Biomedical subjects

D Theodorescu

Publications and source records attributed to D Theodorescu.

At least 19 recordsLinked to original sources

PubMed2006

Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia.

Most deaths from urinary bladder cancer are owing to metastatic disease. A reduction in Rho GDP Dissociation Inhibitor 2 (RhoGDI2) protein has been associated with increased risk of metastasis in patients with locally advanced bladder cancer, whereas in animal models, RhoGDI2 reconstitution in cells without expression results in lung metastasis suppression. Recently, we noted an inverse correlation between tumor RhoGDI2 and Neuromedin U (NMU) expression, suggesting that NMU might be a target of the lung metastasis suppressor effect of RhoGDI2. Here we evaluated whether NMU is regulated by RhoGDI2 and is functionally important in tumor progression. We used small interfering RNA knockdown of endogenous RhoGDI2 in poorly tumorigenic and non-metastatic human bladder cancer T24 cells and observed increased NMU RNA expression. Although NMU overexpression did not increase the monolayer growth of T24 or related T24T poorly metastatic human bladder cancer cells, it did augment anchorage-independent growth for the latter. Overexpression of NMU in T24 and T24T cells significantly promoted tumor formation of both cell lines in nude mice, but did not alter the growth rate of established tumors. Furthermore, NMU-overexpressing xenografts were associated with lower animal body weight than control tumors, indicating a possible role of NMU in cancer cachexia. NMU overexpression in T24T cells significantly enhanced their lung metastatic ability. Bioluminescent in vivo imaging revealed that lung metastases in T24T grew faster than the same tumors in the subcutaneous microenvironment. In conclusion, NMU is a RhoGDI2-regulated gene that appears important for tumorigenicity, lung metastasis and cancer cachexia, and thus a promising therapeutic target in cancer.

Animals↗

PubMed2006

Conditional expression of PTEN alters the androgen responsiveness of prostate cancer cells.

BACKGROUND: Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is lost as a function of prostate tumor androgen dependence. While the transcriptional activity of the androgen receptor (AR) is inhibited by PTEN in androgen sensitive prostate cancer (CaP), the role of PTEN in androgen disease is unclear. METHODS: We developed a system where PTEN can be conditionally re-expressed at physiologic levels into a PTEN null metastatic human CaP cell line, C4-2, and androgen responsiveness examined. RESULTS: PTEN induction reduces cell growth and blocks the growth effect of synthetic androgen R1881. The anti-androgen Casodex enhances the growth-inhibitory action of PTEN and this effect is independent of Akt phosphorylation. Combined PTEN induction and Casodex, result in a further decrease in prostate specific antigen promoter activity compared to PTEN but not Casodex alone. CONCLUSIONS: PTEN induction confers androgen independent CaP cells enhanced responsiveness to the anti-proliferative effects of anti-androgens and this action may involve non-AR mediated effects.

Androgen Antagonists↗

PubMed2006

A novel method for gene expression mapping of metastatic competence in human bladder cancer.

Expression profiling by DNA microarray analysis has provided insights into molecular alterations that underpin cancer progression and metastasis. Although differential expression of microarray-defined probes can be related to numerical or structural chromosomal alterations, it is unclear if such changes are also clustered in distinct chromosomes or genomic regions and whether chromosomal alterations always reflect changes in gene expression. Here we apply the dChip algorithm and a novel technique to test the hypothesis that expression changes occurring as a function of tumor progression and metastasis are nonrandomly distributed. Expression profiling of a human xenograft model of lung metastasis phenotype indicates that chromosomes 2, 11, and 20 contain higher percentages of differentially expressed genes (P < .05). Furthermore, we show that a number of differentially expressed probes mapped to chromosome 17q, defining the existence of an expression "hot spot" corresponding to an area of gain determined by comparative genomic hybridization (CGH). Interestingly, other areas of gains detected by CGH were not associated with expression hot spots. In summary, we show that gene expression changes during bladder cancer lung metastasis occur nonrandomly in specific chromosomes and intrachromosomal locations.

Algorithms↗

PubMed2004

The effect of sampling more cores on the predictive accuracy of pathological grade and tumour distribution in the prostate biopsy.

