Androgen deprivation triggers a cytokine signaling switch to induce immune suppression and prostate cancer recurrence.

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.

Rate of castration-induced prostate stroma regression is reduced in a mouse model of benign prostatic hyperplasia.

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.

TNF Signaling Is Required for Castration-Induced Vascular Damage Preceding Prostate Cancer Regression.

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.

Loss of MAGEC3 Expression Is Associated with Prognosis in Advanced Ovarian Cancers.

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 = 394 advanced ovarian cancers, assessed the correlation of these values with clinicopathologic and immunological features and modeled survival using univariate and multivariate models.

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma.

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.

Prostate tumor-derived GDF11 accelerates androgen deprivation therapy-induced sarcopenia.

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.

Validation of Melanoma Immune Profile (MIP), a Prognostic Immune Gene Prediction Score for Stage II-III Melanoma.

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.

Castration induces satellite cell activation that contributes to skeletal muscle maintenance.

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.

Paternal lineage early onset hereditary ovarian cancers: A Familial Ovarian Cancer Registry study.

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.

Infiltrating Myeloid Cells Exert Protumorigenic Actions via Neutrophil Elastase.

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.

MicroRNA-141 suppresses prostate cancer stem cells and metastasis by targeting a cohort of pro-metastasis genes.

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.

TGFβ Superfamily Members Mediate Androgen Deprivation Therapy-Induced Obese Frailty in Male Mice.

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.

Pitfalls of improperly procured adjacent non-neoplastic tissue for somatic mutation analysis using next-generation sequencing.

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.

Photoacoustic imaging with an acoustic lens detects prostate cancer cells labeled with PSMA-targeting near-infrared dye-conjugates.

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.

Opportunities and challenges in combination gene cancer therapy.

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.

Quantitative volumetric imaging of normal, neoplastic and hyperplastic mouse prostate using ultrasound.

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.

TNF signaling mediates an enzalutamide-induced metastatic phenotype of prostate cancer and microenvironment cell co-cultures.

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.

Infiltrated pre-adipocytes increase prostate cancer metastasis via modulation of the miR-301a/androgen receptor (AR)/TGF-β1/Smad/MMP9 signals.

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.

Loss of PLZF expression in prostate cancer by immunohistochemistry correlates with tumor aggressiveness and metastasis.

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).

Laminated microfluidic system for small sample protein analysis.

We describe a technology based on lamination that allows for the production of highly integrated 3D devices suitable for performing a wide variety of microfluidic assays. This approach uses a suite of microfluidic coupons ("microfloupons") that are intended to be stacked as needed to produce an assay of interest. Microfloupons may be manufactured in paper, plastic, gels, or other materials, in advance, by different manufacturers, then assembled by the assay designer as needed.

Sequential proteolytic processing of an interferon-alpha receptor subunit by TNF-alpha converting enzyme and presenilins.

It is well established that interferons trigger tyrosine-kinase-dependent signaling via JAK kinases and STAT transcription factors. However, we have observed both IFNaR2 receptor cleavage and functional activity of the liberated intracellular domain (ICD), suggesting that interferon-alpha (IFN-alpha) can also signal via regulated intramembrane proteolysis (RIP), an evolutionarily conserved mechanism of receptor-mediated signaling. Sequential cleavage of the receptor ectodomain and transmembrane domain is a hallmark of the most common class of RIP.

TNF is necessary for castration-induced prostate regression, whereas TRAIL and FasL are dispensable.

TNF, a proinflammatory and immune-regulatory cytokine, is a potent apoptotic stimulus in vitro. However, there have been few examples of a physiologic role for TNF-induced apoptosis in vivo. Here, we describe a novel role for TNF in prostate epithelial cell apoptosis after androgen withdrawal.

Transforming growth factor beta1 induces apoptosis by suppressing FLICE-like inhibitory protein in DU145 prostate epithelial cells.

Transforming growth factor beta (TGFbeta) is a paracrine mediator of prostate epithelial cell apoptosis. In rodents, castration induces production of TGFbeta by stromal cells, which leads to apoptosis of epithelial cells. To identify potential mediators of this cell death pathway, we developed a model using DU145 cells, a tumorigenic human prostate epithelial cell line.

FLIP-ping out: death receptor signaling in the prostate.

Prostate cancer is a leading cause of cancer related death. The growth of normal prostate epithelial cells is under the tight control of various growth factors, most notably androgens, such that castration leads to apoptosis of this cell population. Androgen-depletion has a similar effect on prostate cancers; however, following initial regression tumors often return in an androgen-depletion independent form that is frequently lethal.