Androgen receptor signaling and mutations in prostate cancer

Normal and neoplastic growth of the prostate gland are dependent on androgen receptor （AR） expression and function. Androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-independent （AI） progression of the disease. In addition, cross-modulation by various nuclear transcription factors acting through basal transcriptional machinery could positively or negatively affect the AR or AR target genes expression and activity. Androgen ablation leads to an initial favorable response in a significant number of patients; however, almost invariably patients relapse with an aggressive form of the disease known as castration-resistant or hormone-refractory prostate cancer （PCa）. Understanding critical molecular events that lead PCa cells to resist androgen-deprivation therapy is essential in developing successful treatments for hormone-refractory disease. In a significant number of hormone-refractory patients, the AR is overexpressed, mutated or genomically amplified. These genetic alterations maintain an active presence for a highly sensitive AR, which is responsive to androgens, antiandrogens or nonandrogenic hormones and collectively confer a selective growth advantage to PCa cells. This review provides a brief synopsis of the AR structure, AR coregulators, posttranslational modifications of AR, duality of AR function in prostate epithelial and stromal cells, AR-dependent signaling, genetic changes in the form of somatic and germline mutations and their known functional significance in PCa cells and tissues.

Saposin C stimulates growth and invasion,activates p42/44 and SAPK/JNK signaling pathways of MAPK and upregulates uPA/uPAR expression in prostate cancer and stromal cells

Aim:To determine the effect of saposin C (a known trophic domain of prosaposin) on proliferation,migration and invasion,as well as its effect on the expression of urokinase plasmonogen activator (uPA),its receptor (uPAR) and matrix metalloproteinases (MMP)-2 and -9 in normal and malignant prostate cells.In addition,we tested whether saposin C can activate p42/44 and stress-activated protein kinase/c-Jun NH_2-terminal kinase (SAPK/JNK) signal transduction pathways of the mitogen-activated protein kinase (MAPK) superfamily.Methods:We employed West- ern blot analysis,phospho-specific antibodies,cell proliferation assay,reverse transcriptase-polymerase chain reaction, in vitro kinase assays and migration and invasion to determine the effect of saposin C on various biological behaviors of prostate stromal and cancer cells.Results:Saposin C,in a cell type-specific manner,upregulates uPA/uPAR and immediate early gene c-Jun expression,stimulates cell proliferation,migration and invasion and activates p42/44 and SAPK/JNK MAPK pathways in prostate stromal and cancer cells.Normal prostate epithelial cells were not responsive to saposin C treatment in the above studies.Conclusion:Saposin C functions as a multipotential modulator of diverse biological activities in prostate cancer and stromal cells.These results strongly suggest that saposin C functions as a potent growth factor for prostatic cells and may contribute to prostate carcinogenesis and/or the development of hormone-refractory prostate cancer.

Identification of speckle-type POZ protein somatic mutations in African American prostate cancer

The speckle-type POZ protein （SPOP） is a tumor suppressor in prostate cancer （PCa）. SPOP somatic mutations have been reported in up to 15% of PCa of those of European descent. However, the genetic roles of SPOP in African American （AA）-PCa are currently unknown. We sequenced the SPOP gene to identify somatic mutations in 49 AA prostate tumors and identified three missense mutations （p.Y87C, p.F102S, and p.G111E） in five AA prostate tumors （10%） and one synonymous variant （p.11061） in one tumor. Intriguingly, all of mutations and variants clustered in exon six, and all of the mutations altered conserved amino acids. Moreover, two mutations （p.F102S and p.G111E） have only been identified in AA-PCa to date. Quantitative real-time polymerase chain reaction analysis showed a lower level of SPOP expression in tumors carrying SPOP mutations than their matched normal prostate tissues. In addition, SPOP mutations and novel variants were detected in 5 of 27 aggressive PCa and one of 22 less aggressive PCa （P 〈 0.05）. Further studies with increased sample size are needed to validate the clinicopathological significance of these SPOP mutations in AA-PCa.

Human prostate cancer heterotransplants： a review on this experimental model

A common model used for preclinical research was in vitro human tumor cell culture. An alternative model was the direct implantation of a unique patient＇s tumor biopsy specimens into immunodeficient host mice. Published data from PubMed （http：//www.ncbi.nlm.nih.gov） and Current Contents Connect databases （http：//thomsonreuters.com/ products_services/science/science_roducts/a-z/current_contents_connect） were reviewed. Prostate cancer （PCa） heterotransplantation was evaluated using histopathology, morphology, cell differentiation, DNA content, tumor marker expression, metastases, tumor kinetics, tumor take rate and tumor vasculature in the first tumor heterotransplant. The heterotransplanted tumor retained the biological properties of the original tumor, such as morphology, degree of differentiation, pathology, secretory activity, expression of tumor markers and human vasculature. Human PCa heterotransplants have considerable experimental advantages over cell culture following xenotransplantation.

