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Prostate cancer is a prevalent public health problem, especially because noncutaneous advanced malignant forms significantly affect the lifespan and quality of life of men worldwide. New therapeutic targets and approaches are urgently needed. The current study reports elevated expression of R1 (CDCA7L/RAM2/JPO2), a c-Myc–interacting protein and transcription factor, in human prostate cancer tissue specimens. In a clinical cohort, high R1 expression is associated with disease recurrence and decreased patient survival. Overexpression and knockdown of R1 in human prostate cancer cells indicate that R1 induces cell proliferation and colony formation. Moreover, silencing R1 dramatically reduces the growth of prostate tumor xenografts in mice. Mechanistically, R1 increases c-Myc protein stability by inhibiting ubiquitination and proteolysis through transcriptional suppression of HUWE1, a c-Myc–targeting E3 ligase, via direct interaction with a binding element in the promoter. Moreover, transcriptional repression is supported by a negative coexpression correlation between R1 and HUWE1 in a prostate cancer clinical dataset. Collectively, these findings, for the first time, characterize the contribution of R1 to prostate cancer pathogenesis. Implications: These findings provide evidence that R1 is a novel regulator of prostate tumor growth by stabilizing c-Myc protein, meriting further investigation of its therapeutic and prognostic potential.

Perineural invasion (PNI), a pathologic feature defined as cancer cell invasion in, around, and through nerves, is an indicator of poor prognosis and survival in prostate cancer (PC). Despite widespread recognition of the clinical significance of PNI, the molecular mechanisms are largely unknown. Here, we report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PNI in PC. MAOA promotes PNI of PC cells in vitro and tumor innervation in an orthotopic xenograft model. Mechanistically, MAOA activates SEMA3C in a Twist1-dependent transcriptional manner, which in turn stimulates cMET to facilitate PNI via autocrine or paracrine interaction with coactivated PlexinA2 and NRP1. Furthermore, MAOA inhibitor treatment effectively reduces PNI of PC cells in vitro and tumor-infiltrating nerve fiber density along with suppressed xenograft tumor growth and progression in mice. Collectively, these findings characterize the contribution of MAOA to the pathogenesis of PNI and provide a rationale for using MAOA inhibitors as a targeted treatment for PNI in PC.

Metastasis is a predominant cause of death for prostate cancer (PCa) patients; however, the underlying mechanisms are poorly understood. We report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PCa bone and visceral metastases, activating paracrine Shh signaling in tumor-stromal interactions. MAOA provides tumor cell growth advantages in the bone microenvironment by stimulating interleukin-6 (IL6) release from osteoblasts, and triggers skeletal colonization by activating osteoclastogenesis through osteoblast production of RANKL and IL6. MAOA inhibitor treatment effectively reduces metastasis and prolongs mouse survival by disengaging the Shh-IL6-RANKL signaling network in stromal cells in the tumor microenvironment. These findings provide a rationale for targeting MAOA and its associated molecules to treat PCa metastasis.

Sterol regulatory element-binding protein-2 (SREBP-2) transcription factor mainly controls cholesterol biosynthesis and homeostasis in normal cells. The role of SREBP-2 in lethal prostate cancer (PCa) progression remains to be elucidated. Here, we showed that expression of SREBP-2 was elevated in advanced pathologic grade and metastatic PCa and significantly associated with poor clinical outcomes. Biofunctional analyses demonstrated that SREBP-2 induced PCa cell proliferation, invasion and migration. Furthermore, overexpression of SREBP-2 increased the PCa stem cell population, prostasphere-forming ability and tumor-initiating capability, whereas genetic silencing of SREBP-2 inhibited PCa cell growth, stemness, and xenograft tumor growth and metastasis. Clinical and mechanistic data showed that SREBP-2 was positively correlated with c-Myc and induced c-Myc activation by directly interacting with an SREBP-2-binding element in the 5'-flanking c-Myc promoter region to drive stemness and metastasis. Collectively, these clinical and experimental results reveal a novel role of SREBP-2 in the induction of a stem cell-like phenotype and PCa metastasis, which sheds light on translational potential by targeting SREBP-2 as a promising therapeutic approach in PCa.

