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1.  Infrared spectroscopy and microscopy in cancer research and diagnosis 
Since the middle of 20th century infrared (IR) spectroscopy coupled to microscopy (IR microspectroscopy) has been recognized as a non destructive, label free, highly sensitive and specific analytical method with many potential useful applications in different fields of biomedical research and in particular cancer research and diagnosis. Although many technological improvements have been made to facilitate biomedical applications of this powerful analytical technique, it has not yet properly come into the scientific background of many potential end users. Therefore, to achieve those fundamental objectives an interdisciplinary approach is needed with basic scientists, spectroscopists, biologists and clinicians who must effectively communicate and understand each other's requirements and challenges. In this review we aim at illustrating some principles of Fourier transform (FT) Infrared (IR) vibrational spectroscopy and microscopy (microFT-IR) as a useful method to interrogate molecules in specimen by mid-IR radiation. Penetrating into basics of molecular vibrations might help us to understand whether, when and how complementary information obtained by microFT-IR could become useful in our research and/or diagnostic activities. MicroFT-IR techniques allowing to acquire information about the molecular composition and structure of a sample within a micrometric scale in a matter of seconds will be illustrated as well as some limitations will be discussed. How biochemical, structural, and dynamical information about the systems can be obtained by bench top microFT-IR instrumentation will be also presented together with some methods to treat and interpret IR spectral data and applicative examples. The mid-IR absorbance spectrum is one of the most information-rich and concise way to represent the whole “… omics” of a cell and, as such, fits all the characteristics for the development of a clinically useful biomarker.
PMCID: PMC3236568  PMID: 22206042
Molecular vibrations; vibrational spectroscopy; infrared radiation; synchrotron radiation; infrared microspectroscopy; mid-infrared absorbance spectroscopy; cancer biomarker; cancer diagnosis; pre-clinical drug screening; unsupervised multivariate analysis
2.  The warts gene as a novel target of the Drosophila DRE/DREF transcription pathway 
The Hippo tumor suppressor pathway in Drosophila represses expression of DIAP1 and Cyclin E via inactivation of the transcription co-activator Yorkie, resulting in cell cycle arrest and induction of apoptosis. The warts (wts) gene is well known as a core kinase in this pathway, but its transcriptional regulation has yet to be clarified. In Drosophila, DREF binds to a target sequence named DRE (5'-TATCGATA) and regulates transcription of cell proliferation-related genes containing the DRE sequence in their promoter regions. Here we found half reduction of the wts gene dose to enhance the DREF-induced rough eye phenotype, suggesting a DREF genetic interaction with the Hippo pathway in vivo. Three DREs indentified in the wts gene promoter region exhibited strong promoter activity with a luciferase transient expression assay in Drosophila S2 cells, this decreasing under DREF-RNAi conditions. In addition, knockdown of DREF in S2 cells reduced the level of endogenous wts mRNA. Chromatin immunoprecipitation assays with anti-DREF antibody revealed that DREF binds specifically to the wts gene promoter region containing DREs in vivo. These results indicate that the DRE/DREF pathway is required for transcriptional regulation of the wts gene, indicating a novel link between the DRE/DREF and the Hippo pathways.
PMCID: PMC3236570  PMID: 22206044
DRE; DREF; warts; Hippo pathway; transcription; tumor suppressor
3.  Understanding the role of miRNA in regulating NF-κB in blood cancer 
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by binding to complementary sequences in mRNAs encoding downstream target genes. A large variety of cellular processes, including differentiation, development, apoptosis and cell cycle progression, are dependent on miRNA-mediated suppression of gene expression for their regulation. As such, it is unsurprising that these small RNA molecules are associated with signaling networks that are often altered in various diseases, including many blood cancers. One such network is the nuclear factor-κB (NF-κB) pathways that universally stimulate transcription of proteins which generally promote cell survival, inhibit apoptosis, allow cellular growth, induce angiogenesis and generate many pro-inflammatory responses. The NF-κB signalling pathway is often constitutively activated in blood cell cancers including myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), lymphomas and in multiple myeloma (MM). This review focuses on the function of miRNAs that directly target NF-κB signaling cascade. Recent findings that connect this pathway through various miRNA families to human blood cancers are reviewed, and support for using miRNA-based therapy as a novel method to counteract this tumour-promoting signalling event is discussed.
