Synthesis and anti-cancer potential of potent peripheral MAOA inhibitors designed to limit blood:brain penetration.

Monoamine oxidases (MAOA/MAOB) are enzymes known for their role in neurotransmitter regulation in the central nervous system (CNS). Irreversible and non-selective MAO inhibitors (MAOi's) were the first class of antidepressants, thus subsequent work on drugs such as the selective MAOA inhibitor clorgyline has focussed on selectivity and increased CNS penetration. MAOA is highly expressed in high grade and metastatic prostate cancer with a proposed effect on prostate cancer growth, recurrence, and drug resistance.

Non-Thermal, Selective Cancer Treatment With High-Frequency Medium-Intensity Focused Ultrasound.

Focused ultrasound (FUS) has proven its efficacy in non-invasive, radiation-free cancer treatment. However, the commonly used low-frequency high-intensity focused ultrasound (HIFU) destroys both cancerous and healthy tissues non-specifically through extreme heat and inertial cavitation with low spatial resolution. To address this issue, we evaluate the therapeutic effects of pulsed (60 Hz pulse repetition frequency, 1.

CCR2-targeted micelles for anti-cancer peptide delivery and immune stimulation.

Signaling between the CC chemokine receptor 2 (CCR2) with its ligand, monocyte chemoattractant protein-1 (MCP-1) promotes cancer progression by directly stimulating tumor cell proliferation and downregulating the expression of apoptotic proteins. Additionally, the MCP-1/CCR2 signaling axis drives the migration of circulating monocytes into the tumor microenvironment, where they mature into tumor-associated macrophages (TAMs) that promote disease progression through induction of angiogenesis, tissue remodeling, and suppression of the cytotoxic T lymphocyte (CTL) response. In order to simultaneously disrupt MCP-1/CCR2 signaling and target CCR2-expressing cancer cells for drug delivery, KLAK-MCP-1 micelles consisting of a CCR2-targeting peptide sequence (MCP-1 peptide) and the apoptotic KLAKLAK peptide were synthesized.

MAOA-mediated reprogramming of stromal fibroblasts promotes prostate tumorigenesis and cancer stemness.

The tumor microenvironment plays a critical role in prostate cancer (PC) development and progression. Inappropriate activation of the stroma potentiates the growth and transformation of epithelial tumor cells. Here, we show that upregulation of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, in stromal cells elevates production of reactive oxygen species, triggers an inflammatory response including activation of IL-6, and promotes tumorigenesis in vitro and in vivo.

Effect of Monoamine oxidase A (MAOA) inhibitors on androgen-sensitive and castration-resistant prostate cancer cells.

Background: Monoamine oxidase A (MAOA) is best known for its role in neuro-transmitter regulation. Monoamine oxidase inhibitors are used to treat atypical depression. MAOA is highly expressed in high grade prostate cancer and modulates tumorigenesis and progression in prostate cancer.

Loss of MAOA in epithelia inhibits adenocarcinoma development, cell proliferation and cancer stem cells in prostate.

Monoamine oxidase A (MAOA) is a mitochondrial enzyme, which degrades monoamine neurotransmitters and dietary amines and produces HO. Recent studies have shown increased MAOA expression in prostate cancer (PCa), glioma, and classical Hodgkin lymphoma. However, the biological function of MAOA in cancer development remains unknown.

Monoamine Oxidase Deficiency Causes Prostate Atrophy and Reduces Prostate Progenitor Cell Activity.

Monoamine oxidases (MAOs) degrade a number of biogenic and dietary amines, including monoamine neurotransmitters, and play an essential role in many biological processes. Neurotransmitters and related neural events have been shown to participate in the development, differentiation, and maintenance of diverse tissues and organs by regulating the specialized cellular function and morphological structures of innervated organs such as the prostate. Here we show that mice lacking both MAO isoforms, MAOA and MAOB, exhibit smaller prostate mass and develop epithelial atrophy in the ventral and dorsolateral prostates.

Androgen receptor in cancer-associated fibroblasts influences stemness in cancer cells.

Androgen receptor (AR) regulation pathways are essential for supporting the growth and survival of prostate cancer cells. Recently, sub-populations of prostate cancer cells have been identified with stem cell features and are associated with the emergence of treatment-resistant prostate cancer. Here, we explored the function of AR in prostate cancer-associated fibroblasts (CAFs) relative to growth and stem cell-associated characteristics.

Expression and functional role of orphan receptor GPR158 in prostate cancer growth and progression.

