Biomedical subjects

Kenneth J Pienta

Publications and source records attributed to Kenneth J Pienta.

At least 73 records · Page 4Linked to original sources

PubMed2003

Germ cell tumors: review of selected studies from 2002.

Testicular cancer remains a major success story in the realm of solid tumors. There are still many remaining challenges in diagnosis, treatment, and prevention of long-term toxicity. Surgery and platinum-based chemotherapy, however, still encompass the main treatment modalities. Attempts to limit toxicity from both surgery and chemotherapy remain at the forefront of research. New chemotherapeutic options are available for patients with platinum-resistant disease, and stem cell transplant remains an area of active study.

Adult↗

PubMed2003

The effect of bone-associated growth factors and cytokines on the growth of prostate cancer cells derived from soft tissue versus bone metastases in vitro.

Prostate cancer metastasis to bone may be mediated by preferential proliferation of these cells in the bone's microenvironment. We hypothesize that this preferential proliferation is mediated by bone-associated growth factors (GFs) and cytokines. To test our hypothesis, human prostate cancer cells, derived from both soft tissue (LNCaP, DuCaP, DU145) and bone metastases (PC-3, VCaP, MDA-2a, MDA-2b), were treated with bone-associated GFs and cytokines (PDGF, IGF-1, TGF-beta, EGF, bFGF, TNF-alpha, IL-1, and IL-6) for 48 h, and their growth responses were compared. The responses of soft tissue-derived prostate cancer cell lines to bone GFs and cytokines were variable. LNCaP cell growth was stimulated by IGF-1 but was inhibited by TNF-alpha. DU145 cell growth was stimulated with EGF. Prostate cancer cell lines derived from bone metastases also responded variably to bone GFs and cytokines. IL-1 stimulated the growth of MDA-2a and 2b cell lines in a dose-dependent manner. PDGF and bFGF both demonstrated variable effects on bone-derived prostate cancer cell lines. TNF-alpha inhibited proliferation of the VCaP cells. These findings demonstrate that human prostate cancer cell lines derived from bone metastases may not respond preferentially to bone-associated GFs and cytokines.

Bone Neoplasms↗

PubMed2003

Rationale for the Radiation Therapy Oncology Group Study RTOG P-0014.

Chemotherapy currently has an established role in the treatment of hormonere-fractory prostate cancer. There is strong evidence that combined-modality treatment, using androgen ablation in addition to radiotherapy, provides a benefit above and beyond radiotherapy alone in patients with a poor prognosis, perhaps due to the effect of androgen ablation on subclinical distant disease. Several clinical trials currently under way are investigating whether the addition of chemotherapy with known efficacy in the hormone-refractory setting can provide a survival advantage when used adjuvantly.

Journal Article↗

PubMed2003

Rationale for the Radiation Therapy Oncology Group Study RTOG P-0014.

Chemotherapy currently has an established role in the treatment of hormonerefractory prostate cancer. There is strong evidence that combined-modality treatment, using androgen ablation in addition to radiotherapy, provides a benefit above and beyond radiotherapy alone in patients with a poor prognosis, perhaps due to the effect of androgen ablation on subclinical distant disease. Several clinical trials currently under way are investigating whether the addition of chemotherapy with known efficacy in the hormone-refractory setting can provide a survival advantage when used adjuvantly.

Journal Article↗

PubMed2002

The polycomb group protein EZH2 is involved in progression of prostate cancer.

Prostate cancer is a leading cause of cancer-related death in males and is second only to lung cancer. Although effective surgical and radiation treatments exist for clinically localized prostate cancer, metastatic prostate cancer remains essentially incurable. Here we show, through gene expression profiling, that the polycomb group protein enhancer of zeste homolog 2 (EZH2) is overexpressed in hormone-refractory, metastatic prostate cancer. Small interfering RNA (siRNA) duplexes targeted against EZH2 reduce the amounts of EZH2 protein present in prostate cells and also inhibit cell proliferation in vitro. Ectopic expression of EZH2 in prostate cells induces transcriptional repression of a specific cohort of genes. Gene silencing mediated by EZH2 requires the SET domain and is attenuated by inhibiting histone deacetylase activity. Amounts of both EZH2 messenger RNA and EZH2 protein are increased in metastatic prostate cancer; in addition, clinically localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis. Thus, dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.

