Burkitt Lymphoma Presenting as Obstructive Jaundice: A Case Report and Literature Review.

Burkitt lymphoma (BL) is an aggressive, high-grade B-cell lymphoma common in children and young adults. Despite being frequently discovered in extranodal sites, BL rarely occurs in the pancreas. We present a case of a patient with BL presenting as obstructive jaundice.

Splenic Cysts and the Case of Mistaken Identity.

Endometriosis is a well-described pathology, with anatomic location of endometrial cell implantation extending both intraperitoneal and rarely extraperitoneal. Interestingly, previous reports indicated that the spleen enjoys immunity to endometriosis. Here, we present a patient with unremitting abdominal pain who, upon further workup, revealed multicystic disease of the spleen. The patient underwent an open splenectomy with pathology revealing intraparenchymal endometriosis likely due to seeding from traumatic splenorrhaphy. Two-week follow-up demonstrated resolution of symptoms and a well-healing incision with no postoperative complications.

Tumor-selective, futile redox cycle-induced bystander effects elicited by NQO1 bioactivatable radiosensitizing drugs in triple-negative breast cancers.

AIMS: ß-Lapachone (ß-lap), a novel radiosensitizer with potent antitumor efficacy alone, selectively kills solid cancers that over-express NAD(P)H: quinone oxidoreductase 1 (NQO1). Since breast or other solid cancers have heterogeneous NQO1 expression, therapies that reduce the resistance (e.g., NQO1(low)) of tumor cells will have significant clinical advantages. We tested whether NQO1-proficient (NQO1(+)) cells generated sufficient hydrogen peroxide (H2O2) after ß-lap treatment to elicit bystander effects, DNA damage, and cell death in neighboring NQO1(low) cells. RESULTS: ß-Lap showed NQO1-dependent efficacy against two triple-negative breast cancer (TNBC) xenografts. NQO1 expression variations in human breast cancer patient samples were noted, where ~60% cancers over-expressed NQO1, with little or no expression in associated normal tissue. Differential DNA damage and lethality were noted in NQO1(+) versus NQO1-deficient (NQO1(-)) TNBC cells and xenografts after ß-lap treatment. ß-Lap-treated NQO1(+) cells died by programmed necrosis, whereas co-cultured NQO1(-) TNBC cells exhibited DNA damage and caspase-dependent apoptosis. NQO1 inhibition (dicoumarol) or H2O2 scavenging (catalase [CAT]) blocked all responses. Only NQO1(-) cells neighboring NQO1(+) TNBC cells responded to ß-lap in vitro, and bystander effects correlated well with H2O2 diffusion. Bystander effects in NQO1(-) cells in vivo within mixed 50:50 co-cultured xenografts were dramatic and depended on NQO1(+) cells. However, normal human cells in vitro or in vivo did not show bystander effects, due to elevated endogenous CAT levels. Innovation and Conclusions: NQO1-dependent bystander effects elicited by NQO1 bioactivatable drugs (ß-lap or deoxynyboquinone [DNQ]) likely contribute to their efficacies, killing NQO1(+) solid cancer cells and eliminating surrounding heterogeneous NQO1(low) cancer cells. Normal cells/tissue are protected by low NQO1:CAT ratios.

Urinary cytology for the detection of urothelial carcinoma of the bladder--a flawed adjunct to cystoscopy?

OBJECTIVES: To test the sensitivity of urinary cytology at a tertiary academic institution and to assess the impact of pathologist' experience on detection of urothelial carcinoma of the bladder (UCB). MATERIALS AND METHODS: Between April 1999 and September 2008, 8,574 cytology specimens were evaluated. There were 882 consecutive patients (612 males, 270 females) who underwent bladder biopsy or transurethral resection of bladder tumor for UCB. Sensitivity rates of prior urinary cytology were determined. We tested the influence of experience of pathologist on sensitivity. RESULTS: Urinary cytology detected 237 out of 503 UCB (overall sensitivity 47.1%). Cytology after bladder washing resulted in higher sensitivity than in voided urine (50.4% vs. 36.2%; P = 0.008). Sensitivity rates significantly increased by UCB stage; 30.6% in pTa (n = 245), 60.5% in patients with any form of CIS (n = 119), 62.9% in pT1 (n = 89), and 69.6% in ≥pT2 (n = 46; P < 0.001). Similarly, higher sensitivity was observed with increasing grade, ranging from 16.7% in low (n = 108) to 62.2% in high grade tumors (n = 283; P < 0.001). No statistically significant difference between more and less experienced investigators was observed. CONCLUSIONS: Sensitivity rates of urinary cytology at our institution are not superior to those reported in the literature. Cytology missed many high grade cancers, pointing to inherent methodological limitations of urinary cytology. A higher experience level of the pathologist was not significantly associated with higher sensitivity rates. Urinary cytology represents a flawed adjunct to cystoscopy with limited potential of improvement even in the hands of experienced pathologists.

