Experimental Support for the Possibility of Retrograde Genesis of Intraductal Carcinoma of the Prostate.

Historically, intraductal carcinoma of the prostate (IDC-P) was postulated to be a retrograde spread of high-grade invasive prostate cancer. There is evidence that IDC-P can primarily originate in the prostatic ducts. The retrograde genesis has never been experimentally or clinically confirmed before.

A Multimodality Image Guided Precision Radiation Research Platform: Integrating X-ray, Bioluminescence, and Fluorescence Tomography With Radiation Therapy.

Purpose: Small animal irradiation is crucial to the investigation of radiobiological mechanisms. The paradigm of clinical radiation therapy is trending toward high-precision, stereotactic treatment. However, translating this scheme to small animal irradiation is challenging owing to the lack of high-quality image guidance.

Radiation Attenuates Prostate Tumor Antiviral Responses to Vesicular Stomatitis Virus Containing IFNβ, Resulting in Pronounced Antitumor Systemic Immune Responses.

Vesicular stomatitis virus (VSV) expressing IFNβ induces apoptosis in multiple tumor models while maintaining an excellent safety profile. VSV-IFNβ is oncoselective due to permissive replication in cells with an altered IFN pathway. The human VSV-IFNβ (hIFNβ) vector is currently used in clinical trials as a standalone therapy; however, we hypothesized that oncolytic virotherapy might be more effective when used in combination with radiotherapy (RT).

Plasmonic Optical Imaging of Gold Nanorods Localization in Small Animals.

Gold nanoparticles (GNP) have been intensively investigated for applications in cancer imaging and therapy. Most imaging studies focused on microscopic imaging. Their potential as optical imaging probes for whole body small animal imaging has rarely been explored.

Bioluminescence Tomography Guided Small-Animal Radiation Therapy and Tumor Response Assessment.

Purpose: The image guided small animal arc radiation treatment platform has adopted onboard cone beam computed tomography and bioluminescence tomography (BLT). We used BLT to guide irradiation delivery and quantitatively assess irradiation-induced tumor response.

Methods And Materials: BLT was first validated on a tissue-simulating phantom, where the internal chemiluminescent liquid had a constant volume while its luminescence intensity gradually decayed.

Liposomes: Clinical Applications and Potential for Image-Guided Drug Delivery.

Liposomes have been extensively studied and are used in the treatment of several diseases. Liposomes improve the therapeutic efficacy by enhancing drug absorption while avoiding or minimizing rapid degradation and side effects, prolonging the biological half-life and reducing toxicity. The unique feature of liposomes is that they are biocompatible and biodegradable lipids, and are inert and non-immunogenic.

Optical molecular imaging-guided radiation therapy part 1: Integrated x-ray and bioluminescence tomography.

Purpose: X-ray CT faces challenges in differentiating tumors from surrounding healthy tissues. A bioluminescence tomography (BLT) system which can directly reconstruct the internal luminescent tumors, was developed and integrated with CT system to accurately guide radiation dose delivery.

Methods: The BLT system, employing a lens-coupled CCD camera, was physically registered with an onboard cone beam CT system in an image-guided small animal arc radiation treatment system (iSMAART).

Optical molecular imaging-guided radiation therapy part 2: Integrated x-ray and fluorescence molecular tomography.

Purpose: Differentiating tumor from its surrounding soft tissues is challenging for x-ray computed tomography (CT). Fluorescence molecular tomography (FMT) can directly localize the internal tumors targeted with specific fluorescent probes. A FMT system was developed and integrated onto a CT-guided irradiator to improve tumor localization for image-guided radiation.

An image guided small animal stereotactic radiotherapy system.

Small animal radiotherapy studies should be performed preferably on irradiators capable of focal tumor irradiation and healthy tissue sparing. In this study, an image guided small animal arc radiation treatment system (iSMAART) was developed which can achieve highly precise radiation targeting through the utilization of onboard cone beam computed tomography (CBCT) guidance. The iSMAART employs a unique imaging and radiation geometry where animals are positioned upright.

Edelfosine Promotes Apoptosis in Androgen-Deprived Prostate Tumors by Increasing ATF3 and Inhibiting Androgen Receptor Activity.

