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1.
bioRxiv ; 2024 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-38405929

RESUMO

Androgen deprivation therapy (ADT) is an effective but not curative treatment for advanced and recurrent prostate cancer (PC). We investigated the mechanisms controlling the response to androgen-deprivation by surgical castration in genetically-engineered mouse models (GEMM) of PC, using high frequency ultrasound imaging to rigorously measure tumor volume. Castration initially causes almost all tumors to shrink in volume, but many tumors subsequently recur within 5-10 weeks. Blockade of tumor necrosis factor (TNF) signaling a few days in advance of castration surgery, using a TNFR2 ligand trap, prevents regression in a PTEN-deficient GEMM. Following tumor regression, a basal stem cell-like population within the tumor increases along with TNF protein levels. Tumor cell lines in culture recapitulate these in vivo observations, suggesting that basal stem cells are the source of TNF. When TNF signaling blockade is administered immediately prior to castration, tumors regress but recurrence is prevented, implying that a late wave of TNF secretion within the tumor, which coincides with the expression of NFkB regulated genes, drives recurrence. The inhibition of signaling downstream of one NFkB-regulated protein, chemokine C-C motif ligand 2 (CCL2), prevents post-castration tumor recurrence, phenocopying post-castration (late) TNF signaling blockade. CCL2 was originally identified as a macrophage chemoattractant and indeed at late times after castration gene sets related to chemotaxis and migration are up-regulated. Importantly, enhanced CCL2 signaling during the tumor recurrence phase coincides with an increase in pro-tumorigenic macrophages and a decrease in CD8 T cells, suggesting that recurrence is driven at least in part by tumor immunosuppression. In summary, we demonstrate that a therapy-induced switch in TNF signaling, a consequence of the increased stem cell-like character of the residual tumor cells surviving ADT, induces an immunosuppressive tumor microenvironment and concomitant tumor recurrence.

2.
Am J Clin Exp Urol ; 11(1): 12-26, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36923722

RESUMO

Benign prostatic hyperplasia (BPH) is a non-neoplastic proliferative disease producing lower urinary tract symptoms related to the resulting enlarged prostate. BPH is pathologically characterized by hyperplastic growth in both epithelial and stromal compartments. Androgen signaling is essential for prostate function and androgen blockade is the second-line medical therapy to relieve symptoms of BPH. Here we examined the prostates of probasin promoter-driven prolactin (Pb-PRL) transgenic mice, a robust model of BPH that spontaneously develops prostate enlargement, to investigate prostate regression in response to surgical castration. Serial ultrasound imaging demonstrated very uniform self-limited growth of Pb-PRL prostate volume that is consistent with the benign, limited cellular proliferation characteristic of BPH and that contrasts with the highly variable, exponential growth of murine prostate cancer models. Castration elicited only a partial reduction in prostate volume, relative to castration-induced regression of the normal prostate gland. The anti-androgen finasteride induced a diminished reduction of Pb-PRL prostate volume versus castration. The limited extent of Pb-PRL mouse prostate volume regression correlated with the initial volume of the stromal compartment, suggesting a differential sensitivity of the epithelial and stromal compartments to androgen withdrawal. Indeed, two-dimensional morphometric analyses revealed a distinctly reduced rate of regression for the stromal compartment in Pb-PRL mice. The myofibroblast component of the Pb-PRL prostate stroma appeared normal, but the stromal compartment contained more fibroblasts and extracellular collagen deposition. Like normal prostate, the rate of regression of the Pb-PRL prostate was partially dependent on TGFß and TNF signaling, but unlike the normal prostate, the extent of castration-induced regression was not affected by TGFß or TNF blockade. Our studies show that androgen deprivation can effectively reduce the overall volume of hyperplastic prostate, but the stromal compartment is relatively resistant, suggesting additional therapies might be required to offer an effective treatment for the clinical manifestations of BPH.