PMCID: PMC3236572  PMID: 22206046
Leukemia; NF-κB; microRNA; gene regulation; apoptosis
4.  Targeted ovarian cancer treatment: the TRAILs of resistance 
Ovarian cancer (OC) is the leading cause of death from gynecological malignancies. Although most patients respond to the initial therapy when presenting with advanced disease, only 10-15% maintain a complete response following first-line therapy. Recurrence defines incurable disease in most cases. Despite improvements with conventional chemotherapy combinations, the overall cure rate remained mostly stable over the years. Increased long-term survival in OC patients will only be achieved through a comprehensive understanding of the basic mechanisms of tumor cell resistance. Such knowledge will translate into the development of new targeted strategies. In addition, because OC is considered to be a heterogeneous group of diseases with distinct gene expression profiles, it is likely that different approaches to treatment for distinct sub-types will be required to optimize response. One of the new promising anti-cancer therapies is the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL has the ability to selectively induce apoptosis in tumor cells with little toxicity to normal cells. Death receptor ligands such as TRAIL rely on the activation of the apoptotic signaling pathway to destroy tumor cells. TRAIL induces the formation of a pro-apoptotic death-inducing signaling complex (DISC) via its death receptors, TRAIL receptor 1 (TRAIL R1) and TRAIL receptor 2 (TRAIL R2). The formation of the DISC activates caspase-8 which requires further signal amplification through the mitochondrial pathway for an efficient activation of effector caspases in OC cells. The initial enthusiasm for TRAIL has been hampered by accumulating data demonstrating TRAIL resistance in various tumor types including OC cells. There is, therefore, a need to identify markers of TRAIL resistance, which could represent new hits for targeted therapy that will enhance TRAIL efficacy. In addition, the identification of patients that are more likely to respond to TRAIL therapy would be highly desirable. In this review, we discuss the different molecular and cellular mechanisms leading to TRAIL resistance in OC. In particular, we address the mechanisms involved in intrinsic, acquired and environment-mediated TRAIL resistance, and their potential implication in the clinical outcome.
PMCID: PMC3236573  PMID: 22206047
Ovarian cancer; death receptors; resistance; TRAIL
5.  Expression of FOXO1 is associated with GATA3 and Annexin-1 and predicts disease-free survival in breast cancer 
Purpose
To determine the prognostic value of FOXO1, GATA3 and Annexin-1 expression in breast cancer.
Methods
Tissue microarray and individual paraffin tissue slides from 131 patients were used for the study. The association of FOXO1, GATA3 and Annexin-1 expression with clinicopathological features of breast cancer and disease outcome was examined in retrospective samples. Kaplan-Meier survival curves and Cox regression with multivariate analysis were used for assessing the relative risk (RR) and disease-free survival (DFS). The expression of FOXO1, GATA3 and Annexin-1 were determined by immunohistochemistry and the association among the three proteins was analyzed by Logistic regression analysis.
Results
The nuclear expression of FOXO1 was observed in most of the normal breast tissues and 51.3% of the malignant breast tissues. GATA3 and Annexin-1 were expressed at 73% and 24.6% respectively in breast cancer tissues. The expression of FOXO1, GATA3 and Annexin-1 were all inversely correlated with lymph node-positive tumors. Both FOXO1 and Annexin-1 expression were also inversely associated with HER2-overexpressing tumors. FOXO1 expression was significantly associated with both GATA3 and Annexin-1 expression. In addition, Multivariate analyses confirm that only FOXO1 levels independently predict DFS.
Conclusion
FOXO1 expression in breast cancer is regulated by the PI3K/Akt pathway. The expression of FOXO1 is also associated with GATA3 and/or Annexin-1. Restoring or targeting FOXO1 to the cell nucleus in breast cancer tissues may improve response to therapy and disease outcome. Further clinical studies are warranted to test this hypothesis.
PMCID: PMC3236574  PMID: 22206049
FOXO1; GATA3; annexin-1; survival; breast cancer
6.  Prognostic significance of aberrant gene methylation in gastric cancer 
Promoter methylation acts as an important alternative to genetic alterations for gene inactivation in gastric carcinogenesis. Although a number of gastric cancer-associated genes have been found to be methylated in gastric cancer, valuable methylation markers for early diagnosis and prognostic evaluation of this cancer remain largely unknown. In the present study, we used methylation-specific PCR (MSP) to analyze promoter methylation of 9 gastric cancer-associated genes, including MLF1, MGMT, p16, RASSF2, hMLH1, HAND1, HRASLS, TM, and FLNc, and their association with clinicopathological characteristics and clinical outcome in a large cohort of gastric cancers. Our data showed that all of these genes were aberrantly methylated in gastric cancer, ranging from 8% to 51%. Moreover, gene methylation was strongly associated with certain clinicopathological characteristics, such as tumor differentiation, lymph node metastasis, and cancer-related death. Of interest, methylation of MGMT, p16, RASSF2, hMLH1, HAND1, and FLNc was closely associated with poor survival in gastric cancer, particularly MGMT, p16, RASSF2 and FLNc. Thus, our findings suggested these epigenetic events may contribute to the initiation and progression of gastric cancer. Importantly, methylation of some genes were closely relevant to poor prognosis in gastric cancer, providing the strong evidences that these hypermethylated genes may be served as valuable biomarkers for prognostic evaluation in this cancer.
