Prognostic value of Ki67 in localized prostate carcinoma: a multi-institutional study of >1000 prostatectomies.

BACKGROUND: Expanding interest in and use of active surveillance for early state prostate cancer (PC) has increased need for prognostic biomarkers. Using a multi-institutional tissue microarray resource including over 1000 radical prostatectomy samples, we sought to correlate Ki67 expression captured by an automated image analysis system with clinicopathological features and validate its utility as a clinical grade test in predicting cancer-specific outcomes. METHODS: After immunostaining, the Ki67 proliferation index (PI) of tumor areas of each core (three cancer cores/case) was analyzed using a nuclear quantification algorithm (Aperio). We assessed whether Ki67 PI was associated with clinicopathological factors and recurrence-free survival (RFS) including biochemical recurrence, metastasis or PC death (7-year median follow-up). RESULTS: In 1004 PCs (∼4000 tissue cores) Ki67 PI showed significantly higher inter-tumor (0.68) than intra-tumor variation (0.39). Ki67 PI was associated with stage (P<0.0001), seminal vesicle invasion (SVI, P=0.02), extracapsular extension (ECE, P<0.0001) and Gleason score (GS, P<0.0001). Ki67 PI as a continuous variable significantly correlated with recurrence-free, overall and disease-specific survival by multivariable Cox proportional hazard model (hazards ratio (HR)=1.04-1.1, P=0.02-0.0008). High Ki67 score (defined as ⩾5%) was significantly associated with worse RFS (HR=1.47, P=0.0007) and worse overall survival (HR=2.03, P=0.03). CONCLUSIONS: In localized PC treated by radical prostatectomy, higher Ki67 PI assessed using a clinical grade automated algorithm is strongly associated with a higher GS, stage, SVI and ECE and greater probability of recurrence.

Metastatic conventional prostatic adenocarcinoma with diffuse chromogranin A and androgen receptor positivity.

Conventional prostate adenocarcinomas consist mainly of tumour cells of luminal immunophenotype with scattered neuroendocrine (NE) cells. NE cells are defined by chromogranin A (CGA) immunoreactivity. Unlike luminal cells, NE cells lack androgen receptor (AR) and prostate specific antigen (PSA) immunoreactivity. This report describes the first case of conventional prostate adenocarcinoma expressing CGA, PSA, and AR as determined by immunohistochemistry. A 64 year old man was diagnosed with conventional prostate adenocarcinoma in 1993; he underwent cystoprostatectomy in 1994; he developed an iliac bone metastasis in 1997 and mediastinal lymph node metastases in 1999. All specimens obtained during the progression of the disease consisted primarily of luminal cells with only scattered NE cells. In contrast, in samples of non-osseous and osseous metastases obtained at necropsy in 2001, greater than 80% of tumour cells were shown to express PSA, AR, and CGA. This suggests that during tumour progression, conventional prostate adenocarcinomas may evolve into an NE cell phenotype.

Bone histology at autopsy and matched bone scintigraphy findings in patients with hormone refractory prostate cancer: the effect of bisphosphonate therapy on bone scintigraphy results.

Bisphosphonates (BisP) are non-metabolized compounds with high bone affinity used in bone metastasis diagnosis and treatment. Currently, BisP are used to treat hypercalcemia of malignancy as well as to prevent, minimize, or delay skeletal morbidity. These compounds have a long half-life in bone. Thus long-term BisP treatment might saturate bone and interfere with a single-dose scanning agent used for bone scintigraphy when visualizing bone metastases. In an effort to answer this question, this study evaluated the concordance of histology and Technetium99 methylene diophosphonate (Tc99 MDP) bone scintigraphy in the diagnosis of bone metastases in prostate cancer patients. We assessed the concordance of findings between bone scintigraphy and histology using 188 bone biopsies from 11 autopsied patients who died with metastatic prostate cancer, 5 of whom were treated with pamidronate for 2 to 13 months before death. Overall agreement between histology and bone scintigraphy was 84%, 86% in non-pamidronate-treated patients and 82% in pamidronate-treated patients. Scintigraphic bone metastases without histological metastasis (false negatives = 12.7%) were observed in 24 anatomic locations; half of these were in one patient who had been treated with pamidronate and had no histological bone response to the carcinoma. There were only 4 sites where a positive bone scan was not associated with histologic metastasis (false positives = 2.21%). There was no statistical difference between the treated and non-treated group for concordance, specificity, sensitivity, positive and negative predictive values of bone scintigraphy and prevalence of histological abnormality. Long-term pamidronate treatment of prostate cancer bone metastases does not generally affect the ability to detect bone metastases with Tc99 MDP bone scintigraphy.