A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.

Most anticancer drugs entering clinical trials fail to achieve approval from the U.S. Food and Drug Administration. Drug development is hampered by the lack of preclinical models with therapeutic predictive value. Herein, we report the development and validation of a tumorgraft model of renal cell carcinoma (RCC) and its application to the evaluation of an experimental drug. Tumor samples from 94 patients were implanted in the kidneys of mice without additives or disaggregation. Tumors from 35 of these patients formed tumorgrafts, and 16 stable lines were established. Samples from metastatic sites engrafted at higher frequency than those from primary tumors, and stable engraftment of primary tumors in mice correlated with decreased patient survival. Tumorgrafts retained the histology, gene expression, DNA copy number alterations, and more than 90% of the protein-coding gene mutations of the corresponding tumors. As determined by the induction of hypercalcemia in tumorgraft-bearing mice, tumorgrafts retained the ability to induce paraneoplastic syndromes. In studies simulating drug exposures in patients, RCC tumorgraft growth was inhibited by sunitinib and sirolimus (the active metabolite of temsirolimus in humans), but not by erlotinib, which was used as a control. Dovitinib, a drug in clinical development, showed greater activity than sunitinib and sirolimus. The routine incorporation of models recapitulating the molecular genetics and drug sensitivities of human tumors into preclinical programs has the potential to improve oncology drug development.

BAP1 loss defines a new class of renal cell carcinoma.

The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes, including BAP1. The BAP1 protein, a nuclear deubiquitinase, is inactivated in 15% of clear cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation but not deubiquitination of monoubiquitinated histone 2A lysine 119 (H2AK119ub1). BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Notably, mutations in BAP1 and PBRM1 anticorrelate in tumors (P = 3 × 10(-5)), [corrected] and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q = 0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q = 0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.

Impact of histological variants on clinical outcomes of patients with upper urinary tract urothelial carcinoma.

PURPOSE: We investigated the clinical and prognostic impact of variant histologies on upper tract urothelial carcinoma outcomes after radical nephroureterectomy. MATERIALS AND METHODS: Data on 1,648 patients with upper tract urothelial carcinoma treated with radical nephroureterectomy without preoperative chemotherapy or radiotherapy were reviewed for histological differentiation and variants. We analyzed differences between pure upper tract urothelial carcinoma and upper tract urothelial carcinoma with variant histology, and differences in the histological variants using different stratifications. RESULTS: A total of 398 patients (24.2%) had histological upper tract urothelial carcinoma variants. The most common variants were squamous cell and glandular differentiation in 9.9% and 4.4% of cases, respectively. Histological variants were associated with advanced tumor stage, tumor multifocality, sessile tumor architecture, tumor necrosis, lymphovascular invasion and lymph node metastasis compared to pure upper tract urothelial carcinoma (p ≤0.031). On univariable analysis variant histology was associated with disease recurrence (p = 0.002) and cancer specific mortality (p = 0.003). In 174 patients treated with adjuvant chemotherapy there was no difference in disease recurrence or survival between variant histology and pure upper tract urothelial carcinoma (p = 0.42 and 0.59, respectively). On multivariable analysis adjusted for the effects of standard clinicopathological characteristics variant histology was not associated with either end point. CONCLUSIONS: Almost 25% of patients with upper tract urothelial carcinoma treated with radical nephroureterectomy harbored histological variants. Variant histology was associated with features of biologically aggressive upper tract urothelial carcinoma. While variant histology is associated with worse outcomes on univariable analysis but this effect did not remain significant on multivariable analysis.

Prognostic value of apoptotic markers in squamous cell carcinoma of the urinary bladder.