PMCID: PMC3236575  PMID: 22206050
Gastric cancer; gene methylation; methylation-specific PCR (MSP); early diagnosis; poor prognosis
7.  HCG variants, the growth factors which drive human malignancies 
The term human chorionic gonadotropin (hCG) refers to a group of 5 molecules, each sharing the common amino acid sequence but each differing in meric structure and carbohydrate side chain structure. The 5 molecules are each produced by separate cells and each having separate biological functions. hCG and sulfated hCG are hormones produced by placental syncytiotrophoblast cells and pituitary gonadotrope cells. Hyperglycosylated hCG is an autocrine produced by placental cytotrophoblast cells. Hyperglycosylated hCG drives malignancy in placental cancers, and in testicular and ovarian germ cell malignancies. hCGβ and hyperglycosylated hCGβ are autocrines produce by most advanced malignancies. These molecules, particularly the malignancy promoters are presented in this review on hCG and cancer. hCGβ and hyperglycosylated hCGβ are critical to the growth and invasion, or malignancy of most advanced cancers. In many ways, while hCG may appear like a nothing, a hormone associated with pregnancy, it is not, and may be at the center of cancer research.
PMCID: PMC3236569  PMID: 22206043
Human chorionic gonadotropin (hCG); variants; groth factors; human malignancies; cancer
8.  Molecular signature and pathway analysis of human primary squamous and adenocarcinoma lung cancers 
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with a poor response to chemotherapy and low survival rate. This unfavorable treatment response is likely to derive from both late diagnosis and from complex, incompletely understood biology, and heterogeneity among NSCLC subtypes. To define the relative contributions of major cellular pathways to the biogenesis of NSCLC and highlight major differences between NSCLC subtypes, we studied the molecular signatures of lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), based on analysis of gene expression and comparison of tumor samples with normal lung tissue. Our results suggest the existence of specific molecular networks and subtype-specific differences between lung ADC and SCC subtypes, mostly found in cell cycle, DNA repair, and metabolic pathways. However, we also observed similarities across major gene interaction networks and pathways in ADC and SCC. These data provide a new insight into the biology of ADC and SCC and can be used to explore novel therapeutic interventions in lung cancer chemoprevention and treatment.
PMCID: PMC3238469  PMID: 22206048
NSCLC; adenocarcinoma; squamous cell carcinoma; molecular signature; gene expression; pathway
9.  TRAIL receptor signaling and therapeutic option in bone tumors: the trap of the bone microenvironment 
Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL/TNFSF10) has been reported to specifically induce malignant cell death being relatively nontoxic to normal cells. Since its identification 15 years ago, the antitumor activity and therapeutic value of TRAIL have been extensively studied. Five receptors quickly emerged, two of them being able to induce programmed cell death in tumor cells. This review takes a comprehensive look at this ligand and its receptors, and its potential role in primary bone tumors (osteosarcoma and Ewing's sarcoma) therapy. The main limit of clinical use of TRAIL being the innate or acquired resistance mechanisms, different possibilities to sensitize resistant cells are discussed in this review, together with the impact of bone microenvironment in the regulation of TRAIL activity.
PMCID: PMC3236571  PMID: 22206045
Tumor Necrosis Factor-Related Apoptosis Inducing Ligand; TRAIL/TNFSF10; receptor; signalingbone tumor; microenvironment
10.  Squamous Cell Carcinoma – Similarities and Differences among Anatomical Sites 
Squamous cell carcinoma (SCC) is an epithelial malignancy involving many anatomical sites and is the most common cancer capable of metastatic spread. Development of early diagnosis methods and novel therapeutics are important for prevention and mortality reduction. In this effort, numerous molecular alterations have been described in SCCs. SCCs share many phenotypic and molecular characteristics, but they have not been extensively compared. This article reviews SCC as a disease, including: epidemiology, pathology, risk factors, molecular characteristics, prognostic markers, targeted therapy, and a new approach to studying SCCs. Through this comparison, several themes are apparent. For example, HPV infection is a common risk factor among the four major SCCs (NMSC, HNSC, ESCC, and NSCLC) and molecular abnormalities in cell-cycle regulation and signal transduction predominate. These data reveal that the molecular insights, new markers, and drug targets discovered in individual SCCs may shed light on this type of cancer as a whole.