Cathepsin K mRNA and protein expression in prostate cancer progression.

Prostate cancer (CaP) is the most commonly diagnosed malignancy in men and is often associated with bone metastases, which cause much of the morbidity associated with CaP. Lesions associated with CaP generally exhibit increased bone formation and resorption. Increased bone resorption may release factors from the extracellular matrix that contribute to tumor growth. Cathepsin K (cat K) is a cysteine protease that exhibits strong degradative activity against the extracellular matrix and is involved in osteoclast-mediated bone destruction. In this study, we analyzed the expression of cat K in CaP cell lines and patient samples. Cat K message was detected in CaP cell lines by reverse transcription-polymerase chain reaction (RT-PCR) and in primary CaP and metastases by in situ hybridization. Immunohistochemistry revealed variable expression of cat K in primary CaP samples, as well as nonosseous metastases, whereas expression in bone metastases was significantly higher than in primary CaP, and normal prostate tissues were negative. Cat K protein was detected in CaP cell lines by Western blotting after immunoprecipitation. Cat K enzymatic activity was also detected in CaP cell lines by a fluorogenic assay and by an assay for degradation of collagen type I. Increased levels of NTx, a marker of bone matrix degradation mediated primarily by cat K, were also detected in sera of patients with CaP bone metastases. We hypothesize that CaP-expressed cat K may contribute to the invasive potential of CaP, while increased expression in bone metastases is consistent with a role in matrix degradation.

Consensus development of a histopathological classification system for chronic prostatic inflammation.

OBJECTIVE: To develop a standardized histopathological classification system for chronic prostatitis (standardized description of prostatic inflammatory infiltrates) based on a literature review, extensive prospective evaluations in two recognized prostatitis research centres and widespread consensus of international urological centres identified as having major expertise or interest in chronic prostatitis. METHODS: Relevant articles for review were identified by a Medline search undertaken by the Cochrane Review Group in Prostate Diseases and Urologic Malignancies, and cross-checking bibliographies of retrieved studies, reviews, book chapters and abstracts of the American Urological Association and International Prostatitis Collaborative Network Annual Meetings. Initial drafts were based on classification systems independently developed by the Prostatitis Research Centers at Queen's University in Canada and University of Washington in the USA. A collaborative draft was distributed to 20 urological/pathological clinical centres who participated in the North American Chronic Prostatitis Collaborative Research Network and First International Prostatitis Collaborative Network. A consensus classification system was then distributed to the participating panel for acceptance. RESULTS: The literature review identified a reasonably consistent description of inflammatory infiltrate locations and patterns that were further incorporated into the draft based on the Queen's University and University of Washington proposals. Eighteen (90%) of the identified Prostatitis Centers participated in the revision of the draft and the final consensus process. The final consensus document classifies prostatic inflammation according to its extent and grade/severity in each tissue compartment (location). Conclusion The consensus of the expert panel was that this classification system can be used in the evaluation of prostatic inflammation in prostate biopsies, transurethral resected prostate chips or prostatectomy specimens. A standardized accepted framework to describe histopathological prostate inflammation will prove useful in evaluating prostate disease.

Placental bone morphogenetic protein (PLAB) gene expression in normal, pre-malignant and malignant human prostate: relation to tumor development and progression.