OBJECTIVE: To determine if increasing the number of cores at biopsy improves the predictive accuracy of the Gleason score or aids in anticipating the location and volume of prostate tumour. PATIENTS AND METHODS: The charts of 75 consecutive patients who underwent radical retropubic prostatectomy for clinical T1-2 adenocarcinoma of the prostate were reviewed retrospectively; 31 patients had a sextant biopsy (group 1) and 44 had > or = 8 cores taken (group 2). The concordance between biopsy data and final prostatectomy Gleason score, tumour location and volume was determined for each group. RESULTS: There were no differences in mean age, prostate-specific antigen level before biopsy or biopsy Gleason score for the two groups; 58% of group 1 had their final pathological grade changed after prostatectomy, vs 29% of group 2 (P < 0.05). In neither group was there a significant correlation between the percentage of cores positive for tumour and the percentage volume of prostate involved with cancer, or the ability of the biopsy to predict tumour location. CONCLUSION: Taking > or = 8 biopsy cores improved the pathological grading accuracy, which may be valuable in choosing a treatment for the patient with newly diagnosed prostate cancer.

Adenocarcinoma↗

PubMed2003

Motivations and influences on the use of complementary medicine in patients with localized prostate cancer treated with curative intent: results of a pilot study.

OBJECTIVES: To analyse descriptively the use of complementary medicine (CM) by patients with localized prostate cancer treated with curative intent, assessing the major influences on their choice to use CM, and the major critics and advocates of CM. PATIENTS AND METHODS: From January 1997 to June 2000, 351 men with stage T1c-T3 adenocarcinoma of the prostate were treated with either radical prostatectomy (RP) or brachytherapy. On the final date all patients were mailed a questionnaire relating to their use of CM and the results analysed cross-sectionally. RESULTS: In all, 238 (67.8%) patients returned the questionnaires, of whom 37% acknowledged using some type of CM, with a similar overall use of CM among those treated with RP or brachytherapy. Of these, 43% began using CM before and 32% after starting conventional treatment, and most indicated they would never discontinue these therapies. The most common reason for using CM was the patient's impression that it made them feel better, and secondarily that they felt it helped to cure their cancer. Physicians were the most common source of information about CM, with twice as many patients identifying physicians as being advocates rather than critics of CM. Many patients felt their urologist or radiation oncologist was neutral or chose not to discuss CM. However, when these physicians discussed CM, more patients felt that they encouraged rather than discouraged the use of CM. CONCLUSIONS: These data on the motivations for patient choices relating to CM are novel; the sources of information, both positive and negative, that patients find useful in their decision to use these therapies were explored. Interestingly, physicians were generally supportive of the use of such approaches.

Adenocarcinoma↗

PubMed2003

Molecular pathogenesis of urothelial bladder cancer.

Carcinoma of the urinary bladder is the second most common urologic malignancy. In addition, these tumors are one of the best understood genitourinary neoplasms with a well defined etiology, natural history, tumor biology, treatment options and outcome. This level of understanding arises as a consequence of multiple factors and represents a convergence of knowledge from diverse scientific disciplines. Insight provided by these disciplines, coupled with unique features of this neoplasm which make it assessable for detection, monitoring and treatment, combine to make this disease a model system for modern oncology. The intent of this review is to provide the reader an overview of our current understanding of this tumor from the standpoint of its molecular biology as related to tumor development and progression.

Cadherins↗

PubMed2003

Molecular therapeutics in prostate cancer.

The purpose of this review is to provide information on the molecular basis of prostate cancer biology and to identify some of the targets for therapy, and highlight some potential strategies for molecular treatment. Here we give a synopsis of what we have learned regarding molecular biology of cancer in general and the directions research might take in the future in order to impact prostate cancer specifically. This work is certainly not encyclopedic in nature and we apologize in advance to colleagues whose work we were no able to include. Hope lies in learning to utilize some of these molecular workings for better prevention, diagnosis, and treatment of the most common solid organ cancer in men. Prostate cancer is a formidable disease and at current rates of diagnosis will affect one-in-six men living in the United States (Greenlee et al., 2000) Many of these men are diagnosed at an early stage of the disease and can be effectively treated by surgery or radiation. However, a significant fraction of men are diagnosed with later stage disease or progress despite early curative therapeutic attempts. Unfortunately, many of these men succumb to prostate cancer, as management options are limited and not always successful. Through an understanding of the molecular processes that occur in the development and progression of prostate cancer, novel therapies will arise that will provide longer survival, better quality of life, and a chance for cure in men afflicted with this disease.