Biomarkers, Tumor↗

PubMed2002

alpha-Methylacyl coenzyme A racemase as a tissue biomarker for prostate cancer.

CONTEXT: Molecular profiling of prostate cancer has led to the identification of candidate biomarkers and regulatory genes. Discoveries from these genome-scale approaches may have applicability in the analysis of diagnostic prostate specimens. OBJECTIVES: To determine the expression and clinical utility of alpha-methylacyl coenzyme A racemase (AMACR), a gene identified as being overexpressed in prostate cancer by global profiling strategies. DESIGN: Four gene expression data sets from independent DNA microarray analyses were examined to identify genes expressed in prostate cancer (n = 128 specimens). A lead candidate gene, AMACR, was validated at the transcript level by reverse transcriptase polymerase chain reaction (RT-PCR) and at the protein level by immunoblot and immunohistochemical analysis. AMACR levels were examined using prostate cancer tissue microarrays in 342 samples representing different stages of prostate cancer progression. Protein expression was characterized as negative (score = 1), weak (2), moderate (3), or strong (4). Clinical utility of AMACR was evaluated using 94 prostate needle biopsy specimens. MAIN OUTCOME MEASURES: Messenger RNA transcript and protein levels of AMACR; sensitivity and specificity of AMACR as a tissue biomarker for prostate cancer in needle biopsy specimens. RESULTS: Three of 4 independent DNA microarray analyses (n = 128 specimens) revealed significant overexpression of AMACR in prostate cancer (P<.001). AMACR up-regulation in prostate cancer was confirmed by both RT-PCR and immunoblot analysis. Immunohistochemical analysis demonstrated an increased expression of AMACR in malignant prostate epithelia relative to benign epithelia. Tissue microarrays to assess AMACR expression in specimens consisting of benign prostate (n = 108 samples), atrophic prostate (n = 26), prostatic intraepithelial neoplasia (n = 75), localized prostate cancer (n = 116), and metastatic prostate cancer (n = 17) demonstrated mean AMACR protein staining intensity of 1.31 (95% confidence interval, 1.23-1.40), 2.33 (95% CI, 2.13-2.52), 2.67 (95% CI, 2.52-2.81), 3.20 (95% CI, 3.10-3.28), and 2.50 (95% CI, 2.20-2.80), respectively (P<.001). Pairwise comparisons demonstrated significant differences in staining intensity between clinically localized prostate cancer compared with benign prostate tissue, with mean expression scores of 3.2 and 1.3, respectively (mean difference, 1.9; 95% CI, 1.7-2.1; P<.001). Using moderate or strong staining intensity as positive (score = 3 or 4), evaluation of AMACR protein expression in 94 prostate needle biopsy specimens demonstrated 97% sensitivity and 100% specificity for detecting prostate cancer. CONCLUSIONS: AMACR was shown to be overexpressed in prostate cancer using independent experimental methods and prostate cancer specimens. AMACR may be useful in the interpretation of prostate needle biopsy specimens that are diagnostically challenging.

Biomarkers, Tumor↗

PubMed2002

Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone.