BACKGROUND We previously reported that the activation of RANK and c-Met signaling components in both experimental mouse models and human prostate cancer (PC) specimens predicts bone metastatic potential and PC patient survival. This study addresses whether a population of metastasis-initiating cells (MICs) known to express a stronger RANKL, phosphorylated c-Met (p-c-Met), and neuropilin-1 (NRP1) signaling network than bystander or dormant cells (BDCs) can be detected in PC tissues from patients subjected to transurethral resection of the prostate (TURP) for urinary obstruction prior to the diagnosis of PC with or without prior hormonal manipulation, and whether the relative abundance of MICs over BDCs could predict castration-resistant progression and PC patient survival. METHODS We employed a multiplexed quantum-dot labeling (mQDL) protocol to detect and quantify MICs and BDCs at the single cell level in TURP tissues obtained from 44 PC patients with documented overall survival and castration resistance status. RESULTS PC tissues with a higher number of MICs and an activated RANK signaling network, including increased expression of RANKL, p-c-Met, and NRP1 compared to BDCs, were found to correlate with the development of castration resistance and overall survival. CONCLUSIONS The assessment of PC cells with MIC and BDC phenotypes in primary PC tissues from hormone-naive patients can predict the progression to castration resistance and the overall survival of PC patients. Prostate 75:1312–1321, 2015. © 2015 Wiley Periodicals, Inc.

// Changhong Shi 1, 2 , Jason Boyang Wu 2 , Gina C-Y. Chu 2 , Qinlong Li 2 , Ruoxiang Wang 2 , Caiqin Zhang 1 , Yi Zhang 3 , Hyung L. Kim 4 , Jing Wang 5 , Haiyen E. Zhau 2 , Dongfeng Pan 3 , Leland W.K. Chung 2 1 Laboratory Animal Center, the Fourth Military Medical University, Xi’an, Shaanxi 710032, China 2 Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 3 Department of Radiology, the University of Virginia, Charlottesville, VA 22908, USA 4 Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 5 Department of Nuclear Medicine, Xijing Hospital, the Fourth Military Medical University, Xi’an, Shaanxi 710032, China Correspondence to: Leland W.K. Chung, e-mail: Leland.Chung@cshs.org Changhong Shi, e-mail: changhong@fmmu.edu.cn Dongfeng Pan, e-mail: DP3R@hscmail.mcc.virginia.edu Keywords: HIF-1α, imaging canine cancer, imaging human prostate cancer, near-infrared dye, organic anion-transporting polypeptides Received: July 13, 2014 Accepted: September 06, 2014 Published: October 25, 2014 ABSTRACT Near-infrared (NIR) fluorescence imaging agents are promising tools for noninvasive cancer imaging. This study explored the specific uptake and retention of a NIR heptamethine carbocyanine MHI-148 dye by canine cancer cells and tissues and human prostate cancer (PCa) specimens and also the dye uptake mechanisms. The accumulation of MHI-148 was detected specifically in canine cancer cells and tissues and freshly harvested human PCa tissues xenografted in mice by NIR fluorescence microscopy and whole-body NIR optical imaging. Specific dye uptake in canine spontaneous tumors was further confirmed by PET imaging. Higher hypoxia-inducible factor-1α (HIF-1α) and organic anion-transporting polypeptide (OATP) protein and mRNA expression was demonstrated by multiplex quantum dots labeling and qPCR in tumors over that of normal tissues. Treating cancer cells with HIF-1α stabilizers activated HIF-1α downstream target genes, induced OATP superfamily gene expression and enhanced cellular uptake and retention of NIR dyes. Moreover, silencing HIF-1 α by siRNA significantly decreased OATP mRNA expression and blocked NIR dye uptake in cancer cells. Together, these results demonstrated the preferential uptake of NIR dyes by canine and human cancer cells and tissues via the HIF-1α/OATPs signaling axis, which provides insights into future application of these dyes for cancer detection and treatment.