Androgens↗

PubMed2002

Multimodality radiotherapy and androgen ablation in the treatment of clinically localized prostate cancer: early results in high risk patients.

In patients presenting with clinically localized prostate cancer, the risk of biochemical failure increases significantly with higher Gleason scores, prostate specific antigen (PSA) levels, and clinical stages. Current surgical and radiotherapeutic approaches appear to offer limited success in patients with highly adverse prognostic factors. In an attempt to improve on these outcomes, we have combined external beam radiotherapy (EBRT) with a brachytherapy (BT) boost and neo adjuvant and adjuvant androgen ablation in a population at significant risk of biochemical failure. Here we present early biochemical progression data for this approach. From October 1997 to July 1999, 72 men with a serum PSA >or=10 ng/ml or Gleason score >or=7 or clinical stage >or=T2c (AJC/UICC 1992) underwent EBRT followed by palladium-103 BT. All patients underwent 8 months of combined androgen ablation with leuprolide and an oral antiandrogen beginning 3 months prior to initiation of EBRT. Patients were followed by PSA and digital rectal examination (DRE) at 3-month intervals and a chart review on all patients was carried out during July 2001. To allow comparisons to contemporary literature, Kaplan-Meier survival curves were generated utilizing three alternate definitions of biochemical recurrence: PSA >0.2 ng/ml, PSA >1.0 ng/ml, and the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus definition of three consecutive rising PSAs. Our results indicate that when PSA >0.2 ng/ml was used to define biochemical progression, 88% (95% CI 80-97) of patients remained free of disease at 24 months. When PSA >1.0 ng/ml was used, 97% (CI 92-100) of patients remained disease free at 24 months. ASTRO criteria yielded 90% (CI 82-98) recurrence-free survival at 24 months. In conclusion, this very early report indicates that in patients who are at increased risk of biochemical failure, EBRT with a BT boost in conjunction with short-term androgen ablation offers potentially superior biochemical disease-free survival to contemporary alternative approaches in the literature. Clearly, longer follow-up is required to confirm the durability of this approach.

Aged↗

PubMed2001

Manipulation of gene expression by an ecdysone-inducible gene switch in tumor xenografts.

BACKGROUND: Rapid, robust and reversible induction of transgene expression would significantly facilitate cancer gene therapy as well as allow the in vivo functional study of newly discovered genes in tumor formation and progression. The popularity of the ecdysone inducible gene switch system has led us to investigate whether such a system can successfully regulate gene expression in a syngeneic tumor system in vivo. RESULTS: MBT-2 and Panc02 carcinoma cells were transfected with components of a modification of the ecdysone switch system driving firefly luciferase (F-Luc). In vitro luciferase expression +/- ecdysone analog GS-E indicated a robust induction with minimal baseline activity and complete decay after 24 hours without drug. In vitro selection of MBT-2 transfected cell clones which had complete absence of F-Luc expression in the absence of stimulation but which expressed this gene at high levels in response to GS-E were chosen for in vivo evaluation. Tumors from engineered MBT-2 cells were grown to 5 mm in diameter prior to GS-E administration, animals euthanized and tumors removed at 6, 12 and 24 hours after GS-E administration and assayed for F-Luc activity. GS-E resulted in a maximal induction of F-Luc activity at 6 hours in tumor tissue with almost complete reversion to control levels by 12 hours. CONCLUSIONS: This study is the first demonstration that robust and reversible transgene expression in tumors is feasible using the ecdysone system, allowing future rapid in vivo functional characterization of gene function or gene therapy applications.

Animals↗

PubMed2001

Cell density mediated pericellular hypoxia leads to induction of HIF-1alpha via nitric oxide and Ras/MAP kinase mediated signaling pathways.

