Expression of autotaxin and acylglycerol kinase in prostate cancer: association with cancer development and progression.

Lysophosphatidic acid (LPA) may enhance diverse biologic activities in prostate cancer. This study was conducted to analyze expression levels of LPA-producing enzymes, autotaxin (ATX) and acylglycerol kinase (AGK), in prostate cancer with relevance to clinicopathological parameters. Real-time RT-PCR and western blotting were performed for ATX and AGK in non-neoplastic prostate cells (PrECs and PrSCs) and prostate cancer cell-lines (DU-145, PC-3, LNCaP, and AILNCaP). Immunohistochemical analyses were conducted in tissue specimens of 132 localized prostate cancer patients who underwent radical prostatectomy between 2001 and 2007 (median observation period, 22 months). Both enzymes were negatively expressed in PrECs and PrSCs at mRNA and protein levels. ATX expression was higher than AGK in AILNCaP, DU-145, and PC-3 cell-lines, while AGK was mainly expressed in LNCaP cells. Immunohistochemically, ATX and AGK expressions were negative in non-neoplastic epithelia, while both were weakly expressed in the majority of high-grade intra-epithelial neoplasia (HG-PIN). In cancer foci, ATX and AGK expressions were strong in 49% and 62%, weak in 40% and 32%, and negative in 11% and 6%, respectively. Expressions of both enzymes were significantly correlated with primary Gleason grade of cancer foci (P < 0.0001) and capsular invasion (P = 0.03 and 0.003 respectively). ATX expression was significantly correlated with probability of prostate specific antigen (PSA)-failure after surgery (P < 0.0001). In conclusion, LPA-producing enzymes (ATX and AGK) were frequently expressed in prostate cancer cells and precancerous HG-PIN. In particular, high expression levels of ATX were associated with both malignant potentials and poor outcomes.

Gene expression profiles of lysophosphatidic acid-related molecules in the prostate: relevance to prostate cancer and benign hyperplasia.

OBJECTIVE: To elucidate gene expression profiles of lysophosphatidic acid (LPA)-related molecules in cancer, pre-cancerous lesion, and benign hyperplasia of the prostate. MATERIALS AND METHODS: Prostate tissue samples were surgically obtained from 10 patients with localized prostate cancer and seven patients with invasive bladder cancer. Cancer cells and the corresponding stromal cells from normal prostate, high grade intraepithelial neoplasia (HGPIN), benign hyperplastic glands were isolated by laser capture microdissection. mRNA levels of three LPA receptors, LPA1, LPA2, LPA3, two LPA-synthesizing enzymes, autotaxin (ATX), acylglycerol kinase (AGK), and a LPA-degradation enzyme, prostatic acid phosphatase (PAP), were quantitatively assessed. The expression levels of the same genes were also determined in three human prostate cancer cell lines LNCaP, PC-3, and DU-145. RESULTS: LPA1 mRNA level was significantly decreased in HGPIN and cancer epithelia when compared to the benign glands. LPA3 mRNA level was elevated in cancer epithelia compared to benign glands. LPA3, AGK, and PAP were predominantly expressed in LNCaP cells while LPA1 and ATX gene expressions were found in PC-3 and Du-145 cells. In BPH, AGK was abundantly expressed in the stroma while PAP was predominant in epithelial cells. CONCLUSIONS: By acting via LPA3, LPA may play an important role in the development of prostate cancer. Switching of LPA receptor expression from LPA3 to LPA1, may be involved in prostate cancer progression and/or androgen independence. LPA may also play a key role in the development of benign prostatic hyperplasia.

Renal Cell Carcinoma with IVC Thrombi; Current Concepts and Future Perspectives.

The incidence of venous extension to the inferior vena cava (IVC) in renal cell carcinoma (RCC) is markedly increased recently mostly due to the advances in diagnostic modalities. Such vascular invasion implies a heightened biologic behavior and a surgical challenge during the course of treatment. In this study, we reviewed the classification guidelines, recent diagnostic tools and up-to-date therapeutic modalities for RCC with IVC tumor thrombi added to the prognostic significance regarding the pathologic nature of vascular invasion; cephalad extent of thrombi and any associated distant metastasis. Also, we are providing our suggestion regarding the use of angioscopy for removal of IVC thrombi in a relatively bloodless field without aggressive surgical manipulations or shunt techniques for maintenance of hemodynamic stability.

18-year recurrence-free survival after extensive surgery for kidney cancer with atrial tumor thrombi.

Tumor thrombus formation is a unique aspect of renal cell carcinoma with significant therapeutic and prognostic implications. The prognostic significance of cephalad extent of tumor thrombi to the right atrium remains controversial. Extended surgical removal, however, is the only way to expect survival. In 1989, a 40-year-old man was diagnosed with an advanced renal cell carcinoma (T(3C)N(2)M(0)) involving perinephric fat, hilar and para-aortic lymph nodes and a tumor thrombus extending to the right atrium. He was treated with extensive surgical resection of the tumor and its lymphatic and vascular extensions. Interferon-alpha injections were given for 2.5 years as an adjuvant immunotherapy. The patient was annually checked with abdominal ultrasound, chest X-ray and computed tomography, but has manifested no local or distant metastasis for 18 years. To our knowledge, this is the first reported case of extensive surgery on advanced renal cell carcinoma with no evidence of recurrence for 18 years.

Human agonistic antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 2 induces cytotoxicity and apoptosis in prostate cancer and bladder cancer cells.

OBJECTIVES: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumor cells through two of its receptors: TRAIL-R1 and TRAIL-R2. In this study, we investigated the susceptibility of human prostate cancer and bladder cancer cells to HGS-ETR2, a human monoclonal agonistic antibody specific for TRAIL-R2. METHODS: The cell surface expression of TRAIL-R1 and TRAIL-R2 on prostate cancer and bladder cancer cells was determined using flow cytometry. Cytotoxicity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and caspase activities were measured by a quantitative colorimetric assay. RESULTS: HGS-ETR2 effectively induced apoptotic cell death in DU145, PC3, and LNCaP human prostate cancer cells and J82 and T24 human bladder cancer cells. The increased effectiveness of HGS-ETR2 for inducing cell death might have been affected by differences in the cell surface expression of the two TRAIL receptors, in that TRAIL-R2, but not TRAIL-R1, was frequently expressed in the prostate cancer and bladder cancer cells. HGS-ETR2 significantly activated the caspase cascade, including caspase-3, -6, -8, and -9, which were the downstream molecules of the death receptors in prostate cancer cells. Caspase-3, -6, and -9 were also significantly activated with HGS-ETR2-induced apoptosis in the bladder cancer cells. CONCLUSIONS: These findings suggest the potential utility of TRAIL-R2 antibody as a novel therapeutic agent against prostate cancer and bladder cancer.