ABSTRACT
Prostate cancer is an age-associated epithelial cancer, and as such, it contributes significantly to the mortality of the elderly. Senescence is one possible mechanism by which the body defends itself against various epithelial cancers. Senescent cells alter the microenvironment, in part, through changes to the extracellular matrix. Laminins (LMs) are extracellular proteins important to both the structure and function of the microenvironment. Overexpression of the senescence-associated gene mac25 in human prostate cancer cells resulted in increased mRNA levels of the LM alpha4 and beta2 chains compared to empty vector control cells. The purpose of this study was to examine the effects of these senescence-induced LM chains on tumorigenicity of prostate cancer cells. We created stable M12 human prostate cancer lines overexpressing either the LM alpha4 or beta2 chain or both chains. Increased expression of either the LM alpha4 or beta2 chain resulted in increased in vitro migration and in vivo tumorigenicity of those cells, whereas high expression of both chains led to decreased in vitro proliferation and in vivo tumorigenicity compared to M12 control cells. This study demonstrates that senescent prostate epithelial cells can alter the microenvironment and that these changes modulate progression of prostate cancer.
Subject(s)
Gene Expression Regulation, Neoplastic , Laminin/metabolism , Prostatic Neoplasms/metabolism , Animals , Cell Line, Tumor , Cell Movement , Cellular Senescence , Humans , Laminin/biosynthesis , Male , Mice , Mice, Nude , Neoplasm Transplantation , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Wound HealingABSTRACT
PURPOSE: To determine the effect of inhibition of insulin-like growth factor-IR (IGF-IR) signaling with an antibody to the IGF-IR, A12, in conjunction with androgen withdrawal on prostate cancer progression in a human prostate xenograft model, LuCaP 35. EXPERIMENTAL DESIGN: LuCaP 35 was implanted s.c. in severe combined immunodeficient mice. At the time of castration, mice were randomized to one of three groups. Group 1 was castrate only; group 2 received A12 40 mg/kg i.p. for 2 weeks beginning 1 week after castration; and group 3 received A12 40 mg/kg i.p. for 2 weeks beginning 2 weeks after castration. RESULTS: In group 1, tumor volume decreased to 60% of the starting volume 4 weeks post-castration. In groups 2 and 3, tumor volumes nadired 6 weeks after castration at <10% of the volume at time of castration (P < 0.01). Tumor regrowth was not seen in groups 2 or 3 until 15 weeks after castration. Androgen receptor (AR) localization in tumors showed a decrease in nuclear staining in groups 2 and 3 compared with group 1 (P < 0.001). Tumor volume correlated with nuclear AR intensity. AR-regulated genes increased early in group 1, but did not increase in groups 2 and 3. Thus, tumor-specific survival was prolonged by the addition of A12 to castration. CONCLUSIONS: This study shows that the inhibition of IGF-IR enhances the effects of castration in prostate cancer. These effects are associated with a decrease in AR signaling and nuclear AR localization, and recurrence is associated with an increase in AR-regulated gene expression.
Subject(s)
Androgens/metabolism , Prostatic Neoplasms/immunology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Receptor, IGF Type 1/chemistry , Animals , Antibodies, Monoclonal/chemistry , Cell Line, Tumor , Cell Nucleus/metabolism , Cell Proliferation , Cytosol/metabolism , Dihydrotestosterone/blood , Humans , Male , Mice , Mice, SCID , Neoplasm Transplantation , Receptor, IGF Type 1/immunology , Receptor, IGF Type 1/metabolism , Receptors, Androgen/metabolism , Signal Transduction , Testosterone/bloodABSTRACT
PURPOSE: A human type 1 insulin-like growth factor receptor antibody (A12) has been shown to effectively inhibit human xenograft tumor growth, including androgen-dependent and androgen-independent prostate tumors. Docetaxel, either as a single agent or combined with others, has shown a survival benefit in prostate cancer patients. Based on these data, we investigated the combined in vivo effect of A12 and docetaxel on human androgen-independent and osseous prostate tumor growth. EXPERIMENTAL DESIGN: To study human androgen-independent prostate cancer model, LuCaP35V tumors were implanted s.c. into castrated severe combined immunodeficient mice. When tumors reached about 100 mm3, animals were treated with vehicle control docetaxel (10 or 20 mg/kg) and docetaxel in combination with A12 (40 microg/kg) for 4 weeks. To study human osseous prostate cancer model, LuCaP 23.1 tumors were implanted intratibiae. When serum prostate-specific antigen reached 5 to 10 ng/mL, treatments were initiated. RESULTS: A12 markedly augmented the inhibition of docetaxel on tumor growth. When docetaxel is combined with A12, the inhibition of tumor growth continued after treatment cessation, which was associated with continued apoptosis and decreased proliferation of tumor cells. Gene expression profiles indicated that the posttreatment suppression of tumor growth may be due to enhanced negative regulation of cell cycle progression- and/or cell survival-associated genes, some of which have been shown to induce resistance to docetaxel. CONCLUSIONS: Our findings suggest that targeting type 1 insulin-like growth factor receptor can enhance the therapeutic effect of docetaxel on advanced prostate cancer. Our findings also suggest a potential mechanism to improve the treatment efficacy of docetaxel in prostate cancer.