The second most common target of prostate-cancer metastasis is bone, and the phenomenon of skeletal metastasis represents the incurable stage of disease. Histologically, skeletal metastasis from prostate cancer is distinctive due to its osteoblastic nature. The osteoblastic bone metastasis shows extensive new bone formation, with possible involvement of the soluble growth factors secreted by tumor cells, such as bone morphogenetic proteins (BMPs). In the present study, we analyzed the gene expression of one of the new members of the BMP family, placental bone morphogenetic protein (PLAB). In situ hybridization studies showed high levels of this gene in normal prostate. However, the gene is down-regulated during the progression of cancer at the primary site. The most significant finding was re-expression of the PLAB gene in osseous metastatic lesions. Our results demonstrate that tumor cells, when released from the primary site and after re-growth elsewhere, are capable of re-expressing specific genes that may play a different role at metastatic sites than at the primary site.

A quantitative model for the dynamics of serum prostate-specific antigen as a marker for cancerous growth: an explanation for a medical anomaly.

Prostate-specific antigen (PSA) is an enzyme produced by both normal and cancerous prostate epithelial cells. Although PSA is the most widely used serum marker to detect and follow patients with prostatic adenocarcinoma, there are certain anomalies in the values of serum levels of PSA that are not understood. We developed a mathematical model for the dynamics of serum levels of PSA as a function of the tumor volume. Our model results show good agreement with experimental observations and provide an explanation for the existence of significant prostatic tumor mass despite a low-serum PSA. This result can be very useful in enhancing the use of serum PSA levels as a marker for cancer growth.

Isolated carcinoid tumor of the terminal filum. Case report.

The authors describe a patient with neurological symptoms caused by a carcinoid tumor at the terminal filum without carcinoid "flushing" syndrome or endocrinological abnormalities. The patient underwent subtotal resection and adjuvant radiotherapy. Extensive postoperative workup revealed no primary site of disease. To the authors' knowledge, this patient represents the first case of terminal filum carcinoid tumor.

Osteoprotegerin and rank ligand expression in prostate cancer.

OBJECTIVES: To investigate the expression of osteoprotegerin (OPG) and RANK ligand (RANKL) in human prostatic tissues. The factors regulating the increased turnover associated with prostate cancer (CaP) bone metastasis are unknown. OPG and RANKL are recently identified regulators of bone resorption and bone remodeling. METHODS: Tissues from 28 patients with CaP and from 4 normal organ donors were analyzed by reverse transcriptase-polymerase chain reaction and immunohistochemistry for the expression of OPG and RANKL. RESULTS: OPG and RANKL messages were detected in both normal and cancerous prostate samples. In the normal prostate, OPG protein was detected in luminal epithelial and stromal cells (5% to 65% and 15% to 70%, respectively) and RANKL immunoreactivity was observed in 15% to 50% of basal epithelial cells, 40% to 90% of luminal epithelial cells, and 70% to 100% of stromal cells. OPG was not detected in 8 of 10 primary CaP specimens; RANKL was heterogeneously expressed in 10 of 11 CaP specimens. The percentage of tumor cells expressing OPG and RANKL was significantly increased in all CaP bone metastases compared with nonosseous metastases or primary CaP. CONCLUSIONS: CaP bone metastases were consistently immunoreactive for both OPG and RANKL compared with nonosseous metastases or primary CaP. The presence of these crucial bone resorption regulators in CaP bone metastases suggests a mechanism whereby CaP cells may modulate bone turnover and has profound implications for the establishment and development of CaP bone metastases in advanced disease.

Prostate short-chain dehydrogenase reductase 1 (PSDR1): a new member of the short-chain steroid dehydrogenase/reductase family highly expressed in normal and neoplastic prostate epithelium.