Neoplasms have a striking tendency to metastasize or "home" to bone. Hematopoietic cells also home to bone during embryonic development, where evidence points to the chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12; expressed by osteoblasts and endothelial cells) and its receptor (CXCR4) as key elements in these processes. We hypothesized that metastatic prostate carcinomas also use the SDF-1/CXCR4 pathway to localize to the bone. To test this, levels of CXCR4 expression were determined for several human prostate cancer cell lines by reverse transcription-PCR and Western blotting. Positive results were obtained for cell lines derived from malignancies that had spread to bone and marrow. Prostate cancer cells were also observed migrating across bone marrow endothelial cell monolayers in response to SDF-1. In in vitro adhesion assays, pretreatment of the prostate cancer cells with SDF-1 significantly increased their adhesion to osteosarcomas and endothelial cell lines in a dose-dependent manner. Invasion of the cancer cell lines through basement membranes was also supported by SDF-1 and inhibited by antibody to CXCR4. Collectively, these results suggest that prostate cancers and perhaps other neoplasms may use the SDF-1/CXCR4 pathway to spread to bone.

Bone Neoplasms↗

PubMed2002

Mind-body effect: insulinlike growth factor-1; clinical depression; and breast, prostate, and other cancer risk-an unmeasured and masked mediator of potential significance?

A possible relation may exist between higher insulinlike growth factor (IGF)-1 levels and the risk of premenopausal breast, prostate, or other cancers from recent prospective and case-control studies. Separately, a large prospective study has shown a potential association between chronic depression and cancer risk, whereas other preliminary studies have suggested a link between increasing IGF levels with major depression. Other studies have found that certain standard cancer treatments reduce the effect and levels of IGF, and 1 small study has found that standard antidepressants may reduce IGF levels in some patients diagnosed with major depression. It is possible that IGF-1 (or other IGFs) may be a mediator between depression and cancer, because separately both have been implicated in the risk of various cancers. This hypothesis first and foremost relies on the unsettled notion that an actual relation already exists or may be found in the future. It requires more extensive investigation because several studies have not found an association between IGF or depression and cancer risk, and other limitations such as small sample sizes and other influential factors on IGF levels need to be elucidated. Whether or not a mind-body effect exists with cancer, as seems to be the case with other diseases, remains to be seen. Is depression a potential confounder of human studies that attempts to establish a relation between IGF and disease? All of the studies to date have attempted to at least determine the effect of a variety of factors on IGF levels-including age, sex, diet, family history, weight, smoking status-and then have adjusted their results accordingly. Depression has not been included in this list of potential factors that may need to be considered when analyzing IGF-1 data and cancer risks. The time seems ripe to at least define further the relation, if any, between IGF-1 and depression.

Adult↗

PubMed2002

A functional thrombin receptor (PAR1) is expressed on bone-derived prostate cancer cell lines.

OBJECTIVES: To identify genes important in prostate cancer metastatic to bone. Bone-specific metastasis is a common feature of prostate cancer and a significant cause of morbidity. METHODS: To identify factors involved in organ-specific metastasis, we used cDNA microarray analysis to compare a bone-derived cell line, VCaP, with a soft tissue-derived cell line, DuCaP. Both cell lines were derived from the same patient and spontaneously passaged. RESULTS: Forty-five genes were differentially expressed, and only seven of these also had increased expression in VCaP compared with normal prostatic tissue. Of these, protease-activated receptor 1 (PAR1) was verified as having increased expression by reverse transcriptase-polymerase chain reaction and Northern blot analysis, as well as by immunohistochemistry. PAR1 expression in a panel of prostate cancer cell lines demonstrated increased expression in those cell lines derived from bone metastases. Alpha-thrombin stimulation of the VCaP cells produced a dose-dependent mobilization of intracellular calcium compared with DuCaP, suggesting that PAR1 expressed on the VCaP prostate cancer cell line is functional. CONCLUSIONS: These data indicate that a functional PAR1 is expressed on prostate cancer cell lines. The prostate cancer cell lines expressing PAR1 appear to have an association with increased bone metastases.

Bone Neoplasms↗

PubMed2002

The regulation of prostate cancer cell adhesion to human bone marrow endothelial cell monolayers by androgen dihydrotestosterone and cytokines.