PMCID: PMC3175764  PMID: 21938273
Squamous cell carcinoma (SCC); Non-melanoma skin cancer (NMSC); Head and neck squamous cell carcinomas (HNSCC); esophageal squamous cell carcinoma (ESCC); Non-small cell lung cancer (NSCLC); epidemiology; risk factors; molecular characteristics; prognostic markers; targeted therapy
11.  Synergy of brief activation of CD8 T-cells in the presence of IL-12 and adoptive transfer into lymphopenic hosts promotes tumor clearance and anti-tumor memory 
Adoptive T-cell therapy holds great promise for the treatment of metastatic melanoma. However, prohibitive costs associated with current technology required for culture and expansion of tumor-reactive T-cells, the need for intense preconditioning regimens to induce lymphopenia, and the unpredictable anti-tumor effect of adoptively transferred T-cells remain significant impediments for its clinical implementation. Here we report a simplified combinatorial approach that involves short activation of CD8+ T cells in the presence of IL-12 followed by adoptive transfer into tumor bearing animals after a single injection of cyclophosphamide. This approach resulted in complete eradication of B16 melanoma, and the establishment of long term immunological memory capable of fully protecting mice after a second B16 melanoma challenge. The activated donor cells were unique because they simultaneously exhibited traits for cytotoxic effector function, central memory-like, homing, and senescence. After tumor eradication and within three months after transfer, CD8+ cells exhibited a conventional memory CTL phenotype. Moreover, these memory CTLs acquired functional attributes characteristic of memory stem cells, including the ability to resist chemotherapy-induced toxicity. Our results suggest that short-term T-cell receptor signaling in the presence of IL-12 promotes promiscuous qualities in naïve CTL which – upon transfer into lymphopenic hosts– are sufficient to eradicate tumors and generate life-long tumor-specific memory.
PMCID: PMC3170749  PMID: 21915391
Pmel; melanoma; IL-12; ACT; T cell therapy; memory; CD8
12.  Expression profiling and pathway analysis of Krüppel-like factor 4 in mouse embryonic fibroblasts 
Background
Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor with diverse regulatory functions in proliferation, differentiation, and development. KLF4 also plays a role in inflammation, tumorigenesis, and reprogramming of somatic cells to induced pluripotent stem (iPS) cells. To gain insight into the mechanisms by which KLF4 regulates these processes, we conducted DNA microarray analyses to identify differentially expressed genes in mouse embryonic fibroblasts (MEFs) wild type and null for Klf4.
Methods
Expression profiles of fibroblasts isolated from mouse embryos wild type or null for the Klf4 alleles were examined by DNA microarrays. Differentially expressed genes were subjected to the Database for Annotation, Visualization and Integrated Discovery (DAVID). The microarray data were also interrogated with the Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA) for pathway identification. Results obtained from the microarray analysis were confirmed by Western blotting for select genes with biological relevance to determine the correlation between mRNA and protein levels.
Results
One hundred and sixty three up-regulated and 88 down-regulated genes were identified that demonstrated a fold-change of at least 1.5 and a P-value < 0.05 in Klf4-null MEFs compared to wild type MEFs. Many of the up-regulated genes in Klf4-null MEFs encode proto-oncogenes, growth factors, extracellular matrix, and cell cycle activators. In contrast, genes encoding tumor suppressors and those involved in JAK-STAT signaling pathways are down-regulated in Klf4-null MEFs. IPA and GSEA also identified various pathways that are regulated by KLF4. Lastly, Western blotting of select target genes confirmed the changes revealed by microarray data.
Conclusions
These data are not only consistent with previous functional studies of KLF4’s role in tumor suppression and somatic cell reprogramming, but also revealed novel target genes that mediate KLF4’s functions.
PMCID: PMC3165197  PMID: 21892412
KLF4; microarray; MEF; DAVID; GSEA; IPA; SAM; FDR
13.  Tumor-targeted RNA-interference: functional non-viral nanovectors 
While small interfering RNA (siRNA) and microRNA (miRNA) have attracted extensive attention and showed significant promise for the study, diagnosis and treatment of human cancers, delivering siRNA or miRNA specifically and efficiently into tumor cells in vivo remains a great challenge. Delivery barriers, which arise mainly from the routes of administration associated with complex physiochemical microenvironments of the human body and the unique properties of RNAs, hinder the development of RNA-interference (RNAi)-based therapeutics in clinical practice. However, in available delivery systems, non-viral nanoparticle-based gene/RNA-delivery vectors, or nanovectors, are showing powerful delivery capacities and huge potential for improvements in functional nanomaterials, including novel fabrication approaches which would greatly enhance delivery performance. In this review, we summarize the currently recognized RNAi delivery barriers and the anti-barrier requirements related to vectors’ properties. Recent efforts and achievements in the development of novel nanomaterials, nanovectors fabrication methods, and delivery approaches are discussed. We also review the outstanding needs in the areas of material synthesis and assembly, multifunction combinations, proper delivery and assisting approaches that require more intensive investigation for the comprehensive and effective delivery of RNAi by non-viral nanovectors.
