nonosseous CaP metastases (27 of 27). However, a large variability in the percentage of immunoreactive cells (5% to 100%) was found among patients, as well as among individual patient samples. A statistically significant negative association between nuclear ERbeta staining and estrogen exposure (P = 0.05) was detected. CONCLUSIONS: Our data have shown that ERbeta is expressed in CaP metastases, validating the initiation of studies to evaluate selective ER modulators for treatment of advanced CaP.

Adenocarcinoma↗
PubMed2003

A novel method of generating prostate cancer metastases from orthotopic implants.

BACKGROUND: Spontaneous metastasis following implantation at the orthotopic site is a highly desired feature in prostate cancer (CaP) models, since it would enable studies of mechanisms associated with tumor cell dissemination. METHODS: LuCaP 23.8 and LuCaP 35, hormone-sensitive CaP xenografts that express PSA and the wild-type androgen receptor, were grown orthotopically in SCID mice. When tumor volumes reached approximately 250-500 mg, primary tumors were removed to allow micrometastases to grow. RESULTS: Using this procedure we generated macroscopic metastases (>20 mg) in 71% (LuCaP 23.8) and 100% (LuCaP 35) of animals, respectively. CONCLUSIONS: These models may be used to evaluate new treatment modalities and study mechanisms associated with development of metastases.

Animals↗
PubMed2003

Prostate cancer expression of runt-domain transcription factor Runx2, a key regulator of osteoblast differentiation and function.

BACKGROUND: Prostate cancer (CaP) bone metastases express numerous proteins associated with bone cells. Specific transcription factors, including Runx2, regulate the expression of many bone-related factors in osteoblasts. Expression of these transcription factors in CaP may be linked to the ability of CaP bone metastases to influence bone remodeling. METHODS: CaP tissues and cell lines were analyzed for expression of Runx2 mRNA by RT-PCR and in situ hybridization, and protein by immunohistochemistry, Western blotting, and electrophoretic mobility shift assays (EMSA). RESULTS: Runx2 mRNA and protein were detected in CaP tissues and cell lines. A specific Runx2: OSE2 complex could be formed with PC-3 nuclear extracts. CONCLUSIONS: Expression of Runx2 in CaP may be the molecular switch that is associated with expression of various bone-specific factors in CaP. In turn, expression of these factors can influence bone remodeling and possibly play a role in the growth and survival of CaP in bone.

Bone Morphogenetic Protein 2↗
PubMed2003

LuCaP 35: a new model of prostate cancer progression to androgen independence.

BACKGROUND: Generation of suitable in vivo models is critical for understanding of processes associated with development and progression of prostate cancer (CaP). METHODS: Lymph nodes containing metastatic androgen-independent CaP were implanted into athymic mice. A xenograft designated LuCaP 35 and its hormone-independent variant LuCaP 35V were established and characterized. RESULTS: LuCaP 35 is an androgen-sensitive, prostate-specific antigen (PSA)-producing xenograft. It expresses the wild-type androgen receptor and exhibits deletions in chromosome 8p, but not in chromosome 10. The response of LuCaP 35 to androgen ablation is similar to that observed in man. Using recurring LuCaP 35 tumors we have also established an androgen-insensitive variant of LuCaP 35. CONCLUSIONS: The availability of hormone-dependent and -independent variants of LuCaP 35, which exhibit many properties analogous to those of CaP in man, provides an excellent model system to study the processes associated with development of androgen independence and to evaluate new treatment modalities.

Aged↗
PubMed2003

Expression of the human cachexia-associated protein (HCAP) in prostate cancer and in a prostate cancer animal model of cachexia.

Prostate cancer (CaP) patients with disseminated disease often suffer from severe cachexia, which contributes to mortality in advanced cancer. Human cachexia-associated protein (HCAP) was recently identified from a breast cancer library based on the available 20-amino acid sequence of proteolysis-inducing factor (PIF), which is a highly active cachectic factor isolated from mouse colon adenocarcinoma MAC16. Herein, we investigated the expression of HCAP in CaP and its potential involvement in CaP-associated cachexia. HCAP mRNA was detected in CaP cell lines, in primary CaP tissues and in its osseous metastases. In situ hybridization showed HCAP mRNA to be localized only in the epithelial cells in CaP tissues, in the metastatic foci in bone, liver and lymph node, but not in the stromal cells or in normal prostate tissues. HCAP protein was detected in 9 of 14 CaP metastases but not in normal prostate tissues from cadaveric donors or patients with organ-confined tumors. Our Western blot analysis revealed that HCAP was present in 9 of 19 urine specimens from cachectic CaP patients but not in 19 urine samples of noncachectic patients. HCAP mRNA and protein were also detected in LuCaP 35 and PC-3M xenografts from our cachectic animal models. Our results demonstrated that human CaP cells express HCAP and the expression of HCAP is associated with the progression of CaP and the development of CaP cachexia.

Animals↗
PubMed2003

Elevation of cytokine levels in cachectic patients with prostate carcinoma.