Comment on ＂Effect of transferred NK4 gene on proliferation, migration, invasion, and apoptosis of human prostate cancer DU145 cells＂ by Dan Yue et al. in Asian Journal of Androtogy

Hepatocyte growth factor/scatter factor （HGF/SF） interacting with its cell surface receptor tyrosine kinase （RTK） c-met proto-oncogene drives downstream signaling pathways which lead to cell proliferation, migration, invasion, apoptotic cell-death protection, angiogenesis during embryogenesis, repair and regeneration, and neoplastic growth and metastatic progression [1-6].

A facile,branched DNA assay to quantitatively measure glucocorticoid receptor auto-regulation in T-cell acute lymphoblastic leukemia

Glucocorticoid(GC) steroid hormones are used to treat acute lymphoblastic leukemia(ALL) because of their pro-apoptotic effects in hematopoietic cells.However,not all leukemia cells are sensitive to GC,and no assay to stratify patients is available.In the GC-sensitive T-cell ALL cell line CEM-C7,auto-up-regulation of RNA transcripts for the glucocorticoid receptor(GR) correlates with increased apoptotic response.This study aimed to determine if a facile assay of GR transcript levels might be promising for stratifying ALL patients into hormone-sensitive and hormone-resistant populations.The GR transcript profiles of various lymphoid cell lines and 4 bone marrow samples from patients with T-cell ALL were analyzed using both an optimized branched DNA(bDNA) assay and a real-time quantitative reverse transcription-polymerase chain reaction assay.There were significant correlations between both assay platforms when measuring total GR(exon 5/6) transcripts in various cell lines and patient samples,but not for a probe set that detects a specific,low abundance GR transcript(exon 1A3).Our results suggest that the bDNA platform is reproducible and precise when measuring total GR transcripts and,with further development,may ultimately offer a simple clinical assay to aid in the prediction of GC-sensitivity in ALL patients.

HER3-targeted therapeutic antibodies and antibody-drug conjugates in non-small cell lung cancer refractory to EGFR-tyrosine kinase inhibitors

Human epidermal growth factor receptor 3(HER3)is a unique member of the human epidermal growth factor receptor(HER/EGFR)family,since it has negligible kinase activity.Therefore,HER3 must interact with a kinase-proficient receptor to form a heterodimer,leading to the activation of signaling cascades.Overexpression of HER3 is observed in various human cancers,including non-small cell lung cancer(NSCLC),and correlates with poor clinical outcomes in patients.Studies on the underlying mechanism demonstrate that HER3-initiated signaling promotes tumor metastasis and causes treatment failure in human cancers.Upregulation of HER3 is frequently observed in EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors(TKIs).Increased expression of HER3 triggers the so-called EGFR-independent mechanism via interactions with other receptors to activate“by-pass signaling pathways”,thereby resulting in resistance to EGFR-TKIs.To date,no HER3-targeted therapy has been approved for cancer treatment.In both preclinical and clinical studies,targeting HER3 with a blocking an-tibody(Ab)is the only strategy being examined.Recent evaluations of an anti-HER3 Ab-drug conjugate(ADC)show promising results in patients with EGFR-TKI-resistant NSCLC.Herein,we summarize our understanding of the unique biology of HER3 in NSCLC refractory to EGFR-TKIs,with a focus on its dimerization partners and subsequent activation of signaling pathways.We also discuss the latest development of the therapeutic Abs and ADCs targeting HER3 to abrogate EGFR-TKI resistance in NSCLC.