PMCID: PMC3092671  PMID: 21572539
Nanoparticles; RNAi; siRNA; miRNA; cancer therapy; tumor-targeting
14.  Potential usage of proteasome inhibitor bortezomib (Velcade, PS-341) in the treatment of metastatic melanoma: basic and clinical aspects 
Protein degradation by proteasome is essential to the regulation of important cellular functions including cell cycle progression, proliferation, differentiation and apoptosis. Abnormal proteasomal degradation of key regulatory proteins perturbs the normal dynamics of these cellular processes culminating in uncontrolled cell cycle progression and decreased apoptosis leading to the characteristic cancer cell phenotype. Proteasome inhibitors are a novel group of therapeutic agents designed to oppose the increased proteasomal degradation observed in various cancers while restoring key cellular functions such as apoptosis, cell cycle progression, and the inhibition of angiogenesis. Several proteasome inhibitors have been evaluated in pre- and clinical studies for their potential usage in clinical oncology. Bortezomib (Velcade, PS-341) is the first Food and Drug Administration-approved proteasome inhibitor for the treatment of multiple myeloma and mantle cell lymphoma. Bortezomib's ability to preferentially induce toxicity and cell death in tumor cells while rendering healthy cells unaffected makes it a powerful therapeutic agent and has extended its use in other types of malignancies. The ability of bortezomib and other proteasome inhibitors to synergize with conventional therapies in killing tumors in various in vitro and in vivo models makes this class of drugs a powerful tool in overcoming acquired and inherent resistance observed in many cancers. This is achieved through modulation of aberrant cellular survival signal transduction pathways and their downstream anti-apoptotic gene products. This review will discuss the anti-neoplastic effects of various proteasome inhibitors in a variety of cancers with a special emphasis on bortezomib, its mechanism of action and role in cancer therapy. We further discuss the potential use of bortezomib in the treatment of metastatic melanoma.
PMCID: PMC3196288  PMID: 22016836
Melanoma; proteasome; apoptosis; immunoresistance; cell signaling; targeted therapy; NF-κB; bortezomib
15.  Synergy of brief activation of CD8 T-cells in the presence of IL-12 and adoptive transfer into lymphopenic hosts promotes tumor clearance and anti-tumor memory 
Adoptive T-cell therapy holds great promise for the treatment of metastatic melanoma. However, prohibitive costs associated with current technology required for culture and expansion of tumor-reactive T-cells, the need for intense preconditioning regimens to induce lymphopenia, and the unpredictable anti-tumor effect of adoptively transferred T-cells remain significant impediments for its clinical implementation. Here we report a simplified combinatorial approach that involves short activation of CD8+ T cells in the presence of IL-12 followed by adoptive transfer into tumor bearing animals after a single injection of cyclophosphamide. This approach resulted in complete eradication of B16 melanoma, and the establishment of long term immunological memory capable of fully protecting mice after a second B16 melanoma challenge. The activated donor cells were unique because they simultaneously exhibited traits for cytotoxic effector function, central memory-like, homing, and senescence. After tumor eradication and within three months after transfer, CD8+ cells exhibited a conventional memory CTL phenotype. Moreover, these memory CTLs acquired functional attributes characteristic of memory stem cells, including the ability to resist chemotherapy-induced toxicity. Our results suggest that short-term T-cell receptor signaling in the presence of IL-12 promotes promiscuous qualities in naïve CTL which - upon transfer into lymphopenic hosts- are sufficient to eradicate tumors and generate life-long tumor-specific memory.
PMCID: PMC3170749  PMID: 21915391
Pmel; melanoma; IL-12; ACT; T cell therapy; memory; CD8
16.  Expanding roles of ZEB factors in tumorigenesis and tumor progression 
The ZEB family of transcription factors regulates key factors during embryonic development and cell differentiation but their role in cancer biology has only more recently begun to be recognized. Early evidence showed that ZEB proteins induce an epithelial-to-mesenchymal transition linking their expression with increased aggressiveness and metastasis in mice models and a wide range of primary human carcinomas. Reports over the last few years have found that ZEB proteins also play critical roles in the maintenance of cancer cell stemness, control of replicative senescence, tumor angiogenesis, overcoming of oncogenic addiction and resistance to chemotherapy. These expanding roles in tumorigenesis and tumor progression set ZEB proteins as potential diagnostic, prognostic and therapeutic targets.