Environmental signals in the cellular milieu such as hypoxia, growth factors, extracellular matrix (ECM), or cell-surface molecules on adjacent cells can activate signaling pathways that communicate the state of the environment to the nucleus. Several groups have evaluated gene expression or signaling pathways in response to increasing cell density as an in vitro surrogate for in vivo cell-cell interactions. These studies have also perhaps assumed that cells grown at various densities in standard in vitro incubator conditions do not have different pericellular oxygen levels. However, pericellular hypoxia can be induced by increasing cell density, which can exert profound influences on the target cell lines and may explain a number of findings previously attributed to normoxic cell-cell interactions. Thus, we first sought to test the hypothesis that cell-cell interactions as evaluated by the surrogate approach of increasing in vitro cell density in routine normoxic culture conditions results in pericellular hypoxia in prostate cancer cells. Second, we sought to evaluate whether such interactions affect transcription mediated by the hypoxia response element (HRE). Thirdly, we sought to elucidate the signal transduction pathways mediating the induction of HRE in response to cell density induced pericellular hypoxia in routine normoxic culture conditions. Our results indicate that paracrine cell interactions can induce nuclear localization of HIF-1a protein and this translocation is associated with strong stimulation of the HRE-reporter activity. We also make the novel observation that cell density-induced activity of the HRE is dependent on nitric oxide production, which acts as a diffusible paracrine factor secreted by densely cultured cells. These results suggest that paracrine cell interactions associated with pericellular hypoxia lead to the physiological induction of HRE activity via the cooperative action of Ras, MEK1, HIF-1a via pericellular diffusion of nitric oxide. In addition, these results highlight the importance of examining pericellular hypoxia as a possible stimulus in experiments involving in vitro cell density manipulation even in routine normoxic culture conditions.

2,2'-Dipyridyl↗

PubMed2001

Use of the aromatase inhibitor anastrozole in the treatment of patients with advanced prostate carcinoma.

BACKGROUND: Men with prostate carcinoma initially respond to therapies designed to inhibit androgen secretion or block its action. Later, the tumors in these patients become refractory to androgen-related therapies. Therefore, additional hormonal maneuvers that would benefit these men currently are needed. Reports of androgen receptor mutations and historic clinical observations raised the hypothesis that estrogens might be involved in the proliferation of androgen-refractory prostate carcinoma. METHODS: To explore this hypothesis, 14 men with advanced prostate carcinoma that was refractory to medical or surgical orchiectomy and antiandrogens were entered into a clinical Phase II trial involving suppression of estrogens. After complete evaluation, each patient received 1 mg daily of the third-generation aromatase inhibitor anastrozole until disease progression. Follow-up included serial determinations of prostate specific antigen (PSA), measurements of evaluable lesions, and assessment of intensity of pain. RESULTS: No patient experienced an objective response or disease stabilization as measured by PSA level or the greatest dimension of the lesion. Minimal improvement of bone pain was reported in two patients receiving intensive analgesic medication. CONCLUSIONS: It was concluded that the dependence of androgen-insensitive prostate carcinoma on estrogens for proliferation is uncommon and that aromatase inhibitors may not have a place in the treatment of prostate carcinoma at this stage of the disease.

Aged↗

PubMed2001

Prospective assessment of voiding and sexual function after treatment for localized prostate carcinoma: comparison of radical prostatectomy to hormonobrachytherapy with and without external beam radiotherapy.