3.
Cancers (Basel) ; 14(24)2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36551505

RESUMO

The mainstay treatment for locally advanced, recurrent, or metastatic prostate cancer (PrCa) is androgen deprivation therapy (ADT). ADT causes prostate cancers to shrink in volume, or regress, by inducing epithelial tumor cell apoptosis. In normal, non-neoplastic murine prostate, androgen deprivation via castration induces prostate gland regression that is dependent on TNF signaling. In addition to this direct mechanism of action, castration has also been implicated in an indirect mechanism of prostate epithelial cell death, which has been described as vascular regression. The initiating event is endothelial cell apoptosis and/or increased vascular permeability. This subsequently leads to reduced blood flow and perfusion, and then hypoxia, which may enhance epithelial cell apoptosis. Castration-induced vascular regression has been observed in both normal and neoplastic prostates. We used photoacoustic, power Doppler, and contrast-enhanced ultrasound imaging, and CD31 immunohistochemical staining of the microvasculature to assess vascular integrity in the period immediately following castration, enabling us to test the role of TNF signaling in vascular regression. In two mouse models of androgen-responsive prostate cancer, TNF signaling blockade using a soluble TNFR2 ligand trap reversed the functional aspects of vascular regression as well as structural changes in the microvasculature, including reduced vessel wall thickness, cross-sectional area, and vessel perimeter length. These results demonstrate that TNF signaling is required for vascular regression, most likely by inducing endothelial cell apoptosis and increasing vessel permeability. Since TNF is also the critical death receptor ligand for prostate epithelial cells, we propose that TNF is a multi-purpose, comprehensive signal within the prostate cancer microenvironment that mediates prostate cancer regression following androgen deprivation.

4.
Cancers (Basel) ; 14(3)2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-35158998

RESUMO

Rare variants in MAGEC3 are associated with BRCA negative, early-onset ovarian cancers. Given this association, we evaluated the impact of MAGEC3 protein expression on prognosis and transcription. We quantified normal and tumor protein expression of MAGEC3 via immunohistochemistry in n = 394 advanced ovarian cancers, assessed the correlation of these values with clinicopathologic and immunological features and modeled survival using univariate and multivariate models. To extend these results, we quantified MAGEC3 protein expression in n = 180 cancers and used matching RNA sequencing data to determine MAGEC3-associated differentially expressed genes and to build an RNA-based model of MAGEC3 protein levels. This model was tested in a third independent cohort of patients from TCGA's OV dataset (n = 282). MAGEC3 protein was sporadically lost in ovarian cancers, with half of the cases falling below the 9.5th percentile of normal tissue expression. Cases with MAGEC3 loss demonstrated better progression-free survival [HR = 0.71, p = 0.004], and analyses performed on predicted protein scores were consistent [HR = 0.57 p = 0.002]. MAGEC3 protein was correlated with CD8 protein expression [Pearson's r = 0.176, p = 0.011], NY-ESO-1 seropositivity, and mRNA expression of tumor antigens at Xq28. Results of gene set enrichment analysis showed that genes associated with MAGEC3 protein expression cluster around G2/M checkpoint (NES = 3.20, FDR < 0.001) and DNA repair (NES = 2.28, FDR < 0.001) hallmark pathways. These results show that MAGEC3 is a prognostic biomarker in ovarian cancer.

5.
J Exp Clin Cancer Res ; 40(1): 254, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384473

RESUMO

The incidence of renal cell carcinoma (RCC) is increasing worldwide with an approximate 20% mortality rate. The challenge in RCC is the therapy-resistance. Cancer resistance to treatment employs multiple mechanisms due to cancer heterogeneity with multiple genetic and epigenetic alterations. These changes include aberrant overexpression of (1) anticancer cell death proteins (e.g., survivin/BIRC5), (2) DNA repair regulators (e.g., ERCC6) and (3) efflux pump proteins (e.g., ABCG2/BCRP); mutations and/or deregulation of key (4) oncogenes (e.g., MDM2, KRAS) and/or (5) tumor suppressor genes (e.g., TP5/p53); and (6) deregulation of redox-sensitive regulators (e.g., HIF, NRF2). Foci of tumor cells that have these genetic alterations and/or deregulation possess survival advantages and are selected for survival during treatment. We will review the significance of survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, TP5/p53, KRAS and AKT in treatment resistance as the potential therapeutic biomarkers and/or targets in RCC in parallel with our analized RCC-relevant TCGA genetic results from each of these gene/protein molecules. We then present our data to show the anticancer drug FL118 modulation of these protein targets and RCC cell/tumor growth. Finally, we include additional data to show a promising FL118 analogue (FL496) for treating the specialized type 2 papillary RCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/terapia , Neoplasias Renais/diagnóstico , Neoplasias Renais/terapia , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/patologia
6.
JCI Insight ; 5(6)2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32078585