Edelfosine is a synthetic alkyl-lysophospholipid that possesses significant antitumor activity in several human tumor models. Here, we investigated the effects of edelfosine combined with androgen deprivation (AD) in LNCaP and VCaP human prostate cancer cells. This treatment regimen greatly decreased cell proliferation compared with single agent or AD alone, resulting in higher levels of apoptosis in LNCaP compared with VCaP cells.

The microRNA-23b/-27b cluster suppresses prostate cancer metastasis via Huntingtin-interacting protein 1-related.

Deregulation of microRNAs (miRs) contributes to progression and metastasis of prostate and other cancers. miR-23b and -27b, encoded in the same miR cluster (miR-23b/-27b), are downregulated in human metastatic prostate cancer compared with primary tumors and benign tissue. Expression of miR-23b/-27b decreases prostate cancer cell migration, invasion and results in anoikis resistance.

Interaction of HIF-1α and Notch3 Is Required for the Expression of Carbonic Anhydrase 9 in Breast Carcinoma Cells.

Expression of carbonic anhydrase 9 (CA9) is associated with poor prognosis and increased tumor aggressiveness and does not always correlate with HIF-1α expression. Presently, we analyzed the regulation of CA9 expression during hypoxia by HIF-1α, Notch3, and the von Hippel-Lindau (VHL) in breast carcinoma cells. Both HIF-1α and Notch3 were absolutely required for the expression of CA9 mRNA, protein, and reporter.

Adenovirus E2F1 overexpression sensitizes LNCaP and PC3 prostate tumor cells to radiation in vivo.

Purpose: We previously showed that E2F1 overexpression radiosensitizes prostate cancer cells in vitro. Here, we demonstrate the radiosensitization efficacy of adenovirus (Ad)-E2F1 infection in growing (orthotopic) LNCaP and (subcutaneous) PC3 nude mice xenograft tumors.

Methods And Materials: Ad-E2F1 was injected intratumorally in LNCaP (3 × 10(8) plaque-forming units [PFU]) and PC3 (5 × 10(8) PFU) tumors treated with or without radiation.

The E2F1/Rb and p53/MDM2 pathways in DNA repair and apoptosis: understanding the crosstalk to develop novel strategies for prostate cancer radiotherapy.

Both the p53- and E2F1-signaling pathways are defective in almost all types of tumors, suggesting very important roles for their signaling networks in regulating the process of tumorigenesis and therapy response. Studies on Radiation Therapy Oncology Group tissue samples have identified aberrant expression of p53, MDM2 (an E3 ubiquitin ligase that targets p53 for proteosomal degradation), and p16 (an upstream regulator of retinoblastoma and hence E2F1 in prostate cancer); abnormal expression of these biomarkers has been associated with clinical outcome after radiotherapy ± androgen deprivation therapy. Although the proapoptotic properties of p53 are well documented, a relatively new aspect of p53 function as an active mediator of prosurvival signaling pathways is now emerging.

Antisense MDM2 enhances E2F1-induced apoptosis and the combination sensitizes androgen-sensitive [corrected] and androgen-insensitive [corrected] prostate cancer cells to radiation.

We have previously shown in separate studies that MDM2 knockdown via antisense MDM2 (AS-MDM2) and E2F1 overexpression via adenoviral-mediated E2F1 (Ad-E2F1) sensitized prostate cancer cells to radiation. Because E2F1 and MDM2 affect apoptosis through both common and independent pathways, we hypothesized that coupling these two treatments would result in increased killing of prostate cancer cells. In this study, the effect of Ad-E2F1 and AS-MDM2 in combination with radiation was investigated in three prostate cancer cell lines: LNCaP cells, LNCaP-Res cells [androgen insensitive with functional p53 and androgen receptor (AR)], and PC3 cells (androgen insensitive, p53(null), and AR(null)).

Regulation of Aurora-A kinase gene expression via GABP recruitment of TRAP220/MED1.

The TRAP/Mediator coactivator complex serves as a functional interface between DNA-bound transactivators and the RNA polymerase II-associated basal transcription apparatus. TRAP220/MED1 is a variably associated subunit of the complex that plays a specialized role in selectively targeting TRAP/Mediator to specific genes. Ablation of the Trap220/Med1 gene in mice impairs embryonic cell growth, yet the underlying mechanism is unknown.

Mechanistic relationship between androgen receptor polyglutamine tract truncation and androgen-dependent transcriptional hyperactivity in prostate cancer cells.