Prostate cancer (PCa) is the second-leading cause of cancer-related mortality, after lung cancer, in men from developed countries. In its early stages, primary tumor growth is dependent on androgens, thus generally can be controlled by androgen deprivation therapy (ADT). Eventually however, the disease progresses to castration-resistant prostate cancer (CRPC), a lethal form in need of more effective treatments.

Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis.

Tumors from patients with high-grade aggressive prostate cancer (PCa) exhibit increased expression of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines. Despite the association between MAOA and aggressive PCa, it is unclear how MAOA promotes PCa progression. Here, we found that MAOA functions to induce epithelial-to-mesenchymal transition (EMT) and stabilize the transcription factor HIF1α, which mediates hypoxia through an elevation of ROS, thus enhancing growth, invasiveness, and metastasis of PCa cells.

Dependence of castration-resistant prostate cancer (CRPC) stem cells on CRPC-associated fibroblasts.

We previously established a role for cancer-associated fibroblasts (CAF) in enhancing the self-renewal and differentiation potentials of putative prostate cancer stem cells (CSC). Our published work focused on androgen-dependent prostate cancer (ADPC) using the conditional Pten deletion mouse model. Employing the same model, we now describe the interaction of CAF and CSC in castration-resistant prostate cancer (CRPC).

Detection of live circulating tumor cells by a class of near-infrared heptamethine carbocyanine dyes in patients with localized and metastatic prostate cancer.

Tumor cells are inherently heterogeneous and often exhibit diminished adhesion, resulting in the shedding of tumor cells into the circulation to form circulating tumor cells (CTCs). A fraction of these are live CTCs with potential of metastatic colonization whereas others are at various stages of apoptosis making them likely to be less relevant to understanding the disease. Isolation and characterization of live CTCs may augment information yielded by standard enumeration to help physicians to more accurately establish diagnosis, choose therapy, monitor response, and provide prognosis.

CAF-secreted annexin A1 induces prostate cancer cells to gain stem cell-like features.

Unlabelled: Annexin A1 (AnxA1), a phospholipid-binding protein and regulator of glucocorticoid-induced inflammatory signaling, has implications in cancer. Here, a role for AnxA1 in prostate adenocarcinoma was determined using primary cultures and a tumor cell line (cE1), all derived from the conditional Pten deletion mouse model of prostate cancer. AnxA1 secretion by prostate-derived cancer-associated fibroblasts (CAF) was significantly higher than by normal prostate fibroblasts (NPF).

Contextual effect of repression of bone morphogenetic protein activity in prostate cancer.

Several studies have focused on the effect of bone morphogenetic protein (BMP) on prostate cancer homing and growth at distant metastatic sites, but very little effect at the primary site. Here, we used two cell lines, one (E8) isolated from a primary tumor and the other (cE1) from a recurrent tumor arising at the primary site, both from the conditional Pten deletion mouse model of prostatic adenocarcinoma. Over-expression of the BMP antagonist noggin inhibited proliferation of cE1 cells in vitro while enhancing their ability to migrate.

Loss of survivin in the prostate epithelium impedes carcinogenesis in a mouse model of prostate adenocarcinoma.

The inhibitor of apoptosis protein survivin is expressed in most cancers. Using the conditional PTEN deletion mouse model, we previously reported that survivin levels increase with prostate tumor growth. Here we evaluated the functional role of survivin in prostate tumor growth.

α(V)β(6) integrin expression is induced in the POET and Pten(pc-/-) mouse models of prostatic inflammation and prostatic adenocarcinoma.

Chronic inflammation is proposed to prime the development of prostate cancer. However, the mechanisms of prostate cancer initiation and development are not completely understood. The α(v)β(6) integrin has been shown to play a role in epithelial development, wound healing and some epithelial cancers [1, 2].

An enhancer from the 8q24 prostate cancer risk region is sufficient to direct reporter gene expression to a subset of prostate stem-like epithelial cells in transgenic mice.

Regions in the 8q24 gene desert contribute significantly to the risk of prostate cancer and other adult cancers. This region contains several DNA regions with enhancer activity in cultured cells. One such segment, histone acetylation peak 10 (AcP10), contains a risk single nucleotide polymorphism (SNP) that is significantly associated with the pathogenesis of colorectal, prostate and other cancers.

Cancer stem cells and microenvironment in prostate cancer progression.