RESUMO

Most prostate cancers depend on androgens for growth, and therefore, the mainstay treatment for advanced, recurrent, or metastatic prostate cancer is androgen deprivation therapy (ADT). A prominent side effect in patients receiving ADT is an obese frailty syndrome that includes fat gain and sarcopenia, defined as the loss of muscle function accompanied by reduced muscle mass or quality. Mice bearing Pten-deficient prostate cancers were examined to gain mechanistic insight into ADT-induced sarcopenic obesity. Castration induced fat gain as well as skeletal muscle mass and strength loss. Catabolic TGF-ß family myokine protein levels were increased immediately prior to strength loss, and pan-myokine blockade using a soluble receptor (ActRIIB-Fc) completely reversed the castration-induced sarcopenia. The onset of castration-induced strength and muscle mass loss, as well as the increase in catabolic TGF-ß family myokine protein levels, were coordinately accelerated in tumor-bearing mice relative to tumor-free mice. Notably, growth differentiation factor 11 (GDF11) increased in muscle after castration only in tumor-bearing mice, but not in tumor­free mice. An early surge of GDF11 in prostate tumor tissue and in the circulation suggests that endocrine GDF11 signaling from tumor to muscle is a major driver of the accelerated ADT-induced sarcopenic phenotype. In tumor-bearing mice, GDF11 blockade largely prevented castration-induced strength loss but did not preserve muscle mass, which confirms a primary role for GDF11 in muscle function and suggests an additional role for the other catabolic myokines.


Assuntos
Antagonistas de Androgênios/toxicidade , Proteínas Morfogenéticas Ósseas/metabolismo , Fatores de Diferenciação de Crescimento/metabolismo , Neoplasias da Próstata/metabolismo , Sarcopenia/induzido quimicamente , Animais , Masculino , Camundongos , Músculo Esquelético/metabolismo
7.
Clin Cancer Res ; 25(8): 2494-2502, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30647081

RESUMO

PURPOSE: Biomarkers are needed to stratify patients with stage II-III melanoma for clinical trials of adjuvant therapy because, while immunotherapy is protective, it also confers the risk of severe toxicity. We previously defined and validated a 53-immune gene melanoma immune profile (MIP) predictive both of distant metastatic recurrence and of disease-specific survival (DSS). Here, we test MIP on a third independent population. EXPERIMENTAL DESIGN: A retrospective cohort of 78 patients with stage II-III primary melanoma was analyzed using the NanoString assay to measure expression of 53 target genes, and MIP score was calculated. Statistical analysis correlating MIP with DSS, overall survival, distant metastatic recurrence, and distant metastasis-free interval was performed using ROC curves, Kaplan-Meier curves, and standard univariable and multivariable Cox proportional hazards models. RESULTS: MIP significantly distinguished patients with distant metastatic recurrence from those without distant metastatic recurrence using ROC curve analysis (AUC = 0.695; P = 0.008). We defined high- and low-risk groups based on the cutoff defined by this ROC curve and find that MIP correlates with both DSS and overall survival by ROC curve analysis (AUC = 0.719; P = 0.004 and AUC = 0.698; P = 0.004, respectively). Univariable Cox regression reveals that a high-risk MIP score correlates with DSS (P = 0.015; HR = 3.2). CONCLUSIONS: MIP identifies patients with low risk of death from melanoma and may constitute a clinical tool to stratify patients with stage II-III melanoma for enrollment in clinical trials.


Assuntos
Biomarcadores Tumorais , Suscetibilidade a Doenças , Imunidade/genética , Melanoma/diagnóstico , Melanoma/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Espécies Reativas de Oxigênio , Estudos Retrospectivos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/mortalidade , Adulto Jovem , Melanoma Maligno Cutâneo
8.
Artigo em Inglês | MEDLINE | ID: mdl-29782610