PMCID: PMC3196287  PMID: 22016835
Cancer; cancer stem cells; chemotherapy resistance; E-cadherin; EMT; transcription; tumor invasiveness; ZEB1; ZEB2
17.  Ionizing radiation induces neuroendocrine differentiation of prostate cancer cells in vitro, in vivo and in prostate cancer patients 
Prostate cancer remains the most common noncutaneous cancer among American men. Although most patients can be cured by surgery and radiotherapy, 32,050 patients still died of the disease in 2010. Many patients receive radiotherapy either as a primary therapy, salvage therapy, or in combination with surgery or hormonal therapy. Despite initial treatment, several studies suggest that approximately 10% of low-risk prostate cancer patients and up to 30-60% with more advanced cancer patients experience biochemical recurrence within five years after radiotherapy. Thus, elucidating the molecular mechanisms underlying radioresistance and tumor recurrence has the potential to significantly reduce prostate cancer mortality. We previously demonstrated that fractionated ionizing radiation (IR) can induce the prostate cancer cell line LNCaP to undergo neuroendocrine differentiation (NED) by activation of cAMP response element binding protein (CREB) and cytoplasmic sequestration of ATF2, two CRE-binding transcription factors that oppose each other to regulate NED. Importantly, IR-induced NED is reversible and de-differentiated cells are cross-resistant to IR, androgen depletion and docetaxel treatments. These findings suggest that radiation-induced NED may allow prostate cancer cells to survive treatment and contribute to tumor recurrence. In the present study, we further demonstrated that IR also induces NED in a subset of DU-145 and PC-3 cells. In addition, we confirmed that IR induces NED in LNCaP xenograft tumors in nude mice, and observed that the plasma chro-mogranin A (CgA) level, a biomarker for NED, is increased by 2- to 5-fold in tumor-bearing mice after fractionated radiation doses of 20 and 40 Gy, respectively. Consistent with these in vivo findings, a pilot study in prostate cancer patients showed that the serum CgA level is elevated in 4 out of 9 patients after radiotherapy. Taken together, these findings provide evidence that radiation-induced NED is a general therapeutic response in a subset of prostate cancer patients. Thus, a large scale analysis of radiotherapy-induced NED in prostate cancer patients and its correlation to clinical outcomes will likely provide new insight into the role of NED in prostate cancer radiotherapy and prognosis.
PMCID: PMC3196282  PMID: 22016831
Ionizing radiation; prostate cancer; neuroendocrine differentiation; ATF2; CREB; radiotherapy
18.  An in vitro multistep carcinogenesis model for both HPV-positive and -negative human oral squamous cell carcinomas 
Oral squamous cell carcinomas (OSCCs) are considered to arise from human oral keratinocytes. DNAs of human papillomaviruses (HPVs), predominantly types 16 and 18, etiological agents of cervical cancer, have been detected in approximately 25% of OSCCs. In accordance with the established role of E6 and E7 in inactivating p53 and pRB, respectively, mutations of p53 and inactivation of p16INK4a are frequently observed in HPV-negative OSCCs. In addition, other alterations such as overexpression of epidermal growth factor receptor (EGFR) are often observed in both HPV-positive and -negative OSCCs. However, causal-relationships between accumulation of these abnormalities and multi-step carcinogenesis are not fully understood. To elucidate underlying processes, we transduced either HPV16 E6/E7 or mutant CDK4 (CDK4R24C), cyclin D1 and human telomerase reverse transcriptase (TERT) into primary human tongue keratinocytes (HTK), and obtained immortal cell populations, HTK-16E6E7 and HTK-K4DT. Additional transduction of oncogenic HRAS or EGFR together with MYC into the HTK-16E6E7 and dominant-negative p53 expressing HTK-K4DT resulted in anchorage-independent growth and subcutaneous tumor formation in nude mice. These results indicate that either HRAS mutation or activation of EGFR in cooperation with MYC overexpression play critical roles in transformation of HTKs on a background of inactivation of the pRB and p53 pathways and telomerase activation. This in vitro model system recapitulating the development of OSCCs should facilitate further studies of mechanisms of carcinogenesis in the oral cavity.