Genes regulated by androgenic hormones are of critical importance for the normal physiological function of the human prostate gland, and they contribute to the development and progression of prostate carcinoma. We used cDNA microarrays comprised of prostate-derived cDNAs to profile transcripts regulated by androgens in prostate cancer cells. This study identified a novel gene that we have designated prostate short-chain dehydrogenase/reductase 1 (PSDR1), that exhibits increased expression on exposure to androgens in the LNCaP prostate cancer cell line. Northern analysis demonstrated that PSDR1 is highly expressed in the prostate gland relative to other normal human tissues. The PSDR1 cDNA and putative protein exhibit homology to the family of short-chain dehydrogenase/reductase enzymes and thus identify a new member of this family. Cloning and analysis of the putative PSDR1 promoter region identified a potential androgen-response element. We used a radiation-hybrid panel to map the PSDR1 gene to chromosome 14q23-24.3. In situ hybridization localizes PSDR1 expression to normal and neoplastic prostate epithelium. These results identify a new gene involved in the androgen receptor-regulated gene network of the human prostate that may play a role in the pathogenesis of prostate carcinoma.

Preexisting histologic evidence of prostatitis is unrelated to postimplant urinary morbidity.

The presence and extent of prostatitis on the patients' preimplant biopsy slides was correlated with their postimplant course to determine if any relationship exists between histological prostatitis and postimplant morbidity. Biopsy slides from 56 patients treated with I-125 (144 Gy, TG-43), Pd-103 (125 Gy, NIST-1999), or Pd-103 plus supplemental external beam radiation (20-44 Gy) were studied. As part of ongoing prospective protocols, treatment-related morbidity is monitored by mailed questionnaires at 1, 3, 6, 12, and 24 months postimplant, using standard American Urologic Association (I-PSS) and Radiation Therapy Oncology Group criteria. Patient's preimplant biopsies, stained with standard hematoxylin and eosin, were retrieved for review by one uropathologist (LT). Separate evaluations of the degree and extent of inflammation in biopsy cores free of cancer and in cancerous biopsy cores were undertaken. Infiltrates were classified as periglandular if they were within 50 microns of a glandular structure. They were otherwise classified as stromal. Distribution of the inflammation was reported as focal, multifocal, or diffuse. The intensity of inflammation was separately graded as mild if there were fewer than 10 inflammatory cells per high-power field, moderate if there were 10-200 cells per high-power microscopic field, or severe if there were more than 200 cells per field. In all cases the great majority of inflammatory cells were mononuclear, predominantly lymphocytes. Periglandular inflammation was most common, with 18% of patients having focal periglandular and 20% having multifocal periglandular inflammation on their preimplant biopsies. Cancer-related infiltrates were the second most common, with 23% of patients having focal, 13% multifocal, and 13% diffuse cancer-related inflammation on their preimplant biopsies. Eight of the 55 patients developed postimplant urinary retention, requiring catheterization for 2 to 8 days. The overall incidence of postimplant urinary retention was low and there was no obvious relationship between the presence of inflammation on preimplant biopsy and the likelihood of postimplant urinary retention. AUA score changes at 1 and 6 months postimplant were highly variable and unrelated to the presence or severity of periglandular or cancer-related inflammation. Considering the apparent lack of relationship between histological findings and clinical outcomes in the patients reported here, the authors conclude that histologic evidence of prostatitis is not a contraindication to brachytherapy.

The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response.