RESUMO

BACKGROUND: Sarcopenia, the age-related loss of skeletal muscle, is a side effect of androgen deprivation therapy (ADT) for prostate cancer patients. Resident stem cells of skeletal muscle, satellite cells (SCs), are an essential source of progenitors for the growth and regeneration of skeletal muscle. Decreased androgen signaling and deficits in the number and function of SCs are features of aging. Although androgen signaling is known to regulate skeletal muscle, the cellular basis for ADT-induced exacerbation of sarcopenia is unknown. Furthermore, the consequences of androgen deprivation on SC fate in adult skeletal muscle remain largely unexplored. METHODS: We examined SC fate in an androgen-deprived environment using immunofluorescence and fluorescence-activated cell sorting (FACS) with SC-specific markers in young castrated mice. To study the effects of androgen deprivation on SC function and skeletal muscle regenerative capacity, young castrated mice were subjected to experimental regenerative paradigms. SC-derived-cell contributions to skeletal muscle maintenance were examined in castrated Pax7CreER/+; ROSA26mTmG/+ mice. SCs were depleted in Pax7CreER/+; ROSA26DTA/+ mice to ascertain the consequences of SC ablation in sham and castrated skeletal muscles. Confocal immunofluorescence analysis of neuromuscular junctions (NMJs), and assessment of skeletal muscle physiology, contractile properties, and integrity were conducted. RESULTS: Castration led to SC activation, however this did not result in a decline in SC function or skeletal muscle regenerative capacity. Surprisingly, castration induced SC-dependent maintenance of young skeletal muscle. The functional dependence of skeletal muscles on SCs in young castrated mice was demonstrated by an increase in SC-derived-cell fusion within skeletal muscle fibers. SC depletion was associated with further atrophy and functional decline, as well as the induction of partial innervation and the loss of NMJ-associated myonuclei in skeletal muscles from castrated mice. CONCLUSION: The maintenance of skeletal muscles in young castrated mice relies on the cellular contributions of SCs. Considering the well-described age-related decline in SCs, the results in this study highlight the need to devise strategies that promote SC maintenance and activity to attenuate or reverse the progression of sarcopenia in elderly androgen-deprived individuals.

9.
PLoS Genet ; 14(2): e1007194, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29447163

RESUMO

Given prior evidence that an affected woman conveys a higher risk of ovarian cancer to her sister than to her mother, we hypothesized that there exists an X-linked variant evidenced by transmission to a woman from her paternal grandmother via her father. We ascertained 3,499 grandmother/granddaughter pairs from the Familial Ovarian Cancer Registry at the Roswell Park Cancer Institute observing 892 informative pairs with 157 affected granddaughters. We performed germline X-chromosome exome sequencing on 186 women with ovarian cancer from the registry. The rate of cancers was 28.4% in paternal grandmother/granddaughter pairs and 13.9% in maternal pairs consistent with an X-linked dominant model (Chi-square test X2 = 0.02, p = 0.89) and inconsistent with an autosomal dominant model (X2 = 20.4, p<0.001). Paternal grandmother cases had an earlier age-of-onset versus maternal cases (hazard ratio HR = 1.59, 95%CI: 1.12-2.25) independent of BRCA1/2 status. Reinforcing the X-linked hypothesis, we observed an association between prostate cancer in men and ovarian cancer in his mother and daughters (odds ratio, OR = 2.34, p = 0.034). Unaffected mothers with affected daughters produced significantly more daughters than sons (ratio = 1.96, p<0.005). We performed exome sequencing in reported BRCA negative cases from the registry. Considering age-of-onset, one missense variant (rs176026 in MAGEC3) reached chromosome-wide significance (Hazard ratio HR = 2.85, 95%CI: 1.75-4.65) advancing the age of onset by 6.7 years. In addition to the well-known contribution of BRCA, we demonstrate that a genetic locus on the X-chromosome contributes to ovarian cancer risk. An X-linked pattern of inheritance has implications for genetic risk stratification. Women with an affected paternal grandmother and sisters of affected women are at increased risk for ovarian cancer. Further work is required to validate this variant and to characterize carrier families.


Assuntos
Genes Ligados ao Cromossomo X , Hereditariedade , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Herança Paterna/genética , Adulto , Idade de Início , Neoplasias da Mama/complicações , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Família , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Neoplasias Ovarianas/complicações , Linhagem , Sistema de Registros
10.
Mol Cancer Res ; 15(9): 1138-1152, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28512253