FLT3在急性白血病靶向治疗中的研究进展

FMS-like Tyrosine Kinase 3(FLT3)是一种受体酪氨酸激酶,在造血干细胞、前体B细胞等的增殖、分化以及存活中具有重要作用。急性白血病的发病往往伴随着FLT3的异常活化,FLT3突变是造成其异常活化的主要原因,且FLT3突变的患者往往具有较差的预后。FLT3抑制剂的研究为白血病靶向治疗提供了广阔的前景。

MicroRNAs mediate therapeutic and preventive effects of natural agents in breast cancer

MicroRNAs(miRNAs) are a set of non-coding small RNA molecules that play a critical role in regulation of protein coding genes in cells. Mi RNAs have been extensively studied as novel biomarkers, therapeutic targets, and new drugs in various human diseases. Breast cancer is a one of the leading tumor types significantly affecting women health worldwide. Over the past decade, a number of natural agents, such as paclitaxel and curcumin, have been applied for treatment and prevention of breast cancer due to their relatively low toxicity. However, the mechanisms of action have not been completely understood. Investigation on mi RNAs is able to potentially provide a novel insight into better understanding the anticancer activities of these natural products. Given that a single miRNA can target multiple genes, theoretically, those genes involved in a certain phenotype can be clustered with one or a few miRNAs. Therefore, pleiotropic activities of natural agents should be interpreted by interactions between selected miRNAs and their targets. In this review, we summarize the latest publications related to the alterations of mi RNAs by two natural agents(paclitaxel and curcumin) that are currently used in intervention of breast cancer, and conclude that the mechanism involving the regulation of miRNA expression is one of the keys to understand pleiotropic activities of natural agents.

Oridonin and its derivatives for cancer treatment and vercoming therapeutic resistance

Cancer is one of the diseases with high morbidity and mortality on a global scale.Chemotherapy remains the primary treatment option for most cancer patients,including patients with progressive,metastatic,and recurrent diseases.To date,hundreds of chemotherapy drugs are used to treat various cancers,however,the anti-cancer eficacy and outcomes are largely hampered by chemotherapy-associated toxicity and acquired therapeutic resistance.The natural product(NP)oridonin has been extensively studied for its anti-cancer efficacy.More recently,oridonin has been shown to overcome drug resistance through multiple mechanisms,with yet-to-be-defined bona fide targets.Hundreds of oridonin derivative analogs(oridonalogs)have been synthesized and screened for improved potency,bioavailability,and other drug properties.Particularly,many of these oridonalogs have been tested against oridonin for tumor growth inhibition,potential for overcoming therapeutic resistance,and immunity modulation.This concise review seeks to summarize the advances in this field in light of identifying clinical-trial level drug candidates with the promise for treating progressive cancers and reversing chemoresistance.

前列腺的小细胞神经内分泌癌：异种移植是一个更好的实验模型吗？

前列腺小细胞神经内分泌癌（SCNCP）是一种罕见的前列腺癌，临床恶性程度高，预后差，对其研究在临床上具有重大意义。目前，研究SCNCP的方法有人工肿瘤细胞系培养法，还有将从患者身上直接获得的新鲜肿瘤组织切片植入免疫缺陷宿主小鼠体内的方法。本综述的目的是整合20多年在前列腺小细胞神经内分泌癌的异种移植的研究数据。异种移植提供的有关数据包括组织病理学、核型、DNA含量、细胞周期频率、肿瘤标志物、雄激素受体表达、转移和成功率。我们尽可能的比较了患者体内获得的原始原位切片和宿主小鼠异种移植组织，发现小细胞神经内分泌前列腺癌异种移植与培养细胞异源移植相比各有千秋。总体而言，肿瘤异种移植均优于传统的异源移植，主要表现在保持肿瘤形态、病理、分泌活动和病人原始样本肿瘤标记物的表达等方面。此外，异种移植组织保留了前列腺肿瘤的三维结构，以保持其关键的基质上皮细胞相互作用。

Cyclin G2,a novel target of sulindac to inhibit cell cycle progression in colorectal cancer

Sulindac has shown significant clinical benefit in preventing colorectal cancer pro-gression,but its mechanism of action has not been fully elucidated.We have found that sulin-dac sulfide(SS)is able to inhibit cell cycle progression in human colorectal cancer cells,particularly through G1 arrest.To understand the underlying mechanisms of sulindac inhibitory activity,we have demonstrated that Cyclin G2 up-regulation upon SS treatment can substan-tially delay cell cycle progression by enhancing the transcriptional activity of FOXO3a in human colorectal tumor cells.MiR-182,an oncogenic microRNA known to inhibit FOXO3a gene expres-sion,is also involved in the suppressive effect of SS on cell cycle progression.This process be-gins with the down-regulation of miR-182,followed by the enhancement of FOXO3a transcriptional activity and the up-regulation of Cyclin G2.To further determine the clinical utility of this axis,we analyzed the expression of miR-182/FOXO3a/Cyclin G2 in human colo-rectal tumor samples.Our results show not only that there are significant dfferences in miR-182/FOXO3a/Cyclin G2 between tumors and normal tissues,but also that the synergetic effect of miR-182 and FOXO3a is associated with predicting tumor progression.Our study dem-onstrates a novel mechanistic axis consisting of miR-182/FOXO3a/Cyclin G2 that mediates su-lindac inhibition of cell cycle progression.