BACKGROUND: Approximately 60-70% of patients with advanced prostate carcinoma (CaP) suffer from cachexia, one of the most devastating conditions associated with advanced malignant disease. The pathophysiology of cachexia is multifactorial, and several cytokines, such as tumor necrosis factor alpha (TNFalpha) and interleukin 1 (IL-1), IL-6, and IL-8, may be involved. The objective of the current study was to determine whether cachexia associated with advanced CaP is accompanied by increased serum levels of TNFalpha, IL-1beta, IL-6, and IL-8. METHODS: The levels of TNFalpha, IL-1beta, IL-6, IL-8, and prostate specific antigen (PSA) were examined in serum samples from normal donors (n = 10 donors), from patients with organ-confined CaP (n = 19 patients), from patients with advanced CaP without cachexia (n = 17 patients), and from patients with cachectic CaP (n = 26 patients). DPC Immulite and Abbott IMx Total-PSA assays were used to determine cytokine and PSA levels, respectively. RESULTS: Levels of TNFalpha, IL-6, and IL-8 were elevated significantly in the group of patients with advanced, cachectic CaP compared with patients who were without cachexia. In the cachectic patients, levels of TNFalpha were correlated positively with IL-8, and there was no correlation between PSA levels and any of the cytokine levels. IL-1beta levels were below the limit of detection in all samples. CONCLUSIONS: The current results show that levels of TNFalpha, IL-6, and IL-8 were increased in CaP patients with cachexia. Increased levels of these cytokines were not correlated with PSA levels, suggesting that they are regulated by a mechanism that is independent of PSA synthesis. Additional fundamental research is needed to determine the mechanisms involved and to identify potential therapeutic targets in patients with cachexia.

Aged↗
PubMed2003

Characterization of C4-2 prostate cancer bone metastases and their response to castration.

UNLABELLED: New well-characterized preclinical models of prostate cancer (CaP) bone metastases are needed to improve our understanding of the development of CaP-related bone disease in patients. Here we describe characterization of a model consisting of direct injection of C4-2 cells into tibias. INTRODUCTION: Prostate cancer (CaP) has a high proclivity to metastasize to bone. Development and characterization of preclinical models of CaP bone metastases are of high interest. The objective of this study was to characterize C4-2 bone metastases and their response to castration. MATERIALS AND METHODS: Cell suspensions of C4-2, a subline of LNCaP, were injected directly into the tibias of intact male mice. In groups A (n = 7) and B (n = 5), animals were killed 3 and 8 weeks after injection of C4-2 cells, respectively. In group C (n = 7), animals were castrated 3 weeks after injection and killed 5 weeks after castration. Serum prostate-specific antigen (PSA) levels and bone mineral density (BMD) were measured, and bone histomorphometric analysis was performed. RESULTS: C4-2 cells decreased BMD of the injected tibias by 36.1% and bone volume by 74.1% versus normal tibias. Castration caused a 32.3% drop in serum PSA (p = 0.0438), with a nadir at day 14, after which it began to rise again. Bone destruction in the tumorous tibias of castrated animals was decreased by 15.9% versus tumorous tibias of intact animals (p = 0.0392). However, BMD in the tumorous tibias of castrated mice was still lower than in normal tibias of intact animals. Castration also decreased BMD and bone volume in nontumorous tibias (p = 0.0406 and 0.0232, respectively). CONCLUSIONS: The C4-2 model of bone metastasis recapitulates the response to androgen deprivation observed in CaP patients with bone metastases and is suitable for study of interactions between tumor and bone cells and evaluation of new therapeutic modalities.

Animals↗
PubMed2003

Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer.

PURPOSE: In this study we have examined the effects of zoledronic acid (ZA), a new-generation bisphosphonate, on prostate cancer (CaP) cells in vitro, and on both osteoblastic and osteolytic CaP metastases in animal models. EXPERIMENTAL DESIGN: In vitro, CaP cells were treated with ZA, and the effects on proliferation, cell cycle, and apoptosis were determined. In vivo, PC-3, and LuCaP 23.1 s.c. and tibial tumors were treated with ZA. Effects on bone and tumor were determined by histomorphometry and immunohistochemistry. RESULTS: ZA decreased proliferation of CaP cells, and caused G(1) arrest and apoptosis of CaP cells in vitro. In vivo, s.c. CaP tumor growth was not affected by ZA. However, growth of osteoblastic and osteolytic metastases of CaP was inhibited significantly in vivo. Matrix metalloproteinase-2, matrix metalloproteinase-9, and Cathepsin K levels were decreased in osteolytic bone metastases after ZA administration. CONCLUSIONS: In conclusion, we have shown that ZA has significant antitumor effects on CaP cells in vitro and in vivo. Antiosteolytic activity and the antitumor effects of this compound could benefit CaP patients with bone metastases.

Animals↗
PubMed2002

Establishment and characterization of osseous prostate cancer models: intra-tibial injection of human prostate cancer cells.

BACKGROUND: To improve the therapy of advanced prostate cancer (CaP), it is critical to develop animal models that mimic CaP bone metastases. Unlike the human disease, CaP xenograft models rarely metastasize spontaneously to bone from the orthotopic site of primary tumor growth. METHODS: Single-cell suspensions of LNCaP, PC-3, LuCaP 35, and LuCaP 23.1 CaP cells were injected directly into tibia of SCID mice. Immunohistochemistry and bone histomorphometrical analyses were performed to characterize these osseous-CaP models. RESULTS: LuCaP 23.1 yields an osteoblastic response, LNCaP yields mixed lesions, and LuCaP 35 and PC-3 result in osteolytic responses. We have detected osteoprotegerin, RANK ligand, parathyroid hormone-related protein, and endothelin-1, proteins associated with bone growth and remodeling, in the CaP cells grown in the bone. CONCLUSIONS: These animal models can be used to study biological interactions, pathways, and potential therapeutic targets, and also to evaluate new agents for treatment and prevention of CaP bone metastasis.

Animals↗