A previous study from our laboratory suggested that prostate cancer metastasis to bone may be mediated, in part, by preferential adhesion to human bone marrow endothelial (HBME) cells. Tumor cell adhesion to endothelial cells may be modulated by the effect of cytokines on cell adhesion molecules (CAMs). Tumor necrosis factor-alpha (TNF-alpha) regulates VCAM expression on the endothelium and this effect is enhanced by dihydrotestosterone (DHT). Transforming growth factor-beta (TGF-beta) stimulates the expression of alpha2beta1 integrin on PC-3 cells. The current study investigated the effects of the above cytokines and DHT (singularly and in various combinations) upon HBME and prostate cancer cell expression of VCAM, alpha2 integrin subunit, and beta1 integrin subunit by flow cytometry. We also monitored the effects of the above treatments on PC-3 cell adhesion to HBME monolayers. The data demonstrate that none of the treatments significantly altered the expression of selected CAMs on HBME cell and neoplastic prostate cell lines. The treatment of HBME monolayers with various combinations of cytokines and DHT prior to performing adhesion assays with PC-3 demonstrates that treatments containing TGF-beta reduced PC-3 cell adhesion to HBME monolayers by 32% or greater (P < 0.05). The reduction in PC-3 cell adhesion to TGF-beta-treated HBME monolayers was dose dependent. Interestingly, LNCaP cells but not PC-3 cells treated with TGF-beta had a reduced ability to adhere to untreated HBME monolayers. These results suggest that TGF-beta may reduce tumor cell adhesion to bone marrow microvascular endothelium, in vivo. The biological significance of this observation is discussed.

Adenocarcinoma↗

PubMed2002

Tissue microarray sampling strategy for prostate cancer biomarker analysis.

High-density tissue microarrays (TMA) are useful for profiling protein expression in a large number of samples but their use for clinical biomarker studies may be limited in heterogeneous tumors like prostate cancer. In this study, the optimization and validation of a tumor sampling strategy for a prostate cancer outcomes TMA is performed. Prostate cancer proliferation determined by Ki-67 immunohistochemistry was tested. Ten replicate measurements of proliferation using digital image analysis (CAS200, Bacus Labs, Lombard, IL, USA) were made on 10 regions of prostate cancer from a standard glass slide. Five matching tissue microarray sample cores (0.6 mm diameter) were sampled from each of the 10 regions in the parallel study. A bootstrap resampling analysis was used to statistically simulate all possible permutations of TMA sample number per region or sample. Statistical analysis compared TMA samples with Ki-67 expression in standard pathology immunohistochemistry slides. The optimal sampling for TMA cores was reached at 3 as fewer TMA samples significantly increased Ki-67 variability and a larger number did not significantly improve accuracy. To validate these results, a prostate cancer outcomes tissue microarray containing 10 replicate tumor samples from 88 cases was constructed. Similar to the initial study, 1 to 10 randomly selected cores were used to evaluate the Ki-67 expression for each case, computing the 90th percentile of the expression from all samples used in each model. Using this value, a Cox proportional hazards analysis was performed to determine predictors of time until prostate-specific antigen (PSA) recurrence after radical prostatectomy for clinically localized prostate cancer. Examination of multiple models demonstrated that 4 cores was optimal. Using a model with 4 cores, a Cox regression model demonstrated that Ki-67 expression, preoperative PSA, and surgical margin status predicted time to PSA recurrence with hazard ratios of 1.49 (95% confidence interval [CI] 1.01-2.20, p = 0.047), 2.36 (95% CI 1.15-4.85, p = 0.020), and 9.04 (95% CI 2.42-33.81, p = 0.001), respectively. Models with 3 cores to determine Ki-67 expression were also found to predict outcome. In summary, 3 cores were required to optimally represent Ki-67 expression with respect to the standard tumor slide. Three to 4 cores gave the optimal predictive value in a prostate cancer outcomes array. Sampling strategies with fewer than 3 cores may not accurately represent tumor protein expression. Conversely, more than 4 cores will not add significant information. This prostate cancer outcomes array should be useful in evaluating other putative prostate cancer biomarkers.