Lhermitte-Duclos disease (LDD) is a rare, non-cancerous entity characterized by enlarged, abnormally developed cerebellar folia containing dysplastic cells. Symptomatic LDD is commonly observed in adults (adult-onset LDD, aLDD) as an isolated condition or associated with Cowden's disease (CD). The present study aimed to investigate the magnetic resonance imaging (MRI) characteristics and the underlying pathological findings in 7 cases of aLDD, with emphasis on the association with CD and the need for active cancer surveillance once the diagnosis of LDD is confirmed. The MRI findings along with the clinical and histopathological data collected from 7 patients with aLDD were retrospectively reviewed. The diagnosis of CD was based on a range of clinical characteristics, according to the International Cowden Consortium Criteria. A thorough review of the published data was conducted and our results indicated that all 7 cases shared similar MRI characteristics, whether the aLDD was sporadic (2 cases) or associated with CD (5 cases), including a highly typical non-enhancing striated MRI appearance of thickened folia, consisting of alternating bands on T1- and T2-weighted images. On gross examination, the involved cerebellar folia were distorted and enlarged, whereas the histopathological examination revealed that the molecular layer was widened and occupied by abnormal ganglion cells. Moreover, a reduction in the number or absence of the Purkinje cells and hypertrophy of the granular cell layer were observed. Our findings were consistent with the diagnosis of LDD. Variable levels of vacuolization of the white matter and the molecular layer were observed in all the cases. Notably, CD34 immunohistochemical analysis revealed the presence of angiogenesis within the lesions. aLDD associated with CD exhibited no pathological or immunohistochemical characteristics that were distinct from those of isolated aLDD. Of the 7 cases of aLDD, 5 presented with symptoms suggestive of CD, which is a syndrome associated with a high risk of multiple benign and malignant neoplasms. In conclusion, aLDD exhibits characteristic MRI and histopathological findings and displays a strong association with CD. Therefore, we recommend that the MRI diagnosis of aLDD triggers active cancer surveillance and preventive care.

The apoptosis-related protein 3 (APR3) gene was first cloned from HL-60 cells treated with all-trans-retinoic acid and was thought to be related to tumor cell apoptosis or differentiation. In this study, we sought to investigate its expression profile in cervical squamous cell carcinoma (SCC) and preneoplastic lesions to determine whether APR3 is involved in the malignant progression of SCC. The purified partial recombinant APR3 proteins were used to immunize rabbits for raising antibodies, and the specificity of the polyclonal anti-APR3 antibody was determined by enzyme-linked immunosorbent assay and Western blot. Sections were assessed for APR3 expression by immunohistochemistry in archived tissues from human normal cervix samples (n = 20), cervical intraepithelial neoplasia (n = 19), and invasive SCC (n = 52). Specific cytoplasmic immunostaining was evaluated for overall intensity and uniformity to derive a combined histoscore. The results of enzyme-linked immunosorbent assay and Western blot indicated that anti-APR3 antibody can serve as a good tool for research. The immunohistochemical analysis demonstrated an increased expression of APR3 in SCC relative to normal cervix epithelium and cervical intraepithelial neoplasia (P.05). Strikingly, APR3 expression level was significantly higher in nonkeratinizing SCCs compared with keratinizing SCCs (P.05) and higher in carcinomas with lymph node metastasis compared with cases without lymph node metastasis (P.05). This study demonstrates that APR3 expression is increased significantly with malignant progression of human cervical SCC, and thus, it may serve as a potential biomarker to predict prognosis of cervical SCC.

Lethal progression of prostate cancer metastasis can be improved by developing animal models that recapitulate the clinical conditions. We report here that cytokeratin 13 (KRT13), an intermediate filament protein, plays a directive role in prostate cancer bone, brain, and soft tissue metastases. KRT13 expression was elevated in bone, brain, and soft tissue metastatic prostate cancer cell lines and in primary and metastatic clinical prostate, lung, and breast cancer specimens. When KRT13 expression was determined at a single cell level in primary tumor tissues of 44 prostate cancer cases, KRT13 level predicted bone metastasis and the overall survival of prostate cancer patients. Genetically enforced KRT13 expression in human prostate cancer cell lines drove metastases toward mouse bone, brain and soft tissues through a RANKL-independent mechanism, as KRT13 altered the expression of genes associated with EMT, stemness, neuroendocrine/neuromimicry, osteomimicry, development, and extracellular matrices, but not receptor activator NF-κB ligand (RANKL) signaling networks in prostate cancer cells. Our results suggest new inhibitors targeting RANKL-independent pathways should be developed for the treatment of prostate cancer bone and soft tissue metastases.