Targeted lapatinib anti-HER2/ErbB2 therapy resistance in breast cancer:opportunities to overcome a difficult problem

Approximately 20%of invasive breast cancers have upregulation/gene amplification of the oncogene human epidermal growth factor receptor-2(HER2/ErbB2).Of these,some also express steroid receptors(the so-called Luminal B subtype),whereas others do not(the HER2 subtype).HER2 abnormal breast cancers are associated with a worse prognosis,chemotherapy resistance,and sensitivity to selected anti-HER2 targeted therapeutics.Transcriptional data from over 3000 invasive breast cancers suggest that this approach is overly simplistic;rather,the upregulation of HER2 expression resulting from gene amplification is a driver event that causes major transcriptional changes involving numerous genes and pathways in breast cancer cells.Most notably,this includes a shift from estrogenic dependence to regulatory controls driven by other nuclear receptors,particularly the androgen receptor.We discuss members of the HER receptor tyrosine kinase family,heterodimer formation,and downstream signaling,with a focus on HER2 associated pathology in breast carcinogenesis.The development and application of anti-HER2 drugs,including selected clinical trials,are discussed.In light of the many excellent reviews in the clinical literature,our emphasis is on recently developed and successful strategies to overcome targeted therapy resistance.These include combining anti-HER2 agents with programmed cell death-1 ligand or cyclin-dependent kinase 4/6 inhibitors,targeting crosstalk between HER2 and other nuclear receptors,lipid/cholesterol synthesis to inhibit receptor tyrosine kinase activation,and metformin,a broadly inhibitory drug.We seek to facilitate a better understanding of new approaches to overcome anti-HER2 drug resistance and encourage exploration of two other therapeutic interventions that may be clinically useful for HER+invasive breast cancer patients.

Neuroendocrine tumors:current therapies,notch signaling,and cancer stem cells

Neuroendocrine tumors(NETs)encompass a broad spectrum of malignancies all derived from neuroendocrine cell lineage,affecting many different organs including the gastrointestinal(GI)tract,the endocrine pancreas,the thyroid,the skin and the respiratory tract.These tumors as a group are very heterogeneous,with varying characteristics attributed to each tissue of origin and tumor subtype.The pathogenesis of the different subtypes of NETs is not fully understood,but recent studies suggest the Notch signaling pathway may be dysregulated in these tumors either by under or overexpression of Notch receptors and/or ligands,or by disruption of pathway functionality through other means.Notch receptors can function as tumor suppressors in some cellular contexts and oncogenes in others which may,in part,account for the wide range of phenotypes present in NETs.Cancer stem cells are present in these tumors and may be responsible for the high rate of chemotherapy resistance,recurrence and metastasis.The heterogeneity of NETs suggests that to fully understand the role of Notch signaling and the therapeutic implications thereof,a comprehensive and systematic analysis of Notch expression and function across all NET subtypes is required.Here we outline the current knowledge base with respect to current therapies and Notch signaling in neuroendocrine tumors of the lung,skin,thyroid,GI tract and endocrine pancreas.

The cellular metabolic landscape in the tumor milieu regulates the activity of myeloid infiltrates

Malignant cells upregulate distinct energy metabolism programs that support their proliferation,migration,and adaptation to the stressful tumor microenvironment(TME).Additionally,this exaggerated metabolic activity allows cancer cells to hijack essential nutrients and outcompete neighboring infiltrating immune cells,thereby impairing antitumor immunity.During recent years,there has been great interest in the field to understand the tumor-induced energy metabolism signals that regulate the function of immune cells in individuals with cancer.Accordingly,it is now well accepted that uncovering the mechanisms that instruct the metabolic behavior of cancer cells and tumor-associated immune cells is an indispensable strategy for the development of new approaches to overcome immune suppression in tumors.Thus,in this minireview,we briefly discuss the interaction between particular metabolic signaling pathways and immunosuppressive activity in different subsets of myeloid cells within the TME.Additionally,we illustrate potential central mechanisms controlling the metabolic reprogramming of myeloid cells in response to tumor-derived factors.