For a study of interactions between the cancer-associated fibroblasts (CAFs) and the putative prostate cancer stem cells (CSCs), we used a conditional Pten deletion mouse model of prostatic adenocarcinoma to isolate both CAF cultures and CSC-enriched cell fractions from the primary tumors. The CSC subpopulation exhibited a collective phenotype of Lin(-)/SCA-1(hi)/CD49f(hi)/p63(hi)/CK5(hi)/AR(lo)/CK18(lo)/Survivin(hi)/Runx2(hi) and contained cells with the ability to both self-renew and differentiate into basal and luminal cells in vitro. The spheroids generated from the CSC-enriched subpopulation mimicked the glandular structures that could be produced from a similarly isolated cell fraction from the normal mouse prostate.

TPL2/COT/MAP3K8 (TPL2) activation promotes androgen depletion-independent (ADI) prostate cancer growth.

Background: Despite its initial positive response to hormone ablation therapy, prostate cancers invariably recur in more aggressive, treatment resistant forms. The lack of our understanding of underlying genetic alterations for the transition from androgen-dependent (AD) to ADI prostate cancer growth hampers our ability to develop target-driven therapeutic strategies for the efficient treatment of ADI prostate cancer.

Methodology/principal Findings: By screening a library of activated human kinases, we have identified TPL2, encoding a serine/threonine kinase, as driving ADI prostate cancer growth.

Cancer-associated fibroblasts enhance the gland-forming capability of prostate cancer stem cells.

Signals originating from cancer-associated fibroblasts (CAF) may positively regulate proliferation and tumorigenicity in prostate cancer. In this study, we investigated whether CAFs may regulate the biology of prostate cancer stem cells (CSC) by using a conditional Pten deletion mouse model of prostate adenocarcinoma to isolate both CAF cultures and CSC-enriched cell fractions from the tumors. CSCs that were isolated possessed self-renewal, spheroid-forming, and multipotential differentiation activities in tissue culture, segregating with a cell fraction exhibiting a signature expression phenotype, including SCA-1 (high), CD49f (high), CK5 (high), p63 (high), Survivin (high), RUNX2 (high), CD44 (low), CD133 (low), CK18 (low), and Androgen Receptor (low).

Mouse prostate cancer cell lines established from primary and postcastration recurrent tumors.

The clinical course of prostate cancer is grouped into two broad phases. The first phase, which is the growth of the androgen-dependent cancer (AD-Ca) responds well to androgen depletion treatment while the second phase, that could be termed as androgen depletion-independent cancer (ADI-Ca) does not. We used two separate prostate tumors, one AD-Ca and one ADI-Ca from the conditional Pten deletion mouse model to generate from each a pair of cell lines.

Reprogramming murine telomerase rapidly inhibits the growth of mouse cancer cells in vitro and in vivo.

Telomerase plays a critical role in cancer, prompting the pursuit of various telomerase-based therapeutic strategies. One such strategy, telomerase interference, exploits the high telomerase activity in cancer cells and reprograms telomerase to encode "toxic" telomeres. To date, telomerase interference has been tested in human cancer cells xenografted into mice, an approach that does not recapitulate spontaneous malignancy and offers few insights about host toxicities, because human telomerase is targeted in a mouse host.

Identification of a novel common proviral integration site, flit-1, in feline leukemia virus induced thymic lymphoma.

A new proviral integration site for feline leukemia virus (FeLV), termed flit-1, was identified from feline thymic lymphoma. Among 35 FeLV-related tumors examined, 5 of 25 thymic lymphomas demonstrated proviral insertion within flit-1 locus whereas none of four alimentary and five multicentric lymphomas and one T-lymphoid leukemia examined had rearrangement in this region. Extensive sequence analysis has shown that flit-1, which is noncoding, is conserved on human chromosome 12 and mouse chromosome 15.

Pten null prostate tumorigenesis and AKT activation are blocked by targeted knockout of ER chaperone GRP78/BiP in prostate epithelium.

GRP78/BiP has recently emerged as a novel biomarker for aggressive prostate cancer. Here, we report that homozygous deletion of Grp78 specifically in mouse prostate epithelium suppresses prostate tumorigenesis without affecting postnatal prostate development and growth. Mouse prostates with double conditional knockout of Grp78 and Pten exhibit normal histology and cytology, in contrast to the invasive adenocarcinoma in mouse prostates with Pten inactivation.

PTEN knockout prostate cancer as a model for experimental immunotherapy.

Purpose: Testing immunotherapeutic strategies for prostate cancer has been impeded by the lack of relevant tumor models in immunocompetent animals. This opportunity is now provided by the recent development of prostate specific PTEN knockout mice, which show spontaneous development of true adenocarcinoma arising from prostate epithelium and more faithfully recapitulate the human disease than any previous model. We investigated the feasibility of using tumor cells derived from this model to test tumor vaccination and adoptive immunotherapeutic strategies for prostate cancer.