Introduction and Objective: Keratins (KRTs) were reported to interact with multiple cellular proteins and initiate signaling cascades that promote cell proliferation, migration and metastasis in cancers. Keratin13 (KRT13), a member of the intermediate filament proteins, plays important role in breast cancer progression and metastasis. The objectives of this study are to determine the role and molecular mechanism of KRT13 in promoting breast cancer growth and metastatic progression. Methods and Results: We evaluated KRT13 protein expression in 58 primary breast cancer tissues by immunohistochesmistry and found that KRT13 is overexpressed in metastatic breast cancer specimens (12/18) (p Conclusion: KRT13 exerts a novel function in the regulation of breast cancer cell growth, progression and metastasis via alterations of nuclear translocation of plakoglobin that modulates downstream c-Myc-dependent signaling, inducing stem cell-like phenotype and metastasis of breast cancer. Our findings could reveal potential novel targeting of breast cancer progression and metastasis. Funded by an NCI P01 CA098912 and a Board of Governors Chair of Cancer Research fund from Cedars-Sinai Medical Center to LWK Chung. Citation Format: Lijuan Yin, Gina Chia-Yi Chu, Qinlong Li, Liyuan Yin, Michael Lewis, Mourad Tighiouart, Leland W. k. Chung, Haiyen E. Zhau. KRT13 promotes stemness and drives metastasis in breast cancer through direct interaction with plakoglobin-desmoplakin complexes regulating c-Myc signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5002.

Regardless of the controversial pathogenesis, intracranial meningeal hemangiopericytoma (M-HPC) is a rare, highly cellular and vascularized mesenchymal tumor that is characterized by a high tendency for recurrence and extraneural metastasis, despite radical excision and postoperative radiotherapy. M-HPC shares similar clinical manifestations and radiological findings with meningioma, which causes difficulty in differentiation of this entity from those prognostically favorable mimics prior to surgery. Treatment of M-HPC, particularly in metastatic settings, remains a challenge. A case is described of primary M-HPC with recurrence at the initial and distant intracranial sites and extraneural multiple-organ metastases in a 36-year-old female. The metastasis of M-HPC was extremely extensive, and to the best of our knowledge this is the first case of M-HPC with delayed metastasis to the bilateral kidneys. The data suggests that preoperative computed tomography and magnetic resonance imaging could provide certain diagnostic clues and useful information for more optimal treatment planning. The results may imply that novel drugs, such as temozolomide and bevacizumab, as a component of multimodality therapy of M-HPC may deserve further investigation.

Brain tumors and brain metastases are among the deadliest malignancies of all human cancers, largely due to the cellular blood–brain and blood–tumor barriers that limit the delivery of imaging and therapeutic agents from the systemic circulation to tumors. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. Here we identified and synthesized a group of near-infrared fluorescence (NIRF) heptamethine carbocyanine dyes and derivative NIRF dye-drug conjugates for effective imaging and therapeutic targeting of brain tumors of either primary or metastatic origin in mice, which is mechanistically mediated by tumor hypoxia and organic anion-transporting polypeptide genes. We also demonstrate that these dyes, when conjugated to chemotherapeutic agents such as gemcitabine, significantly restricted the growth of both intracranial glioma xenografts and prostate tumor brain metastases and prolonged survival in mice. These results show promise in the application of NIRF dyes as novel theranostic agents for the detection and treatment of brain tumors.