RESUMO

Tissue infiltration and elevated peripheral circulation of granulocytic myeloid-derived cells is associated with poor outcomes in prostate cancer and other malignancies. Although myeloid-derived cells have the ability to suppress T-cell function, little is known about the direct impact of these innate cells on prostate tumor growth. Here, it is reported that granulocytic myeloid-derived suppressor cells (MDSC) are the predominant tumor-infiltrating cells in prostate cancer xenografts established in athymic nude mice. MDSCs significantly increased in number in the peripheral circulation as a function of xenograft growth and were successfully depleted in vivo by Gr-1 antibody treatment. Importantly, MDSC depletion significantly decreased xenograft growth. We hypothesized that granulocytic MDSCs might exert their protumorigenic actions in part through neutrophil elastase (ELANE), a serine protease released upon granulocyte activation. Indeed, it was determined that NE is expressed by infiltrating immune cells and is enzymatically active in prostate cancer xenografts and in prostate tumors of prostate-specific Pten-null mice. Importantly, treatment with sivelestat, a small-molecule inhibitor specific for NE, significantly decreased xenograft growth, recapitulating the phenotype of Gr-1 MDSC depletion. Mechanistically, NE activated MAPK signaling and induced MAPK-dependent transcription of the proliferative gene cFOS in prostate cancer cells. Functionally, NE stimulated proliferation, migration, and invasion of prostate cancer cells in vitro IHC on human prostate cancer clinical biopsies revealed coexpression of NE and infiltrating CD33+ MDSCs.Implications: This report suggests that MDSCs and NE are physiologically important mediators of prostate cancer progression and may serve as potential biomarkers and therapeutic targets. Mol Cancer Res; 15(9); 1138-52. ©2017 AACR.


Assuntos
Elastase de Leucócito/metabolismo , Células Mieloides/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , Animais , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias da Próstata/metabolismo
11.
Nat Commun ; 8: 14270, 2017 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-28112170

RESUMO

MicroRNAs play important roles in regulating tumour development, progression and metastasis. Here we show that one of the miR-200 family members, miR-141, is under-expressed in several prostate cancer (PCa) stem/progenitor cell populations in both xenograft and primary patient tumours. Enforced expression of miR-141 in CD44+ and bulk PCa cells inhibits cancer stem cell properties including holoclone and sphere formation, as well as invasion, and suppresses tumour regeneration and metastasis. Moreover, miR-141 expression enforces a strong epithelial phenotype with a partial loss of mesenchymal phenotype. Whole-genome RNA sequencing uncovers novel miR-141-regulated molecular targets in PCa cells including the Rho GTPase family members (for example, CDC42, CDC42EP3, RAC1 and ARPC5) and stem cell molecules CD44 and EZH2, all of which are validated as direct and functionally relevant targets of miR-141. Our results suggest that miR-141 employs multiple mechanisms to obstruct tumour growth and metastasis.


Assuntos
Movimento Celular/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Masculino , Camundongos , Camundongos SCID , MicroRNAs/genética , Invasividade Neoplásica , Neoplasias Experimentais , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismo
12.
BMC Med Genomics ; 9(1): 64, 2016 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-27756300

RESUMO

BACKGROUND: The rapid adoption of next-generation sequencing provides an efficient system for detecting somatic alterations in neoplasms. The detection of such alterations requires a matched non-neoplastic sample for adequate filtering of non-somatic events such as germline polymorphisms. Non-neoplastic tissue adjacent to the excised neoplasm is often used for this purpose as it is simultaneously collected and generally contains the same tissue type as the neoplasm. Following NGS analysis, we and others have frequently observed low-level somatic mutations in these non-neoplastic tissues, which may impose additional challenges to somatic mutation detection as it complicates germline variant filtering. METHODS: We hypothesized that the low-level somatic mutation observed in non-neoplastic tissues may be entirely or partially caused by inadvertent contamination by neoplastic cells during the surgical pathology gross assessment or tissue procurement process. To test this hypothesis, we applied a systematic protocol designed to collect multiple grossly non-neoplastic tissues using different methods surrounding each single neoplasm. The procedure was applied in two breast cancer lumpectomy specimens. In each case, all samples were first sequenced by whole-exome sequencing to identify somatic mutations in the neoplasm and determine their presence in the adjacent non-neoplastic tissues. We then generated ultra-deep coverage using targeted sequencing to assess the levels of contamination in non-neoplastic tissue samples collected under different conditions. RESULTS: Contamination levels in non-neoplastic tissues ranged up to 3.5 and 20.9 % respectively in the two cases tested, with consistent pattern correlated with the manner of grossing and procurement. By carefully controlling the conditions of various steps during this process, we were able to eliminate any detectable contamination in both patients. CONCLUSION: The results demonstrated that the process of tissue procurement contributes to the level of contamination in non-neoplastic tissue, and contamination can be reduced to below detectable levels by using a carefully designed collection method. A standard protocol dedicated for acquiring adjacent non-neoplastic tissue that minimizes neoplasm contamination should be implemented for all somatic mutation detection studies.