UNLABELLED: Study Type - Prognosis (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Apoptotic pathways are important in carcinogenesis. Many studies, involving small numbers of patients, have found an association between one or two apoptotic markers and some of the pathological features of squamous cell carcinoma (SCC). This study included a large number of patients who had undergone radical cystectomy (RC) for SCC with long-term follow-up, allowing us to study biomarker alterations and their prognostic role. This is the first study on the prognostic role of a panel of apoptotic-related markers in SCC of the urinary bladder, introducing the novel concept of a prognostic marker score based on the number of altered markers. We found that apoptotic markers can improve prediction of oncological outcomes after RC for SCC and might potentially help in patient selection for adjunct therapies. OBJECTIVE: To evaluate the association of cleaved caspase-3 (CC-3), Bax, COX-2, and p53 expression with pathological features and clinical outcomes in patients with squamous cell carcinoma (SCC) of the urinary bladder. METHODS: Immunohistochemistry for CC-3, Bax, COX-2, and p53 was performed on tissue microarray sections of radical cystectomy specimens with pure SCC from 1997 to 2003. The relationship between the expression of these markers and pathological features was assessed. • A prognostic marker score (PS) was defined as favourable if ≤2 biomarkers were altered and unfavourable if >2 biomarkers were altered and the association of the PS with oncological outcomes was examined. RESULTS: The study included 151 patients, of whom 98 were men and 53 were women, with a mean age of 52 years. SCC was associated with schistosomiasis (bilharziasis) in 122 (81%) patients. • Pathological stage was T2 in 50%, T3 in 38%, T1 in 6% and T4 in 6% of patients. Tumours were low grade in 53%, lymph node metastasis was found in 30.5% and lymphovascular invasion was found in 16% of patients. • Median follow-up was 63.2 months. • Advanced stage was associated with COX-2, p53 and CC-3 alterations and high grade was associated with COX-2 alterations (P < 0.05). The total number of altered markers and unfavourable PS were associated with both disease recurrence and bladder cancer-specific mortality in Kaplan-Meier analyses (P < 0.05). Unfavourable PS was an independent predictor of disease recurrence (hazard ratio [HR] 2.694, 95% confidence interval [CI] 1.386-5.235, P= 0. 003) and bladder cancer-specific mortality (HR 2.868, 95% CI 1.209-6.802, P= 0. 017) in multivariable Cox regression analysis. CONCLUSION: Markers of apoptosis pathways may play an important role in the prognosis of SCC of the bladder. An increased number of altered markers and an unfavourable PS may identify patients who might benefit from multimodal therapies.

Subclassification of pT3 urothelial carcinoma of the renal pelvicalyceal system is associated with recurrence-free and cancer-specific survival: proposal for a revision of the current TNM classification.

BACKGROUND: The clinical course of pT3 upper tract urothelial carcinoma (UTUC) is highly variable. OBJECTIVES: The aim of the current study was to validate the clinical and prognostic importance of pT3 subclassification in the renal pelvicalyceal system in a large international cohort of patients. DESIGN, SETTING, AND PARTICIPANTS: From a multi-institutional international database, 858 renal pelvicalyceal tumors treated with radical nephroureterectomy (RNU) were systematically reevaluated by genitourinary pathologists. Category pT3 pelvic tumors were categorized as pT3a (infiltration of the renal parenchyma on a microscopic level only) versus pT3b (macroscopic infiltration of the renal parenchyma and/or infiltration of peripelvic adipose tissue). INTERVENTION: RNU. MEASUREMENTS: Associations of pT3 subclassifications with clinicopathologic features were assessed with the chi-square test. Prognostic impact was assessed with the log-rank test and multivariable Cox regression analyses. RESULTS AND LIMITATIONS: Of 858 patients with renal pelvicalyceal tumors, 266 (31%) had pT3 disease. Of these, 146 (54.9%) were classified as pT3a and 120 (45.1%) as pT3b. Compared with pT3a, pT3b cancers were associated with higher tumor grade, nodal disease, and tumor necrosis. Ten-year recurrence-free (pT3a 58% vs pT3b 38%; p<0.001) and cancer-specific (pT3a 60% vs pT3b 39%; p=0.002) survival rates were lower for patients with pT3b disease. In multivariable analyses, classification pT3b was an independent predictor of both disease recurrence (hazard ratio [HR]: 1.8, p=0.003) and cancer-specific mortality (HR: 1.7; p=0.02). The major limitation is the retrospective character of the study. CONCLUSIONS: Subclassification of pT3 renal pelvicalyceal UTUC helps identify patients who are at increased risk of disease progression and cancer-related death. Further research may help assess the value of subclassification and its inclusion in future editions of the American Joint Committee on Cancer-International Union Against Cancer TNM classification system.

Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma.

mTOR complex 1 (mTORC1) is implicated in cell growth control and is extensively regulated. We previously reported that in response to hypoxia, mTORC1 is inhibited by the protein regulated in development and DNA damage response 1 (REDD1). REDD1 is upregulated by hypoxia-inducible factor (HIF)-1, and forced REDD1 expression is sufficient to inhibit mTORC1. REDD1-induced mTORC1 inhibition is dependent on a protein complex formed by the tuberous sclerosis complex (TSC)1 and 2 (TSC2) proteins. In clear-cell renal cell carcinoma (ccRCC), the von Hippel-Lindau (VHL) gene is frequently inactivated leading to constitutive activation of HIF-2 and/or HIF-1, which may be expected to upregulate REDD1 and inhibit mTORC1. However, mTORC1 is frequently activated in ccRCC, and mTORC1 inhibitors are effective against this tumor type; a paradox herein examined. REDD1 was upregulated in VHL-deficient ccRCC by in silico microarray analyses, as well as by quantitative real-time PCR, Western blot, and immunohistochemistry. Vhl disruption in a mouse model was sufficient to induce Redd1. Using ccRCC-derived cell lines, we show that REDD1 upregulation in tumors is VHL dependent and that both HIF-1 and HIF-2 are, in a cell-type-dependent manner, recruited to, and essential for, REDD1 induction. Interestingly, whereas mTORC1 is responsive to REDD1 in some tumors, strategies have evolved in others, such as mutations disrupting TSC1, to subvert mTORC1 inhibition by REDD1. Sequencing analyses of 77 ccRCCs for mutations in TSC1, TSC2, and REDD1, using PTEN as a reference, implicate the TSC1 gene, and possibly REDD1, as tumor suppressors in sporadic ccRCC. Understanding how ccRCCs become refractory to REDD1-induced mTORC1 inhibition should shed light into the development of ccRCC and may aid in patient selection for molecular-targeted therapies.

Primary adenocarcinoma of the urinary bladder: value of cell cycle biomarkers.

Primary adenocarcinomas of the urinary bladder are uncommon, and the molecular pathways are currently not well defined. In this study, we assessed the association between biologic markers and clinicopathologic characteristics in a cohort of 21 patients with primary urinary bladder adenocarcinoma. Immunohistochemical staining for cell cycle-specific markers, including p53, p21, p27, Ki-67, and cyclin E, were performed on sections of a tissue microarray construct. The tumors were high grade in 12 (57%) and pT2 or higher in 18 (86%); lymph nodes were involved in 6 cases (29%); and there was pathologic evidence of schistosomiasis in 14 (67%). The best prognostic combination of markers was combined alterations in p27 and Ki-67 and was associated with stage (P = .012), grade (P = .005), DNA ploidy (P = .005), and lymph node involvement (P = .04). Stage, lymph node involvement, combined alterations of p27 and Ki-67, and combined alterations of all 5 biomarkers were associated with increased probability of disease recurrence and cancer-specific mortality (P < .05).

Tissue compression analysis for magnetically anchored cautery dissector during single-site laparoscopic cholecystectomy.

INTRODUCTION: The purpose of this study was to evaluate the histological effects of dynamic abdominal wall compression using the magnetic anchoring and guidance system (MAGS) platform. METHODS: Cholecystectomy was performed in two nonsurvival and two survival pigs using a single-site laparoscopic (SSL) approach. A deployable MAGS cautery dissector was used to perform the entire dissection in conjunction with a laparoscope and other instruments. The abdominal wall areas corresponding to the region occupied by the MAGS platform were examined grossly and microscopically for signs of tissue damage. Gallbladder dissection time was 36 min with no complications. Compressed abdominal wall thickness was 1.4 cm. RESULTS: In all four animals, a very mild skin erythema was noted immediately postprocedure but was nonvisible within 20 min. Mild peritoneal blanching was noted in two animals, and one animal exhibited a 5-mm area of petechiae. Necropsy demonstrated no adhesions. Light microscopy documented no evidence of tissue injury for all specimens. DISCUSSION: This study demonstrated that the use of the MAGS cautery dissector for a SSL cholecystectomy was advantageous in providing triangulation and did not result in any significant gross or microscopic tissue damage despite the thin abdominal wall of the porcine model.