BACKGROUND: Voiding and sexual function after treatment are major determinants of quality of life in prostate carcinoma patients. Erectile dysfunction, incontinence, and urinary symptoms, both obstructive and irritative, have a significant negative impact on patient quality of life. This prospective study was undertaken to evaluate voiding, sexual function, and their impact on patients with localized prostate carcinoma who were treated with radical retropubic prostatectomy (RP) and to compare these patients with patients who were undergoing hormonobrachytherapy with external bean radiotherapy (HBTC) and patients who were undergoing hormonobrachytherapy without external beam radiotherapy (HBT). METHODS: Patients treated for localized prostate carcinoma with either RP or interstitial palladium-103 (103Pd) HBTC or HBT were prospectively administered a voiding and sexual function questionnaire before any treatment was initiated and at posttreatment visits. Questionnaire components included the American Urological Association Symptom Score (AUASS) and specific items that addressed urinary control and sexual function from the University of California at Los Angeles Prostate Cancer Index. Questionnaire results were compiled, and differences among treatment groups were assessed over time. RESULTS: From January 1997 to November 1999, 127 consecutive patients were treated with either unilateral or bilateral nerve-sparing RP (42 patients), HBTC (40 patients) or HBT (45 patients) by 2 surgeons proficient in all procedures. Using the overall score and the obstructive subscale (OAUA) of the AUASS, the RP group showed a posttreatment decrease in scores compared with both HBTC and HBT groups. OAUA scores of HBTC and HBT groups were significantly greater than scores in RP patients over the course of the study. HBTC patients had increased irritative symptoms initially when compared with RP patients, and, although not statistically significant, the magnitude of the difference persisted over the course of the study. Total AUASS and subscale scores for the RP group returned to near baseline levels within 12 months. The use of incontinence pads was a criterion for urinary incontinence, and the proportion of patients returning to baseline continence was lower in RP patients over the course of the study. No notable differences in Voiding Bother (VB) scores were found. Initially RP patients experienced worse Sexual Function (SF) scores; however, scores for RP patients changed over time and approached the levels seen in HBTC patients at 18 months. The Sexual Function Bother (SFB) scores also were higher initially in the RP group but then decreased to similar levels observed for HBTC patients by 18 months. None of the treatment groups returned to near baseline SF or SFB scores during the course of this study. CONCLUSIONS: Comparison of voiding function indicated that HBTC and HBT patients initially have more obstructive voiding symptoms, whereas urinary incon- tinence is initially worse in RP patients. Initially RP patients demonstrated worse SF and SFB scores, but RP patients returned to HBTC levels within 18 months.

Adenocarcinoma↗

PubMed2001

Impact of second opinion pathology in the definitive management of patients with bladder carcinoma.

BACKGROUND: The accurate diagnosis, staging, and grading of bladder neoplasms depend heavily on the interpretation of biopsies and transurethral resection (TUR) specimens. Although many centers require review of outside pathologic material before definitive treatment such as radical cystectomy, the authors are unaware of data supporting the utility of this approach in urothelial (transitional cell) carcinoma. The authors therefore examined the clinical and cost impact of pathologic review on patients referred to an academic urology department for treatment of bladder neoplasia. METHODS: The pathologic material from 97 patients referred to an academic center for evaluation of urothelial carcinoma of the bladder from July 1996 to July 1999 was reviewed. This material was received from 30 community hospitals and 4 academic centers. The 97 patients had undergone 131 (mean, 1.35; range, 1-10) biopsies or TUR procedures before referral. Surgical pathologists at the authors' institution reviewed all outside patient material, and discordant cases were rereviewed by one of the authors (S.E.M), an experienced genitourinary pathologist. Follow-up chart review was performed in discordant cases to determine clinical and pathologic outcomes. RESULTS: Upon review at the authors' institution, 24 of 131 (18%) specimens with a referring diagnosis of urothelial carcinoma exhibited significant discrepancies with regard to the diagnosis, stage, grade, or tumor histologic type made at the outside institution. Four tumors (3%) were found to be nonurothelial neoplasms. Five specimens (4%) were judged inadequate for staging because they contained no muscularis propria. Three patients were upstaged, including two patients shown to have muscle invasive disease. Eight patients were downstaged, including two patients referred with purported muscle invasive disease who were determined to have only superficial disease on pathology review. Two patients initially thought to have carcinoma in situ (tumor in situ [Tis]) showed no evidence of Tis on pathology review. One patient with purported muscle invasive disease was shown to have only metaplasia, and one patient had a highly significant change in tumor grade. As a result of the pathology review, five radical cystectomies were avoided, whereas five repeat TUR procedures were recommended for inadequate staging. One patient shown to have muscle invasion on pathology review proceeded directly to cystectomy, avoiding a planned repeat TUR. A cystectomy also was recommended to a second patient who was shown to have invasive disease by the pathology review. Pathology review of 131 specimens resulted in net savings of $86,176 or $658 per TUR reviewed. CONCLUSIONS: The review of bladder pathologic materials before definitive therapy can impact clinical decisions significantly and can reduce overall expenditures for the management of this cohort of bladder carcinoma patients.