Assuntos
Análise Mutacional de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Genoma Humano/genética , Humanos , Mutação , Neoplasias/genética
13.
Endocrinology ; 157(11): 4461-4472, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27611336

RESUMO

First line treatment for recurrent and metastatic prostate cancer is androgen deprivation therapy (ADT). Use of ADT has been increasing in frequency and duration, such that side effects increasingly impact patient quality of life. One of the most significant side effects of ADT is sarcopenia, which leads to a loss of skeletal muscle mass and function, resulting in a clinical disability syndrome known as obese frailty. Using aged mice, we developed a mouse model of ADT-induced sarcopenia that closely resembles the phenotype seen in patients, including loss of skeletal muscle strength, reduced lean muscle mass, and increased adipose tissue. Sarcopenia onset occurred about 6 weeks after castration and was blocked by a soluble receptor (ActRIIB-Fc) that binds multiple TGFß superfamily members, including myostatin, growth differentiation factor 11, activin A, activin B, and activin AB. Analysis of ligand expression in both gastrocnemius and triceps brachii muscles demonstrates that each of these proteins is induced in response to ADT, in 1 of 3 temporal patterns. Specifically, activin A and activin AB levels increase and decline before onset of strength loss at 6 weeks after castration, and myostatin levels increase coincident with the onset of strength loss and then decline. In contrast, activin B and growth differentiation factor 11 levels increase after the onset of strength loss, 8-10 weeks after castration. The observed patterns of ligand induction may represent differential contributions to the development and/or maintenance of sarcopenia. We hypothesize that some or all of these ligands are targets for therapy to ameliorate ADT-induced sarcopenia in prostate cancer patients.


Assuntos
Castração/efeitos adversos , Obesidade/metabolismo , Sarcopenia/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Receptores de Activinas Tipo II/metabolismo , Ativinas/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Fatores de Diferenciação de Crescimento/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Força Muscular/genética , Força Muscular/fisiologia , Miostatina/metabolismo , Obesidade/etiologia
14.
J Biomed Opt ; 21(6): 66019, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27367255

RESUMO

There is an urgent need for sensitive and specific tools to accurately image early stage, organ-confined human prostate cancers to facilitate active surveillance and reduce unnecessary treatment. Recently, we developed an acoustic lens that enhances the sensitivity of photoacoustic imaging. Here, we report the use of this device in conjunction with two molecular imaging agents that specifically target the prostate-specific membrane antigen (PSMA) expressed on the tumor cell surface of most prostate cancers. We demonstrate successful imaging of phantoms containing cancer cells labeled with either of two different PSMA-targeting agents, the ribonucleic acid aptamer A10-3.2 and a urea-based peptidomimetic inhibitor, each linked to the near-infrared dye IRDye800CW. By specifically targeting cells with these agents linked to a dye chosen for optimal signal, we are able to discriminate prostate cancer cells that express PSMA.


Assuntos
Diagnóstico por Imagem/métodos , Técnicas Fotoacústicas , Antígeno Prostático Específico/química , Neoplasias da Próstata/diagnóstico por imagem , Diagnóstico por Imagem/instrumentação , Humanos , Indóis/química , Raios Infravermelhos , Masculino
15.
Adv Drug Deliv Rev ; 98: 35-40, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26724249

RESUMO

Treatment for solid tumor malignancies, which constitute the majority of human cancers, is still dominated by surgery and radiotherapies. This is especially true for many localized solid tumors, which are often curable with these treatments. However, metastatic cancers are beyond the reach of these therapies, and many localized cancers that are initially treated with surgery and radiation will recur and metastasize. Thus, for over 60years there has been a concerted effort to develop effective drug treatments for metastatic cancers. Combination therapies are an increasingly important part of the anti-cancer drug armamentarium. In the case of cytotoxic chemotherapy, multi-drug regimens rapidly became the norm, as the earliest single agents were relatively ineffective. In contrast to chemotherapy, where combination therapies were required in order to achieve treatment efficacy, for both hormonal and targeted therapies the impetus to move toward the use of combination therapies is to prevent or reverse the development of treatment resistance. In addition, emerging evidence suggests that combination therapy may also improve cancer treatment by neutralizing an emerging treatment side effect termed therapy-induced metastasis, which accompanies some effective single agent therapies. Finally, although gene therapy is still far from use in the clinic, we propose that combination therapies may enhance its effectiveness.