Biomarkers↗

PubMed2002

Testicular cancer.

Testicular cancer remains a major success story in the realm of solid tumors. Although testicular cancer is highly treatable and curable, there are still many young men who succumb to the disease. Over the past year, important data regarding the diagnosis, treatment, and prognosis of testicular cancer have been reported. The significance of genetic and molecular alterations, such as i12p and epidermal growth factor receptor expression, remain at the forefront of research. However surgery and platinum-based chemotherapy are still the main treatment modalities. Attempts to limit chemotherapy and surgery while preserving cure rates are promising. The contribution of long-term platinum retention to the well-documented risk of late toxicity is unknown but provides a specific avenue for research. New tumor markers, such as lactate dehydrogenase isoenzyme-1, may provide a greater risk stratification. Positron emission tomography imaging may reduce the need for surgical resection posttherapy and provide a more comprehensive means of observation.

Antineoplastic Agents↗

PubMed2002

New discoveries in prostate cancer biology and treatment. 5-9 December 2001, Naples, Florida, USA.

Androgen independence and bone metastasis are lethal complications in patients with advanced prostate cancer. Presently, there is no cure for patients with androgen-independent prostate cancer. In order to develop more effective therapies for this disease, the molecular events involved in the development of androgen independence and bone metastasis must be elucidated and then targeted by therapeutic agents. Several studies presented at a recent conference on prostate cancer sponsored by the American Association for Cancer Research (AACR) provided evidence that prostate cancer metastasis to bone is mediated by the prostate cancer cell expression of molecules that allow the cells to invade, grow in and stimulate cells in the bone microenvironment resulting in an osteoblastic reaction. Androgen independence was reportedly mediated by an increased expression of survival genes following androgen ablation therapies and several molecular mechanisms involved in genetic instability. Treatment strategies are being designed to target some of the molecular events involved in androgen independence and bone metastasis. Targeting these molecular events with combinational therapies will hopefully delay the progression to androgen independence in patients with early stage disease, suppress the growth of androgen-independent cells in patients with advanced disease and enhance the chemosensitivity of androgen-independent cells.

Antineoplastic Agents↗

PubMed2002

Antimetastatic drugs in prostate cancer.

Despite the benefits of local therapy with radical prostatectomy and radiation, many patients with prostate cancer require hormonal ablation. While chemotherapy has proven efficacy when the disease progresses to androgen-independent prostate cancer, patients ultimately succumb to the disease, thus the identification of other active therapies is needed. Future treatment modalities include molecular targeted therapies. Prostate cancer has been an ideal model to study the multiple steps required in the metastatic cascade. These steps have been utilized in the development of metastasis inhibitors. This review will present promising agents that have been tested preclinically or are undergoing clinical investigation for their abilities in preventing prostate cancer metastasis. Because prostate cancer metastasizes preferentially to the bone, special attention will be given to agents that interfere with this pattern of metastasis. Specifically, the efficacy of angiogenesis inhibitors, metalloproteinase inhibitors, inhibitors of prostate cancer cell- endothelial cell interactions, and bisphosphonates will be reported. In addition, the introduction of these novel agents has raised many questions as to the relevance and optimal utilization of current clinical trial designs. Issues regarding combination therapy with chemotherapy, optimal timing of treatment with metastatic inhibitors, and the need for surrogate endpoints for molecular targeted therapies will be discussed.

Angiogenesis Inhibitors↗

PubMed1999

Pain management in patients with advanced prostate cancer.