Although previous studies indicate interracial differences in prostate cancer epidemiology based on gene expression profiles among patients from the United States, China and Japan, evidence at the genetic and phenotypic levels that these differences exist and manifest along ethnic lines has been sparse. Recent studies, however, suggest that genetic differences, such as the lower incidence of Chinese prostate cancers harboring TMPRSS2-ERG translocations compared to patients from Western countries, should be carefully considered in the context of genotypic and phenotypic differences among interracial groups. New, more efficient technologies need to be developed to validate genetic, gene expression and/or phenotypic differences associated with prostate cancer tissue specimens obtained from interracial groups, to establish reliable clinical standards that take racial/ethnic data into account to improve the diagnosis, prognosis and treatment of patients with prostate cancer. Racial/ethnic differences in prostate cancer have become the focus of many epidemiologic and outcome research studies due to the well-recognized differences in the annual death rate between African-Americans and Caucasian-Americans. African-Americans have a 2.4 times higher average annual death rate than Caucasian-Americans, and a 76% higher rate of diagnosed prostate cancer.1 To explain such significant differences between African-Americans and Caucasian-Americans, efforts have been made to compare serum prostate-specific antigen (PSA) and androgenic steroids such as testosterone and dihydrotestosterone levels between African-Americans and Caucasian-Americans. The results of these studies seem to suggest that African-Americans have 15% higher PSA than Caucasian-Americans, based upon the SEARCH and Johns Hopkins databases adjusted to demographic and cancer-specific characteristics including prostate weight.2 These differences could be related to the relative levels of sex steroids in the African-American and Caucasian-American populations. While adolescent non-Hispanic blacks did not have higher testosterone SBG (sex steroid binding globulins) and 17-β-estradiol levels than non-Hispanic whites,3 data show higher serum dihydrotestosterone and the dihydrotestosterone to testosterone ratios in African-Americans than Caucasian-Americans and Hispanics.4 The latter study found no difference in the level of serum testosterone among these three interracial groups. Because of well-known environmental influences on the incidence of prostate cancer among racial/ethnic groups after migration from Japan and China to the United States5,6,7 and the well-known fact that men castrated prior to puberty fail to develop benign or cancerous prostates, a series of studies have been conducted to document potential interracial differences in gene/environment interaction. For example, lower calcium absorption and modified single-nucleotide polymorphism in the CDX-2 binding site to the vitamin D receptor were commoner in Caucasian-Americans than African Americans, which may account for racial differences in cancer development.8 Racial/ethnic differences in CpG island methylation were found at birth.9 These results are supported by differences in the specific methylation of genes such as GSTP1, AR, RAR beta2, SPARC, TIMP3 and NKX2-5 in which higher methylation was found in African-Americans than in Caucasian-Americans.10 The methylation differences found in adulthood could potentially be contributed by neonatal imprinting, as demonstrated in our early studies where we showed that both the growth of sex steroid-sensitive organs and their steroid-metabolizing enzymes in the target organs were affected by prior exposure of animals to testosterone or 17-β-estradiol during the neonatal period.11,12,13 In addition to the report cited above characterizing racial/ethnic differences in prostate cancer among African-Americans, Caucasian-Americans, Chinese and Japanese, numerous other attempts have been made to characterize the differences among Americans, Europeans, Africans and other Asian races.14,15,16 In this review, we will summarize our work highlighting interracial comparative studies of prostate cancer in the United States, China and Japan, focusing on gene expression differences pertinent to cell signaling networks involved in the development of castration-resistant prostate cancer (CRPC) and its subsequent dissemination to bone and soft tissues.

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. Knockdown and overexpression of MAOA in human PCa cell lines indicated that MAOA induces EMT through activation of VEGF and its coreceptor neuropilin-1. MAOA-dependent activation of neuropilin-1 promoted AKT/FOXO1/TWIST1 signaling, allowing FOXO1 binding at the TWIST1 promoter. Importantly, the MAOA-dependent HIF1α/VEGF-A/FOXO1/TWIST1 pathway was activated in high-grade PCa specimens, and knockdown of MAOA reduced or even eliminated prostate tumor growth and metastasis in PCa xenograft mouse models. Pharmacological inhibition of MAOA activity also reduced PCa xenograft growth in mice. Moreover, high MAOA expression in PCa tissues correlated with worse clinical outcomes in PCa patients. These findings collectively characterize the contribution of MAOA in PCa pathogenesis and suggest that MAOA has potential as a therapeutic target in PCa.

Near-infrared fluorescence (NIRF) imaging agents are promising tools for noninvasive cancer imaging. Here, we explored the mechanistic properties of a specific group of NIR heptamethine carbocyanines including MHI-148 dye we identified and synthesized, and demonstrated these dyes to achieve cancer-specific imaging and targeting via a hypoxia-mediated mechanism. We found that cancer cells and tumor xenografts exhibited hypoxia-dependent MHI-148 dye uptake in vitro and in vivo, which was directly mediated by hypoxia-inducible factor 1α (HIF1α). Microarray analysis and dye uptake assay further revealed a group of hypoxia-inducible organic anion-transporting polypeptides (OATPs) responsible for dye uptake, and the correlation between OATPs and HIF1α was manifested in progressive clinical cancer specimens. Finally, we demonstrated increased uptake of MHI-148 dye in situ in perfused clinical tumor samples with activated HIF1α/OATPs signaling. Our results establish these NIRF dyes as potential tumor hypoxia-dependent cancer-targeting agents and provide a mechanistic rationale for continued development of NIRF imaging agents for improved cancer detection, prognosis and therapy.