Assuntos
Antineoplásicos/administração & dosagem , Terapia Genética , Neoplasias/terapia , Animais , Antineoplásicos/uso terapêutico , Apoptose , Terapia Combinada , Humanos
17.
Oncotarget ; 6(28): 25726-40, 2015 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-26327448

RESUMO

The dramatic responses tumors display to targeted therapies are limited by acquired or pre-existing mechanisms of therapy resistance. We recently discovered that androgen receptor blockade by the anti-androgen enzalutamide paradoxically enhanced metastasis and that these pro-metastatic effects were mediated by the chemoattractant CCL2. CCL2 is regulated by TNF, which is negatively regulated by androgen signaling. Thus, we asked if TNF mediates the pro-metastatic effects of enzalutamide. We found that androgen withdrawal or enzalutamide induced TNF mRNA and protein secretion in castration resistant prostate cancer (C4-2) cells, but not in macrophage-like (THP1) or myofibroblast-like (WPMY1) cells. Androgen deprivation therapy (ADT) induced autocrine CCL2 expression in C4-2 (as well as a murine CRPC cell line), while exogenous TNF induced CCL2 in THP1 and WPMY1. TNF was most potent in myofibroblast cultures, suggesting ADT induces CCL2 via paracrine interactions within the tumor microenvironment. A soluble TNF receptor (etanercept) blocked enzalutamide-induced CCL2 protein secretion and mRNA, implying dependence on secreted TNF. A small molecule inhibitor of CCR2 (the CCL2 receptor) significantly reduced TNF induced migration, while etanercept inhibited enzalutamide-induced migration and invasion of C4-2. Analysis of human prostate cancers suggests that a TNF-CCL2 paracrine loop is induced in response to ADT and might account for some forms of prostate cancer therapy resistance.


Assuntos
Antagonistas de Androgênios/farmacologia , Antineoplásicos Hormonais/farmacologia , Miofibroblastos/efeitos dos fármacos , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Animais , Benzamidas , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Invasividade Neoplásica , Metástase Neoplásica , Nitrilas , Comunicação Parácrina/efeitos dos fármacos , Feniltioidantoína/farmacologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima
18.
BMC Urol ; 15: 97, 2015 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-26391476

RESUMO

BACKGROUND: Genetically engineered mouse models are essential to the investigation of the molecular mechanisms underlying human prostate pathology and the effects of therapy on the diseased prostate. Serial in vivo volumetric imaging expands the scope and accuracy of experimental investigations of models of normal prostate physiology, benign prostatic hyperplasia and prostate cancer, which are otherwise limited by the anatomy of the mouse prostate. Moreover, accurate imaging of hyperplastic and tumorigenic prostates is now recognized as essential to rigorous pre-clinical trials of new therapies. Bioluminescent imaging has been widely used to determine prostate tumor size, but is semi-quantitative at best. Magnetic resonance imaging can determine prostate volume very accurately, but is expensive and has low throughput. We therefore sought to develop and implement a high throughput, low cost, and accurate serial imaging protocol for the mouse prostate. METHODS: We developed a high frequency ultrasound imaging technique employing 3D reconstruction that allows rapid and precise assessment of mouse prostate volume. Wild-type mouse prostates were examined (n = 4) for reproducible baseline imaging, and treatment effects on volume were compared, and blinded data analyzed for intra- and inter-operator assessments of reproducibility by correlation and for Bland-Altman analysis. Examples of benign prostatic hyperplasia mouse model prostate (n = 2) and mouse prostate implantation of orthotopic human prostate cancer tumor and its growth (n = ) are also demonstrated. RESULTS: Serial measurement volume of the mouse prostate revealed that high frequency ultrasound was very precise. Following endocrine manipulation, regression and regrowth of the prostate could be monitored with very low intra- and interobserver variability. This technique was also valuable to monitor the development of prostate growth in a model of benign prostatic hyperplasia. Additionally, we demonstrate accurate ultrasound image-guided implantation of orthotopic tumor xenografts and monitoring of subsequent tumor growth from ~10 to ~750 mm(3) volume. DISCUSSION: High frequency ultrasound imaging allows precise determination of normal, neoplastic and hyperplastic mouse prostate. Low cost and small image size allows incorporation of this imaging modality inside clean animal facilities, and thereby imaging of immunocompromised models. 3D reconstruction for volume determination is easily mastered, and both small and large relative changes in volume are accurately visualized. Ultrasound imaging does not rely on penetration of exogenous imaging agents, and so may therefore better measure poorly vascularized or necrotic diseased tissue, relative to bioluminescent imaging (IVIS). CONCLUSIONS: Our method is precise and reproducible with very low inter- and intra-observer variability. Because it is non-invasive, mouse models of prostatic disease states can be imaged serially, reducing inter-animal variability, and enhancing the power to detect small volume changes following therapeutic intervention.