Cell-type-dependent regulation of mTORC1 by REDD1 and the tumor suppressors TSC1/TSC2 and LKB1 in response to hypoxia.

mTORC1 is a critical regulator of cell growth that integrates multiple signals and is deregulated in cancer. We previously reported that mTORC1 regulation by hypoxia involves Redd1 and the Tsc1/Tsc2 complex. Here we show that Redd1 induction by hypoxia is tissue dependent and that hypoxia signals are relayed to mTORC1 through different pathways in a tissue-specific manner. In the liver, Redd1 induction is restricted to the centrilobular area, and in primary hepatocytes, mTORC1 inhibition by hypoxia is independent of Redd1. Furthermore, Tsc1/Tsc2 and Arnt (Hif-1ß) are similarly dispensable. Hypoxia signaling in hepatocytes involves Lkb1, AMP-activated protein kinase (AMPK), and raptor. Differences in signal relay extend beyond hypoxia and involve AMPK signaling. AMPK activation (using 5-aminoimidazole-4-carboxamide riboside [AICAR]) induces raptor phosphorylation and inhibits mTORC1 in both mouse embryo fibroblasts (MEFs) and hepatocytes, but whereas mTORC1 inhibition is Tsc1/Tsc2 dependent in MEFs, it is independent in hepatocytes. In liver cells, raptor phosphorylation is essential for both AMPK and hypoxia signaling. Thus, context-specific signals are required for raptor phosphorylation-induced mTORC1 inhibition. Our data illustrate a heretofore unappreciated topological complexity in mTORC1 regulation. Interestingly, topological differences in mTORC1 regulation by the tumor suppressor proteins Lkb1 and Tsc1/Tsc2 may underlie their tissue specificity of tumor suppressor action.

Upper urinary tract urothelial carcinoma with loco-regional nodal metastases: insights from the Upper Tract Urothelial Carcinoma Collaboration.

OBJECTIVE: • To describe a multicentre experience with preoperative platinum-based chemotherapy before radical nephroureterectomy (RNU) in patients with upper tract urothelial carcinoma (UTUC) with loco-regional nodal metastases. PATIENTS AND METHODS: • We identified 313 patients from the UTUC Collaboration (over 1200 patients), who underwent RNU with concomitant retroperitoneal lymph node dissection between 1990 and 2007 and met the inclusion criteria for one of three groups. • Group 1 comprised patients who received chemotherapy before RNU because of biopsy-proven loco-regional nodal metastases. • Group 2 consisted of patients who underwent primary RNU and were found to have metastatic nodal disease on final pathological review (node-positive). • Group 3 comprised a comparative cohort of patients treated with primary RNU for invasive or locally advanced (pT2/pT4) node-negative (N0) UTUC. RESULTS: • Groups 1, 2 and 3 included 18, 120 and 175 patients, respectively. The 5-year disease-free survival rates were 49%, 30% and 64%, whereas the 5-year cancer-specific survival rates were 44%, 36% and 69% in groups 1, 2 and 3, respectively. • In group 1, on final pathological evaluation, nine patients were pN0, six patients were pT0 and five patients had pT0N0 disease. Kaplan-Meier survival analyses showed similar recurrence and survival rates in group 1 compared with group 3 (P= 0.14 and P= 0.06, respectively). • Meanwhile, group 2 had significantly lower disease-free and cancer-specific survival rates compared with group 3 (P < 0.001 and P < 0.001, respectively) and compared with group 1 (P= 0.04 and P= 0.06, respectively). CONCLUSIONS: • Preoperative chemotherapy followed by aggressive surgical consolidation may yield favourable oncological outcomes in patients with UTUC with loco-regional nodal metastases. • These data support further evaluation of neoadjuvant systemic therapy in patients at risk for locally advanced UTUC.

Prognostic value of cyclooxygenase-2 expression in squamous cell carcinoma of the bladder.