Introduction and Objective: Bone and brain metastases are prevalent in human prostate and breast cancer patients. Keratin 13 (KRT13), a member of the intermediate filament proteins and an epithelial stem cell differentiation marker, induces cancer cell migration and progression toward increased malignant state. The objectives of this study are: 1) to determine KRT13 expression in human prostate and breast cancer and its clinical correlation; 2) to determine the functional cell signaling role of KRT13 in prostate and breast cancer cells using gene transfer technology. Methods and Results: We evaluated KRT13 protein expression in primary prostate cancer tissues from 44 cases with well-documented overall survival by quantitative quantum dot immuno-labelling. We found that KRT13 expression in primary prostate cancer correlated with patient overall survival and bone metastasis (p Conclusion: These results suggest that KRT13 drives prostate and breast cancer bone and brain metastases via osteomimicry and neuromimicry associated genes resulting in downstream cell signaling network convergence between EMT, stemness, cell growth, and survival pathways. Funded in part by NCI-P01-CA098912 Citation Format: Lijuan Yin, Qinlong Li, Jen-Ming Huang, Michael Lewis, Isla P. Garraway, Quanlin Li, Hong Bu, Leland W. K Chung, Haiyen E. Zhau. Keratin 13 drives the dissemination of bone and brain metastases of human prostate and breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4957.

Background APMCF1 is a novel human gene first cloned from apoptotic MCF-7 cells. Our previous study found ectogenic APMCF1 could induce G1 arrest in hepatocarcinoma cell line HHCC. In order to search its broad expression profile for further understanding of its mechanism in tumor, we investigated a subcellular location of APMCF1 and performed an immunohistochemistry study including various tumor and normal tissues. Discovery from the expression characterization of AMPCF1 may have applicability in the analysis of its biological function in tumor. Methods We investigated subcellular localization of APMCF1 by transient transfection in green monkey kidney epithelial cells (COS-7) with a fusion protein vector pEGFP-APMCF1 and detected expression profile in a broad range of normal and malignant human tissues via tissue microarray (TMA) by immunohistochemistry with polyclonal antibody first produced in our laboratory. Results EGFP-APMCF1 was generally localized in the cytoplasm of COS-7 cell. Positive staining of APMCF1 was found in liver, lung, breast, colon, stomach, esophagus and testis, exhibited a ubiquitous expression pattern while its expression was up-regulated in tumor tissues compared with corresponding normal tissues. Normal brain neuron cells also showed expression of APMCF1, but negative in gliocyte cells and glioma. Both the normal and tumor tissues of ovary were absent of APMCF1 expression. Positive immunostaining for APMCF1 with large samples in liver, colon, esophagus, lung and breast carcinomas were 96% (51/53), 80% (44/55), 57% (30/53), 58% (33/57) and 34% (16/47) respectively. Conclusion These results revealed a cytoplastic expression pattern of APMCF1 and up-regulated in tumour tissues suggesting APMCF1 may have potential relationship with oncogenesis. The data presented should serve as a useful reference for further studies of APMCF1 functions in tumorigenesis and might provide a potential anti-tumor target.

We reported (PLoS One 6 (12):e28670, 2011) that the activation of c-Met signaling in RANKL-overexpressing bone metastatic LNCaP cell and xenograft models increased expression of RANK, RANKL, c-Met, and phosphorylated c-Met, and mediated downstream signaling. We confirmed the significance of the RANK-mediated signaling network in castration resistant clinical human prostate cancer (PC) tissues. In this report, we used a multispectral quantum dot labeling technique to label six RANK and c-Met convergent signaling pathway mediators simultaneously in formalin fixed paraffin embedded (FFPE) tissue specimens, quantify the intensity of each expression at the sub-cellular level, and investigated their potential utility as predictors of patient survival in Caucasian-American, African-American and Chinese men. We found that RANKL and neuropilin-1 (NRP-1) expression predicts survival of Caucasian-Americans with PC. A Gleason score ≥ 8 combined with nuclear p-c-Met expression predicts survival in African-American PC patients. Neuropilin-1, p-NF-κB p65 and VEGF are predictors for the overall survival of Chinese men with PC. These results collectively support interracial differences in cell signaling networks that can predict the survival of PC patients.

Epithelial-mesenchymal transition (EMT) is the phenotypic transition of epithelial cells to mesenchymal cells characterized by loss of epithelial markers, loss of intercellular adherence and acquirement of mesenchymal cell markers and increased locomotive ability. EMT is widely considered to be a gene regulated process necessary for cancer metastasis. Yet it is a highly controversial issue. We here propose that EMT is an environmentally induced cell behavior. It is the mimicry of their living environment. It is a survival strategy, a way of immune escape. We also propose here that the epithelial cell markers may functionally act as tumor antigens since in the mesenchymal surroundings there are no other structures bearing the same antigens as epithelial cells.