Assuntos
Interpretação de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Próstata/diagnóstico por imagem , Hiperplasia Prostática/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico por imagem , Ultrassonografia/métodos , Animais , Diagnóstico Diferencial , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
19.
Oncotarget ; 6(14): 12326-39, 2015 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-25940439

RESUMO

High fat dietary intake may increase the risk of prostate cancer (PCa). Pre-adipocytes, one of the basic components in the tumor microenvironment (TME), are capable of differentiating into adipose tissues and play key roles to affect PCa progression. Here we found the pre-adipocytes could be recruited more easily to PCa than its surrounding normal prostate tissue. In vitro co-culture system also confirmed PCa has a better capacity than normal prostate to recruit pre-adipocytes. The consequences of recruiting more pre-adipocytes may then increase PCa cell invasion. Mechanism dissection revealed infiltrating pre-adipocytes might function through down-regulation of the androgen receptor (AR) via modulation of miR-301a, and then increase PCa cell invasion via induction of TGF-ß1/Smad/MMP9 signals. The mouse model with orthotopically xenografted PCa CWR22Rv1 cells with pre-adipocytes also confirmed that infiltrating pre-adipocytes could increase PCa cell invasion via suppressing AR signaling. Together, our results reveal a new mechanism showing pre-adipocytes in the prostate TME can be recruited to PCa to increase PCa metastasis via modulation of the miR-301a/AR/TGF-ß1/Smad/MMP9 signals. Targeting this newly identified signaling may help us to better inhibit PCa metastasis.


Assuntos
Adipócitos/patologia , Invasividade Neoplásica/patologia , Neoplasias da Próstata/patologia , Transdução de Sinais , Células-Tronco/patologia , Microambiente Tumoral/fisiologia , Animais , Western Blotting , Linhagem Celular , Técnicas de Cocultura , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Metástase Neoplásica , Reação em Cadeia da Polimerase em Tempo Real , Receptores Androgênicos/metabolismo , Transdução de Sinais/fisiologia , Proteínas Smad/metabolismo , Transfecção , Fator de Crescimento Transformador beta1/metabolismo
20.
PLoS One ; 10(3): e0121318, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25807461

RESUMO

PLZF is a transcription repressor, which plays a critical role in development, spermatogenesis and oncogenesis. Down-regulation of PLZF has been found in various tumor cell lines. There has been virtually no tissue study on the expression of PLZF in prostate cancer (PCa). PCa is a heterogeneous disease, most of which are indolent and non-lethal. Currently there are no biomarkers that distinguish indolent from aggressive PCa; therefore there is an urgent need for such markers to provide clinical decision support. This study aimed to investigate the expression of PLZF by immunohistochemistry in different grade as well as metastatic PCa and to correlate the alteration of PLZF expression with PCa aggressiveness. We studied a total of 83 primary PCa from biopsies, 43 metastatic PCa and 8 paired primary and metastatic PCa from radical prostatectomies with lymph node dissection. Our results demonstrated that PLZF was strongly expressed in almost all (~100%) benign luminal cells (n=77) and low grade (Gleason pattern 3) PCa (n=70) and weak or absent (100%) in basal cells (n=70). Decreased or lost expression of PLZF was evidenced in 26% of high-grade (Gleason 4 and 5) primary PCa (n=70) and 84% metastatic PCa (n=43). The primary high grade PCa in the prostatectomies shared similar PLZF loss/decrease and histomorphology to that of paired parallel lymph node metastases. These data demonstrated that down-regulation of PLZF is an important molecular process for tumor progression and loss of PLZF expression detected by routine immunohistochemistry is a promising and valuable biomarker for PCa aggressiveness and metastasis in the personalized care of PCa.


Assuntos
Adenocarcinoma/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Invasividade Neoplásica/patologia , Metástase Neoplásica/patologia , Neoplasias da Próstata/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Progressão da Doença , Humanos , Imuno-Histoquímica , Excisão de Linfonodo , Masculino , Gradação de Tumores , Proteína com Dedos de Zinco da Leucemia Promielocítica , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia
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