Prostate cancer is the most commonly diagnosed cancer among American men. The majority of patients with advanced disease have metastatic bone lesions, which are frequently very painful. These lesions tend to respond well to treatment with both nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, although careful dose titration and individualized treatment plans may be needed to achieve maximal analgesia. Opioid side effects are often transient or well controlled with additional medication. Patients with intolerable side effects may experience fewer adverse reactions with a different opioid. Palliative radiation provides pain relief in up to 80% of prostate cancer patients with single or at most a few sites of localized bone pain. Bisphosphonates, powerful inhibitors of osteoclast-mediated bone resorption, are promising new agents for the treatment of painful bone lesions in prostate cancer patients. Radioisotopes, which deliver high-dose radiation to bone lesions without significantly affecting normal bone, are highly effective in providing some degree of pain relief in up to 80% of patients with diffuse, painful bone metastases. Also, chemotherapy shows promise in alleviating pain and possibly extending survival in patients with advanced prostate cancer.

Analgesics, Opioid↗

PubMedDate not supplied

Development of the VCaP androgen-independent model of prostate cancer.

Prostate epithelial cell growth is dependent on the presence of androgens, and transition of prostate cancer to an androgen-independent phenotype results in a highly aggressive, currently incurable cancer. We have developed a new preclinical model of androgen-independent prostate cancer derived from the VCaP prostate cancer epithelial cell line. VCaP cells were subcutaneously implanted and serially passaged in castrated male severe combined immunodeficient mice. Androgen independence was confirmed by WST-1 (a tetrazolium salt) cell proliferation assay in the absence or presence of dihydrotesterone (1-100 nM). VCaP androgen-sensitive cells responded dose dependently to dihydrotesterone, whereas VCaP androgen-independent cells did not alter their proliferation in response to dihydrotesterone. Gene expression of androgen receptor, B-cell lymphoma-2, prostate cancer antigen 3, prostate acid phosphatase, 6 transmembrane epithelial antigen of the prostate, and survivin was determined by polymerase chain reaction amplification. B-cell lymphoma-2 expression was up regulated in the VCaP androgen-independent lines compared to the VCaP androgen-sensitive, suggesting a possible mechanism of androgen independence. Furthermore, tumor-associated angiogenesis was assessed by immunofluorescence confocal microscopy of CD31. VCaP androgen-independent tumors showed enhanced angiogenesis compared to VCaP androgen-sensitive tumors. These results illustrate the development of a novel model of prostate cancer androgen independence and provide a new system to study angiogenesis and the transition to androgen independence.

Androgens↗

PubMedDate not supplied

The truth is out there: an overall perspective on androgen deprivation.

Androgen deprivation therapy (ADT) is a mainstay in the treatment of prostate cancer. The ideal timing, duration and composition of ADT remains undefined. At the present time, first-line therapy consists of orchiectomy, LHRH agonists, or combined androgen blockade (CAB). However, new combinations and treatment settings show promise for improving outcomes and decreasing toxicity.

Androgen Antagonists↗

PubMedDate not supplied

The role of alpha(v)beta(3) in prostate cancer progression.

Integrin alpha(v)beta(3) is involved in varied cell biological activities, including angiogenesis, cell adhesion, and migration on several extracellular matrix components. Although alpha(v)beta(3) is not typically expressed in epithelial cells, it is expressed in macrophages, activated leukocytes, cytokine-stimulated endothelial cells, osteoclasts, and certain invasive tumors. Interestingly, the adhesion and migration of breast cancer cells on bone matrix are mediated, in part, by alpha(v)beta(3). Similar to breast cancer cells, prostate cancer cells preferentially metastasize to the bone. The biological events that mediate this metastatic pattern of prostate cancer are not well defined. This review discusses the role alpha(v)beta(3) plays in prostate cancer progression, with specific emphasis on bone metastasis and on alpha(v)beta(3) signaling in prostate cancer cells. The data suggest that alpha(v)beta(3), in part, facilitates prostate cancer metastasis to bone by mediating prostate cancer cell adhesion to and migration on osteopontin and vitronectin, which are common proteins in the bone microenvironment. These biological events require the activation of focal adhesion kinase and the subsequent activation of PI-3 kinase/Akt signaling pathway.

Cell Adhesion↗