PURPOSE: To assess the safety, tolerance, and efficacy of transurethral surgery plus concomitant cisplatin, 5-fluorouracil (5-FU), and radiation therapy in conjunction with selective bladder preservation in patients with muscle-invading bladder cancer. Patients and Methods. Thirty-four eligible patients with clinical stage T2-T4a, Nx M0 bladder cancer without hydronephrosis were entered into a protocol aimed at selective bladder preservation. Treatment began with as complete a transurethral resection as possible followed by induction chemoradiation. This consisted of cisplatin 15 mg/m(2) i.v. and 5-fluorouracil (5-FU) 400 mg/m(2) i.v. in the mornings on d 1, 2, 3, 15, 16, and 17. On d 1, 3, 15, and 17, radiation was given immediately following the chemotherapy using twice-a-day 3 Gy per fraction cores to the pelvis for a total radiation dose of 24 Gy. Response was evaluated by cystoscopy, cytology, and rebiopsy four weeks later. Patients with a complete response received consolidation therapy with the same drugs and doses on d 1, 2, 3, 15, 16, and 17 combined with twice-daily radiation therapy to the bladder and bladder tumor volume of 2.5 Gy per fraction for a total consolidation dose of 20 Gy and a total induction plus consolidation dose to the bladder and bladder tumor of 44 Gy. Patients who did not achieve a complete response were advised to undergo prompt cystectomy, as were those with a subsequent invasive recurrence. The median follow up is 29 months. RESULTS: Of the 34 eligible patients, 26 had a visibly complete transurethral resection. One patient did not complete induction treatment due to acute hematologic toxicity. After induction treatment, 22 (67%) of the 33 patients had no tumor detectable on urine cytology or rebiopsy. Of the 11 patients who still had detectable tumor, six underwent radical cystectomy and five underwent consolidation chemoradiation (one because of refusal to have the recommended cystectomy and four because the treating institutions erroneously assigned them to receive consolidation chemoradiation rather than cystectomy). No patient has required a cystectomy for radiation toxicity. Six patients have died of bladder cancer. The actuarial overall survival at three years is 83%. The probability of surviving with an intact bladder is 66% at three years. A total of seven patients (21%) developed grade 3 or grade 4 hematologic toxicity in conjunction with this treatment. CONCLUSION: This aggressive protocol comprising local surgery plus concurrent 5-FU, cisplatin, and high-dose hypofractionated radiation has been associated with moderately severe hematologic toxicity. Longer follow-up will be necessary to assess efficacy. Both the 67% complete response rate to induction therapy and the 66% three-year survival with an intact bladder are encouraging.

Pathology residents' use of a Web-based tutorial to improve Gleason grading of prostate carcinoma on needle biopsies.

Little is known about pathology residents' ability to Gleason grade or their ability to learn surgical pathology using Internet-based technology. A free Web-based program (available at www.pathology. jhu.edu/prostate) was developed that consisted of 20 pretutorial images for grading, 24 tutorial images, and the same 20 posttutorial images for Gleason grading. The grading images were selected from cases that had a consensus Gleason grade from 10 uropathology experts. In 2.5 months, 255 residents visited the website, and 151 (59%) completed it. Of those who completed the website, their year in training was known in 85 (56%): 1st year, 25.8%; 2nd year, 20%; 3rd year, 22.3%; 4th year, 14.1%; 5th year, 15.3%; and 6th year, 2.4%. Eighty percent learned Gleason grading in residency versus being self-taught, and 66% were male. In a multivariate analysis, higher pretutorial scores were associated with both their year in training (P = .001) and their hospital size (P = .003). Improvements in grading posttutorial were not related to the residents' year in training. Overall, the website significantly improved grading in 11 of 20 images and had no effect in 9 of 20 images. Improvements were noted in 1 of 1 Gleason score 4; 2 of 7 Gleason score 5 to 6; 2 of 6 Gleason score 7; and 6 of 6 Gleason score above 7 tumors. In summary, a Web-based tutorial improved Gleason grading accuracy by pathology residents to an equal extent regardless of their year in training. It is more difficult to teach residents to grade Gleason scores 5 to 7 tumors, and additional training should be concentrated in this area.

Tricuspid valve metastasis from testicular carcinoma: a case report and review of the literature.

A 20-year-old man with Stage II nonseminomatous germ cell tumor underwent chemotherapy and multiple surgical resections of recurrent abdominal and supradiaphragmatic mature teratomas. Evaluation of a new heart murmur led to the diagnosis of tricuspid valve teratoma, which required complete valve excision and replacement. We present our experience with the first discrete tricuspid valve metastasis from testicular carcinoma and review the literature regarding cardiac metastases from germ cell neoplasms.