PURPOSE: Inflammation is associated with the pathogenesis of carcinoma, including squamous cell carcinoma of the bladder. Cyclooxygenase-2 is an enzyme that is induced at inflammation sites. We assessed the expression pattern of cyclooxygenase-2 in patients with squamous cell carcinoma of the bladder and determined whether cyclooxygenase-2 expression is associated with clinical outcomes after radical cystectomy. MATERIALS AND METHODS: Immunohistochemical staining for cyclooxygenase-2 was done on archival bladder specimens from 152 patients treated with radical cystectomy for squamous cell carcinoma on the Autostainer (DakoCytomation, Carpinteria, California). Bright field microscopy imaging coupled with advanced color detection software was used. Cyclooxygenase-2 was defined as over expressed when greater than 20% cells were positive. We assessed the relationship of cyclooxygenase-2 expression with pathological parameters and clinical outcome. RESULTS: The study included 99 male and 53 female patients with a mean age of 52 years who had squamous cell carcinoma, including 80.9% with bilharziasis. Presenting stage was T2 or greater and presenting grade was GII or less in 93.4% of patients. Median followup was 63.2 months. Cyclooxygenase-2 was over expressed in 74 cystectomy specimens (48.7%) and associated with higher pathological stage (p=0.003) and grade (p=0.049). On multivariate Cox proportional hazards regression analysis cyclooxygenase-2 over expression was associated with disease recurrence (p=0.031) and bladder cancer specific mortality (p=0.046). CONCLUSIONS: Cyclooxygenase-2 over expression is associated with pathological stage, grade and worse outcomes after radical cystectomy, suggesting a role in bladder squamous cell carcinoma progression. Our findings support the need for further evaluation of cyclooxygenase-2 and inflammatory signaling pathways, and cyclooxygenase-2 targeted prevention or therapy in patients with bladder squamous cell carcinoma.

Irreversible electroporation (IRE): a novel method for renal tissue ablation.

OBJECTIVE: • To evaluate the effects of irreversible electroporation (IRE) on renal parenchyma and the renal collecting system in a porcine model. MATERIALS AND METHODS: • Eight female Yorkshire pigs underwent a series of laparoscopic ablations using either monopolar or bipolar IRE (Angiodynamics, Queensbury, NY, USA). • The pigs were killed between 10 min and 14 days after IRE, and the kidneys were harvested for gross and histological analysis, including NADH staining for cellular viability. RESULTS: • In all, 24 ablations were performed and all the pigs survived without complications. • Initial gross lesions were diffusely haemorrhagic, decreasing progressively in size (30-40%) to small white scars over the 14-day period. • Immediately after IRE, ablated tissue was characterized by diffuse tubular desquamation, eosinophilia, and nuclear pyknosis, with absence of cellular viability by NADH. • At 7 days after IRE, there was diffuse cellular necrosis with early peripheral granulation changes, and by 14 days there was marked tissue granulation, chronic inflammation, and dystrophic calcification with early fibrosis and cellular contraction. • Initial patchy urothelial injury and ulceration showed signs of repair and viability by 14 days after IRE. CONCLUSIONS: • Renal IRE in the porcine kidney leads to predictable histological changes characteristic of cellular death within 1 h of ablation, with relative urothelial sparing. • Further animal studies are warranted to determine safety and efficacy of this novel ablation technology.

Evidence of epithelial to mesenchymal transition associated with increased tumorigenic potential in an immortalized normal prostate epithelial cell line.

BACKGROUND: The majority of established human prostate cancer cell lines are derived from metastatic lesions and are already tumorigenic in vivo, therefore immortalized normal prostate cell lines may provide a more relevant model to unveil the mechanisms associated with cancer progression and metastasis. METHODS: PZ-HPV-7, an immortalized human prostate epithelial cell line was used to generate xenograft tumors in mice. A subline designated HPV-PZ-7T was subsequently derived from the subrenal capsule xenograft of a nude mouse. These cells were further characterized using karyotyping, immunofluorescence, qRT-PCR, Western blotting, and three-dimensional cultures in Matrigel. RESULTS: The PZ-HPV-7 cell line possesses a typical epithelial morphology, expresses basal cell markers, and is capable of forming web-like structures with evidence of budding on Matrigel. PZ-HPV-7 is non-tumorigenic in immunocompromised mice by either subcutaneous injection or subrenal grafting. In contrast, the PZ-HPV-7T cells, derived from a xenograft tumor induced by co-inoculation with matrigel using subrenal grafting, possess a mesenchymal phenotype as well as luminal cell markers and are highly tumorigenic and metastatic in nude mice. Functionally and biochemically, the PZ-HPV-7T subline appears to have undergone an epithelial-to-mesenchymal transition (EMT) from the parental PZ-HPV-7 line. CONCLUSION: We have developed a novel EMT model using an immortalized normal prostate epithelial cell line and generated a new prostate cancer cell line, PZ-HPV-7T, which may represent an excellent system to study mechanisms associated with prostate cancer progression and metastasis.