Androgen receptor (AR) signaling pathways mediate critical events in normal and neoplastic prostate growth. Shortening of the polymorphic N-terminal polyglutamine (poly(Q)) tract of the AR gene leads to transcriptional hyperactivity and has been correlated with an increased risk of prostate cancer. The underlying mechanisms for these effects are poorly understood.

Fibroblast growth factor-1 transcriptionally induces membrane type-1 matrix metalloproteinase expression in prostate carcinoma cell line.

Background: We and others have shown that the matrix metalloproteinases, MT1-MMP is overexpressed in human prostate PIN lesions and invasive cancers compared to normal prostate epithelium. However, the mechanism for this overexpression is not understood. Evidence from our laboratory and others has indicated that fibroblast growth factors (FGFs) can regulate the expression of certain matrix metalloproteinase.

Pharmacological inhibition of FGF receptor signaling inhibits LNCaP prostate tumor growth, promatrilysin, and PSA expression.

Previously we have shown that the matrix metalloproteinase matrilysin (MMP-7) is overexpressed in human prostate cancers compared with normal epithelium. However, the mechanism for this overexpression is not understood. Human prostate fibroblasts have been shown to express certain fibroblast growth factors (FGFs), including FGF-1.

Membrane type-1-matrix metalloproteinase expressed by prostate carcinoma cells cleaves human laminin-5 beta3 chain and induces cell migration.

Degradation of the extracellular matrix by proteolytic enzymes is a central aspect of physiological and pathologic tissue-remodeling processes such as trophoblastic implantation, wound healing, and tumor invasion. We have hypothesized that prostate adenocarcinoma cell invasion through the normal basal lamina is attributable in part to metalloproteinase-induced cleavage of laminin-5 (Ln-5) and enhanced motility of the cancer cells. We studied the role of membrane type-1-matrix metalloproteinase (MT1-MMP) expressed on the surface of prostate tumor cells in cleaving Ln-5 and enhancing the migration of prostate tumor cells.

Androgens block interleukin-1 beta-induced promatrilysin expression in prostate carcinoma cells.

Background: We have shown previously that interleukin (IL) -1 beta- and IL-6-induced promatrilysin expression is mediated by an indirect pathway that requires NF kappa B-dependent synthesis of IL-6 and STAT3 signaling. We now demonstrate that IL-1 beta-induced but not IL-6-induced promatrilysin expression can be blocked by androgens in the prostate carcinoma cell line LNCaP (lymph node-derived carcinoma cells of the prostate).

Methods: By using enzyme-linked immunosorbent assay analyses, promatrilysin was measured in LNCaP cells stimulated with IL-1 beta or IL-6 LNCaP-treated cells pretreated with testosterone.

Fibroblast growth factor-1 induced promatrilysin expression through the activation of extracellular-regulated kinases and STAT3.

The MMP, matrilysin (MMP-7), has been shown to be overexpressed in prostate cancer cells and to increase prostate cancer cell invasion. Prostate stromal fibroblasts secrete factor(s), including fibroblast growth factor-1 (FGF-1) that induces promatrilysin expression in LNCaP cells. In the present study, we investigated the signal transduction pathway involved in the FGF-1-induced expression of promatrilysin.

Interleukin-1beta-induced promatrilysin expression is mediated by NFkappaB-regulated synthesis of interleukin-6 in the prostate carcinoma cell line, LNCaP.

Previously, our laboratory showed that interleukin-1beta (IL-1beta) secreted by lipopolysaccharide-activated monocytes induces promatrilysin expression in the prostate carcinoma cell line, LNCaP. We now demonstrate that IL-1beta-induced promatrilysin expression is mediated by an indirect mechanism that requires nuclear factor Kappa B (NFkappaB)-dependent synthesis of IL-6. Inhibition of protein synthesis with cycloheximide blocked IL-1beta-mediated induction of matrilysin mRNA suggesting that synthesis of one or more additional factors is required for IL-1beta-induced promatrilysin protein expression.

Expression of the matrix metalloproteinase promatrilysin in coculture of prostate carcinoma cell lines.

Background: Matrix metalloproteinases (MMPs) are involved in tumor progression. Matrilysin (MMP-7) has been shown to be upregulated in prostatic carcinomas and can increase the invasive capacity of DU-145 cells. Because of the heterogenous nature of prostatic tumors, we examined promatrilysin expression in cocultures containing two different prostatic carcinoma cell lines, DU-145 and LNCaP.