Thyroid transcription factor-1 is expressed in extrapulmonary small cell carcinomas but not in other extrapulmonary neuroendocrine tumors.

Thyroid transcription factor-1 (TTF-1) is a nuclear homeodomain transcription factor that is expressed in the developing thyroid, respiratory epithelium, and diencephalon. TTF-1 is thought to be expressed specifically in pulmonary or thyroid neoplasms, and it is expressed in a significant subset of pulmonary non-small cell carcinomas, small cell carcinomas, and carcinoids but not in nonpulmonary, non-small cell carcinomas. Neuroendocrine tumors from sites other than the lung have not been evaluated for TFF-1 expression. We examined TFF-1 expression using immunohistochemistry on formalin-fixed, paraffin-embedded sections of 49 gastrointestinal carcinoids; 15 pancreatic islet cell tumors; 21 paragangliomas; 8 medullary thyroid carcinomas; 7 small cell carcinomas of the uterine cervix; 4 prostate, 4 bladder, and 6 Merkel cell (primary cutaneous neuroendocrine) carcinomas; and 1 renal carcinoma No gastrointestinal carcinoid tumor, pancreatic islet cell tumor, paraganglioma, or Merkel cell carcinoma expressed TFF-1. All of the medullary thyroid carcinomas strongly expressed TTF-1. However, 44% of nonpulmonary small cell carcinomas were also TTF-1 positive, including four of four prostate, two of four bladder, and one of seven cervical small cell carcinomas. We conclude that TTF-1 expression is not specific for small cell carcinomas of pulmonary origin and should not be used to distinguish primary from metastatic small cell carcinomas in extrapulmonary sites. However, TTF-1 expression may be useful in distinguishing Merkel cell carcinomas and cutaneous metastasis of small cell carcinomas. Among well-differentiated neuroendocrine tumors, TTF-1 expression seems to be present only in carcinoid tumors of the lung and medullary carcinomas of the thyroid and may be of differential diagnostic value when dealing with a metastatic well-differentiated neuroendocrine tumor.

Differential expression of osteonectin/SPARC during human prostate cancer progression.

The precise mechanism(s) involved in invasion and metastasis of prostate cancer (CaP) is poorly understood. Osteonectin [ON (also known as SPARC or BM-40)] is an antiadhesive protein known to be involved in cell-matrix interactions, migration, and angiogenesis. In this report, we studied the expression of ON in human prostate cell lines, primary tumors, and metastatic foci of CaP. Reverse transcription-PCR and nonradioactive in situ hybridization (ISH) techniques were used to determine ON gene expression. Immunohistochemistry was carried out using the polyclonal antibody LF37 and/or the monoclonal antibody ON-mAb. Low to moderate levels of ON mRNA and protein were observed in glandular epithelial cells of normal tissue as well as a few primary CaPs. However, high levels of ON mRNA and protein were observed in most of the CaP metastatic foci, both osseous and nonosseous. This correlated well with our findings that multiple different CaP cell lines including four CaP cell lines derived from metastases show high levels of ON gene expression. Furthermore, ISH analyses and cell-specific reverse transcription-PCR evaluation showed that both the luminal and basal cells express the ON gene. We conclude that the differential pattern of ON expression suggests that it may play an important role in the progression of CaP.

Prostate brachytherapy in patients with prior evidence of prostatitis.

PURPOSE: To refute a misconception that a prior history of prostatitis is a contraindication to prostate brachytherapy. METHODS AND MATERIALS: Five patients with clinical or pathologic evidence of prior prostatitis were treated with transperineal brachytherapy. Four of the patients received a single i.v. dose of ciprofloxacin (500 mg) intraoperatively. Postimplant antibiotics were not given. The pretreatment biopsy slides were reviewed. RESULTS: Two of the five patients developed postimplant urinary retention requiring short-term catheterization, and both resolved spontaneously. One patient developed what appeared to be an exacerbation of his chronic prostatitis. CONCLUSION: We continue to recommend prostate brachytherapy for the treatment of clinically organ-confined cancer, with no concern about prior clinical or pathologic evidence of prostatitis.