Subject(s)
Antibodies/pharmacology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Receptor, IGF Type 1/immunology , Taxoids/pharmacology , Animals , Apoptosis , Cell Cycle , Disease Models, Animal , Docetaxel , Humans , Male , Orchiectomy , Prostatic Neoplasms/immunology , Transplantation, HeterologousABSTRACT
X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a polyglutamine (polyQ) disease in which the affected males suffer progressive motor neuron degeneration accompanied by signs of androgen insensitivity, such as gynecomastia and reduced fertility. SBMA is caused by CAG repeat expansions in the androgen receptor (AR) gene resulting in the production of AR protein with an extended glutamine tract. SBMA is one of nine polyQ diseases in which polyQ expansion is believed to impart a toxic gain-of-function effect upon the mutant protein, and initiate a cascade of events that culminate in neurodegeneration. However, whether loss of a disease protein's normal function concomitantly contributes to the neurodegeneration remains unanswered. To address this, we examined the role of normal AR function in SBMA by crossing a highly representative AR YAC transgenic mouse model with 100 glutamines (AR100) and a corresponding control (AR20) onto an AR null (testicular feminization; Tfm) background. Absence of endogenous AR protein in AR100Tfm mice had profound effects upon neuromuscular and endocrine-reproductive features of this SBMA mouse model, as AR100Tfm mice displayed accelerated neurodegeneration and severe androgen insensitivity in comparison to AR100 littermates. Reduction in size and number of androgen-sensitive motor neurons in the spinal cord of AR100Tfm mice underscored the importance of AR action for neuronal health and survival. Promoter-reporter assays confirmed that AR transactivation competence diminishes in a polyQ length-dependent fashion. Our studies indicate that SBMA disease pathogenesis, both in the nervous system and the periphery, involves two simultaneous pathways: gain-of-function misfolded protein toxicity and loss of normal protein function.
Subject(s)
Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/metabolism , Receptors, Androgen/genetics , Androgen-Insensitivity Syndrome/genetics , Androgen-Insensitivity Syndrome/metabolism , Animals , Disease Models, Animal , Female , Genetic Linkage , Humans , Male , Mice , Mice, Mutant Strains , Mice, Transgenic , Motor Neurons/pathology , Muscular Atrophy, Spinal/pathology , Nerve Degeneration/pathology , Peptides/chemistry , Phenotype , Receptors, Androgen/chemistry , Receptors, Androgen/deficiency , Receptors, Androgen/metabolism , X Chromosome/geneticsABSTRACT
BACKGROUND: Two features of the progression from organ-confined to metastatic prostate cancer are dysregulation of the androgen receptor (AR) and a decrease in insulin-like growth factor-type-I receptor (IGF-IR) expression. The purpose of this study was to determine the effect of changes in IGF-IR expression on AR activity. METHODS: M12 human prostate cells were stably transfected with an AR expression construct to produce the M12-AR parental (PAR) cell line. PAR cells were implanted orthotopically into nude mice and M12-AR primary (PRI) cell lines were derived from intraprostatic tumors and metastatic cell lines (MET) were derived from PRI tumors that had metastasized to diaphragm or lung. RESULTS: Tumor formation in the prostate by PAR cells was decreased significantly compared to M12 controls. PAR, PRI, and MET cells expressed equivalent amounts of AR protein; however, IGF-IR expression was increased significantly in PAR and PRI cells. IGF-IR expression decreased in MET lines to the levels seen in M12 control cells. IGF-I significantly enhanced dihydrotestosterone (DHT)-stimulated, but not basal, AR transcriptional activity in PRI cells. In MET cells, IGF-I significantly suppressed DHT-stimulated transcriptional activity. In MET cells in which the IGF-IR was re-expressed from a retroviral vector, the effects of DHT and IGF-I on AR activity were similar to those seen in PRI cells. CONCLUSIONS: This study demonstrates that the changes in IGF-IR expression exhibited by this model of metastatic progression cause significant alterations in AR signaling and suggest that this interaction may be an important aspect of the changes seen in AR function in disease progression in vivo.