PMCID: PMC3196285  PMID: 22016834
Oral squamous cell carcinoma; HPV; carcinogenesis; human tongue keratinocytes; EGFR; HRAS; MYC
19.  Base excision repair targets for cancer therapy 
Cellular DNA repair is a frontline system that is responsible for maintaining genome integrity and thus preventing premature aging and cancer by repairing DNA lesions and strand breaks caused by endogenous and exogenous mutagens. However, it is also the principal cellular system in cancer cells that counteracts the killing effect of the major cancer treatments e.g. chemotherapy and ionizing radiation. The major goal of this review is to critically exam the base excision repair pathway and mechanisms regulating base excision repair capacity as a potential targets for improving cancer therapy.
PMCID: PMC3196283  PMID: 22016832
DNA repair; base excision; chemotherapy; ionizing radiation; cancer therapy
20.  N-cadherin expression is a potential survival mechanism of gefitinib-resistant lung cancer cells 
Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer and is the most common and fatal cancer worldwide. Specific tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR), such as gefitinib, have been effective in some NSCLC patients and are being used in the clinical setting as pioneer molecularly targeted cancer drugs. However, many patients have not responded to these drugs, and have acquired resistance after long-term treatment. To identify other potential NSCLC molecular targets, we used DNA microarrays to examine gene expression profiles of gefitinib-resistant PC9/ZD cells that are derived from gefitinib-sensitive PC9 cells and harbor a threonine to methionine mutation at codon 790 (T790M) in EGFR, a known mechanism of acquired resistance to gefitinib. We found that N-cadherin expression was significantly upregulated in PC9/ZD cells compared with PC9 cells. Inhibition of N-cadherin expression by siRNA or treatment with antibodies against N-cadherin induced apoptosis of PC9/ZD cells in association with reduced phosphorylation of Akt and Bad, a proapoptotic protein. Moreover, inhibition of Akt expression by siRNA or treatment with an inhibitor for phosphatidylinositol (PI)-3 kinase reduced survival of PC9/ZD cells. In addition, we found several N-cadherin-expressing lung cancer cells that showed inherent resistance to gefitinib treatment and reduced survival owing to siRNA-induced inhibition of N-cadherin expression. Thus, it appears that N-cadherin maintains the survival of the gefitinib-resistant lung cancer cells via the PI-3 kinase/Akt survival pathway. From these results, we propose that N-cadherin signaling contributes, at least in part, to the survival mechanisms of gefitinib-resistant NSCLC cells and that N-cadherin is a potential molecular target in the treatment of NSCLC.
PMCID: PMC3196281  PMID: 22016830
NSCLC; EGFR; TKI; PC9; PI-3 kinase; Akt; microarray; gene expression profiling; Meta Gene profier
21.  Angiogenesis and melanoma - from basic science to clinical trials 
The effective management of malignant melanoma has remained centred around the surgeon. The arrival of anti-angiogenic agents as the ‘fourth’ cancer treatment joining the ranks of surgery, chemotherapy and radiotherapy has been a source of renewed hope. This article provides an up-to-date review of the focus, state and rationale of clinical trials of anti-angiogenic therapies in metastatic malignant melanoma. Vascular Endothelial Growth Factor (VEGF) is by no means the only target, although perhaps the most extensively studied following the successful introduction of the anti-VEGF Antibody bevacizumab. This has been combined with other established therapies to try and improve outcomes in metastatic disease, and is being trialled in the UK to prevent metastasis in high-risk patients. We describe the encouraging preclinical work that lead to great enthusiasm for these agents, assess the key trials and their outcomes, discuss why these therapies have not revolutionised melanoma care and explore how they might be better targeted in the future.
PMCID: PMC3196284  PMID: 22016833
Cancer; angiogenesis; metastatic melanoma; melanoma; anti-angiogenic therapy; vascular endothelial growth factor; VEGF; receptor tyrosine kinase inhibitors; signal transduction inhibitors; bevacizumab
22.  The mass-action law based algorithm for cost-effective approach for cancer drug discovery and development 
The mass-action law based system analysis via mathematical induction and deduction lead to the generalized theory and algorithm that allows computerized simulation of dose-effect dynamics with small size experiments using a small number of data points in vitro, in animals, and in humans. The median-effect equation of the mass-action law deduced from over 300 mechanism specific-equations has been shown to be the unified theory that serves as the common-link for complicated biomedical systems. After using the median-effect principle as the common denominator, its applications are mechanism-independent, drug unit-independent, and dynamic order-independent; and can be used generally for single drug analysis or for multiple drug combinations in constant-ratio or non-constant ratios. Since the “median” is the common link and universal reference point in biological systems, these general enabling lead to computerized quantitative bio-informatics for econo-green bio-research in broad disciplines. Specific applications of the theory, especially relevant to drug discovery, drug combination, and clinical trials, have been cited or illustrated in terms of algorithms, experimental design and computerized simulation for data analysis. Lessons learned from cancer research during the past fifty years provide a valuable opportunity to reflect, and to improve the conventional divergent approach and to introduce a new convergent avenue, based on the mass-action law principle, for the efficient cancer drug discovery and the low-cost drug development.