Prostate histopathology and the chronic prostatitis/chronic pelvic pain syndrome: a prospective biopsy study.

PURPOSE: The chronic prostatitis/chronic pelvic pain syndrome is a common clinical syndrome characterized by lower genitourinary tract symptoms, particularly pain in the perineum or genitalia, voiding symptoms, such as dysuria or frequency, and sexual dysfunction in the absence of uropathogens in the urine or prostatic secretions. The term prostatitis is based on the presumption that prostatic inflammation is important in the pathophysiology of this syndrome. To our knowledge there has been no systematic characterization of the degree and nature of inflammation in the prostate in symptomatic cases. MATERIALS AND METHODS: Prostate histopathology in 368 biopsies from 97 patients with the chronic prostatitis/chronic pelvic pain syndrome was characterized.. RESULTS: Prostatic inflammation was detected in only 33% of patients, including 29% with mild (less than 10 leukocytes per 1 mm. field) and 4% with moderate (between 10 and 200) or severe (more than 200) infiltrate. Of the 3 patients with moderate inflammation 1 had glandular, 1 periglandular and 3 multifocal or diffuse distribution of leukocytes in the interstitium. Some patients had more than 1 pattern of inflammation. CONCLUSIONS: The finding of moderate or severe inflammation in only 5% of 97 patients argues for the need to reevaluate current concepts of the pathophysiology of the chronic prostatitis/chronic pelvic pain syndrome.

Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2.

Genes regulated by androgenic hormones are of critical importance for the normal physiological function of the human prostate gland, and they contribute to the development and progression of prostate carcinoma. We used cDNA microarrays containing 1500 cDNAs to profile transcripts regulated by androgens in prostate cancer cells and identified the serine protease TMPRSS2 as a gene exhibiting increased expression upon exposure to androgens. The TMPRSS2 gene is located on chromosome 21 and contains four distinct domains, including a transmembrane region, indicating that it is expressed on the cell surface. Northern analysis demonstrated that TMPRSS2 is highly expressed in prostate epithelium relative to other normal human tissues. In situ hybridization of normal and malignant prostate tissues localizes TMMPRSS2 expression to prostate basal cells and to prostate carcinoma. These results suggest that TMPRSS2 may play a role in prostate carcinogenesis and should be investigated as a diagnostic or therapeutic target for the management of prostate cancers.

Analysis and sorting of prostate cancer cell types by flow cytometry.

BACKGROUND: Prostate tumor heterogeneity as manifested by differential expression of markers can be attributed to multiple types of cancer cells populating a tumor. Does the composition differ between primary tumor and metastasis? How can one isolate the different cancer cell types to study? What is the relationship among cancer cell types? METHODS: Flow cytometry keying on the prostate epithelial cell surface markers CD57 and CD44 was applied to analyze and sort single cells prepared from tumor tissue samples by collagenase digestion. In normal tissue, CD57 is found on luminal cells and CD44 on basal cells. RESULTS: CD57(+) and CD44(+) cells were sorted from various prostate tumor tissue specimens. The CD57(+) cancer cell type was found to predominate in primary tumors, while the CD44(+) cancer cell type was found to predominate in two visceral metastases. All tumors could be characterized by a ratio of CD57(+) and CD44(+) cancer cells. CONCLUSIONS: Two types of prostate cancer cells, CD57(+) and CD44(+), were identified. The finding that most primary tumors contain a predominantly CD57(+) cancer cell population agrees with the argument that cancer cells arise from the transformation of CD57(+) luminal cells. However, CD44(+) cancer cells are also present in some primary tumors; and in some metastases, they, and not CD57(+) cells, constitute a predominant population.