Biopsy↗

PubMed2001

An 800-kb region of deletion at 13q14 in human prostate and other carcinomas.

Deletions of regions at 13q14 have been detected by various genetic approaches in human cancers including prostate cancer. Several studies have defined one region of loss of heterozygosity (LOH) at 13q14 that seems to reside in a DNA segment of 7.1 cM between genetic markers D13S263 and D13S153. To define the smallest region of overlap (SRO) for deletion at 13q14, we first applied tissue microdissection and multiplex PCR to detect homozygous deletion and/or hemizygous deletion at 13q14 in 134 prostate cancer specimens from 114 patients. We detected deletions at markers D13S1227, D13S1272, and A005O48 in 13 (10%) of these tumor specimens. Of the 13 tumors with deletions, 12 were either poorly differentiated primary tumors or metastases of prostate cancer. To fine-map the deletion region, we then constructed a high-resolution YAC/BAC/STS/EST physical map based on experimental and database analyses. Several markers encompassing the deletion region were analyzed for homozygous deletion and/or hemizygous deletion in 61 cell lines/xenografts derived from human cancers of the prostate, breast, ovary, endometrium, cervix, and bladder, and a region of deletion was defined by duplex PCR assay between markers A005X38 and WI-7773. We also analyzed LOH at 13q14 in the 61 cell lines/xenografts using the homozygosity mapping of deletion approach and 26 microsatellite markers. We found 24 (39%) of the cell lines/xenografts to show LOH at 13q14 and defined a region of LOH by markers M1 and M5. Combination of homozygous or hemizygous deletion and LOH results defined the SRO for deletion to be an 800-kb DNA interval between A005X38 and M5. There are six known genes located in or close to the SRO for deletion. This region of deletion is at least 2 Mb centromeric to the RB1 tumor-suppressor gene and the leukemia-associated genes 1 and 2, each of which is located at 13q14. These data suggest that the 800-kb DNA segment with deletion contains a gene whose deletion may be important for the development of prostate and other cancers. This study also provides a framework for the fine-mapping, cloning, and identification of a novel tumor-suppressor gene at 13q14.

Adult↗

PubMed2001

Evaluation of urinary continence and voiding function: early results in men with neo-urethral modification of the Hautmann orthotopic neobladder.

PURPOSE: At our institution we use the Hautmann orthotopic bladder replacement with a chimney and neo-urethral modification. A neo-urethral tube allows tension-free intestino-urethral anastomosis, thus providing application of this procedure for patients who may otherwise not qualify due to the inability of the small bowel to reach the urethra. However, this neo-urethral tube may also enhance continence by providing significant intra-abdominal urethral length. Conversely, such a modification may be associated with a higher degree of urinary retention. Early evaluation and reporting on the results of this procedure appear warranted. MATERIALS AND METHODS: From April 1996 to March 2000, 14 consecutive male patients underwent cystoprostatectomy and urinary reconstruction with Hautmann repair using chimney and neo-urethral modifications. We performed a retrospective analysis of urinary function and continence with data obtained from patient questionnaires completed preoperatively and at each postoperative office visit. The examining physician chart notes were reviewed for information about urinary retention. The American Urological Association symptom score and voiding bother index were used to assess urinary function and bother, respectively. Urinary continence was defined as the complete absence of any form of urinary leakage protection. RESULTS: Of the 14 patients 12 were completely continent day and night, with a median followup of 17 months. There were 2 patients who wore pads less than 7 months after surgery. Improvement of urinary continence appeared to continue up to 12 months postoperatively. Despite this encouraging effect, when our data were compared to the published literature, we noted a somewhat increased incidence of patients requiring clean intermittent catheterization to manage significant post-void urinary residuals. We had no patients with urethro-intestinal strictures who required clean intermittent catheterization. CONCLUSIONS: The neo-urethral tube modification appears to have a significant and favorable impact on urinary continence while seeming to be associated with a trend towards an increased rate of chronic urinary retention. Longer followup will be required to determine whether this higher rate of chronic urinary retention will remain stable or change with time.

Aged↗

PubMed2001

Angiogenesis in prostate cancer: biology and therapeutic opportunities.

Tumor growth is limited in size without the incorporation of new blood vessels. Tumor cells release soluble factors (angiogenic factors) that induce neovascularization and allow subsequent growth beyond 2-3 mm in diameter meeting the need for cellular uptake of oxygen and nutrients. This process is referred to as the 'angiogenic switch' and indicates the acquisition of an angiogenic phenotype. Tumor angiogenesis requires an imbalance between proangiogenic and antiangiogenic factors with formation of new vessels being a highly regulated process. In this review we discuss the mediators of angiogenesis, the strategies for manipulating angiogenic factors, and possible therapeutic applications with a special emphasis on prostate cancer.

Angiogenesis Inducing Agents↗

PubMed2001

Orthotopic neobladder following cystectomy: indications, management, and outcomes.

Gross painless hematuria often prompts patients to seek medical attention. For some persons, especially those aged 55 to 80 years, this hematuria will prove to be the result of bladder cancer. Patients found to have muscle-invasive disease commonly undergo radical cystectomy and urinary diversion. The decision about which urinary diversion will be best suited to the individual patient is complex and depends on multiple factors relating to the patient and the tumor as well as a clear understanding about the risks and benefits of each diversion. This article will discuss issues such as cancer control, preoperative and postoperative care, management of the condition at home, and quality of life associated with the various urinary diversion options, with a special emphasis on orthotopic neobladder reconstruction. Awareness of the special issues associated with this procedure is needed to safely counsel and care for patients with these forms of bladder substitution.

Aftercare↗

PubMed2001

The role of vascular endothelial growth factor in the tissue specific in vivo growth of prostate cancer cells.

Despite the fact that cancer cells can be found in many vascular beds, continued growth of the metastatic tumor focus exhibits a significant degree of 'organ tropism', with only certain organs exhibiting the ravages of metastatic disease. Since a limiting factor to the growth of metastases beyond 2 mm in diameter, may be a lack of angiogenesis, we sought to determine whether tumor overexpression of vascular endothelial growth factor (VEGF), a potent angiogenic factor related to prostate cancer metastasis, is causally related to organ specific tumor growth in a prostate cancer xenograft model. LnCaP-C4-2 is a subline of the human prostate cancer cell line LnCaP which unlike its parent, has a predilection for growth in bone, a common site for human prostate cancer metastasis. LnCaP-C4-2, is tumorigenic when injected intrafemorally in mice but requires co-injection of stromal components (Matrigel) to be tumorigenic in the subcutaneous site. Because of this site-specific tumorigenicity profile and relatively low VEGF mRNA and protein expression, this line was transfected with a full length cDNA encoding the 165 isoform of VEGF. Cells either overexpressing or not expressing the transfected gene were selected for study in vivo and in vitro. Overexpression of VEGF did not seem to affect in vitro cell growth. Such overexpression did affect tumorigenicity and in vivo tumor growth rates when cells were inoculated in the subcutaneus site. Interestingly, the dependency of subcutaneous tumorigenicity on Matrigel co-inoculation was still observed in cells overexpressing VEGF. In contrast to the impact that VEGF overexpression has on subcutaneous tumorigenicity, no such effect was observed when cells were inoculated in orthotopic/prostate (primary) or intrafemoral (metastatic) sites. In view of the importance of tumor-stromal interactions in growth of xenografts, we sought to determine if the host strain is important to the observed tumorigenicity effects of VEGF overexpression. No differences in subcutaneous tumorigenicity as a function of either Matrigel use or VEGF expression levels were observed when SCID/bg and RAG/pfp mouse strains were compared. In conclusion, our data indicate that the biological impact of prostate tumor VEGF overexpression is organ/site specific, leading to the speculation that it may play a part in the observed organ tropism of metastatic spread. In addition, these results highlight the importance of the tumor microenvironment in determining the biological impact of transfected and overexpressed genes in the study of tumor biology.

Animals↗