PMCID: PMC3196289  PMID: 22016837
Drug discovery; drug development; unified theory for dose-effect pharmacodynamics; median-effect equation and plot of the mass-action law; drug combination; combination index; synergy definition; econo-green revolution for bio-research; experimental design; computer simulation; diagnostic plot; therapeutic cure of xenograft tumor; ardeemin and immunosuppression; iso-oxazole-fludelone and epothilones; small size experiment; conservation of animals; pharmacodynamics; dose-reduction index; polygonogram
23.  Direct evidence for lineage-dependent effects of bone marrow stromal cells on tumor progression 
We sought to characterize the function of bone marrow stromal cell (BMSC) populations in tumor progression. Because this function may depend on the cell-lineage and mouse strain heterogeneity, we first characterized ex vivo the BMSCs harvested from C57BL/6 versus FVB mice and established their in vivo function in tumor growth and metastasis experiments. All plastic-adherent BMSCs expressed platelet-derived growth factor receptor beta (PDGFRβ) and stem cell antigen 1 (Sca1), consistent with a mesenchymal precursor phenotype, as well as CD80. Moreover, these BMSCs were capable of differentiation along mesenchymal lineage into adipocytes, osteoblasts, chondrocytes or myofibroblasts. However, further phenotypic analysis detected a distinct populations of myeloid (CD11b+) precursor cells amongst the ex vivo expanded BMSCs –with specific surface marker phenotypes and gene expression pattern. When co-implanted with metastatic cancer cells, all the BMSCs persisted and integrated into tumor stroma, but only myeloid BMSCs significantly promoted tumor growth and metastasis. These data demonstrate the differential effect of BMSCs sub-populations on tumor progression. These results may have important implications for anti-tumor therapy and for the use of mesenchymal BMSCs as cell-based therapies.
PMCID: PMC3150110  PMID: 21822499
Myeloid; mesenchymal; bone marrow-derived cells; tumor; metastasis
24.  Targeting Rb inactivation in cancers by synthetic lethality 
The retinoblastoma protein, pRb, is a key regulator of cell proliferation, differentiation, apoptosis, as well as checkpoint and stress responses. The function of Rb is often inactivated in many types of cancers, a feature that can potentially be used to target this specific subset of cancers. However little is known about how the loss of Rb function can be exploited in cancer therapies. In this review, we overview the functions of Rb, and discuss a genetic screen that led to the finding that inactivation of TSC2 and Rb induces synergistic cell death in both Drosophila developing tissues and human cancer cells. The mechanisms for synergistic cell death involve the accumulation of cellular stress, suggesting that inactivation of TSC2 and chemotherapeutic agents that result in induction of cellular stress can potentially be combined to treat cancers harboring inactivated Rb.
PMCID: PMC3147291  PMID: 21814623
Rb; E2F; TSC2; mTOR; synthetic lethality; cellular stress; ROS
25.  Natural IAP inhibitor Embelin enhances therapeutic efficacy of ionizing radiation in prostate cancer 
Embelin is an active ingredient of traditional herbal medicine that exhibits anti-tumor effects in human prostate cancer cells. However, therapeutic effect of embelin in combination with conventional radiation therapy is not yet determined. In this study, we evaluate the sensitizing potential of embelin on ionizing radiation (IR) in a human prostate cancer model. In vitro, embelin combined with radiation potently suppressed prostate cancer PC-3 cell proliferation that was associated with S and G2/M arrest in cell cycle. Moreover, the combination treatment promoted caspase-independent apoptosis, as evidenced by the increased apoptotic cell death without caspase-3 activation, but not autophagy. Clonogenic survival assay showed that S-phase arrest was required for embelin-mediated radiosensitization. In vivo, embelin significantly improved tumor response to X-ray radiation in the PC-3 xenograft model. Combination therapy produced enhanced tumor growth delay and prolonged time to progression, with minimal systemic toxicity. Immunohistochemistry studies showed that embelin plus IR significantly inhibited cell proliferation, induced apoptosis, and decreased microvessel density in tumors as compared with either treatment alone, suggesting an enhanced combinatory inhibition on tumor suppression and angiogenesis. Our results demonstrate that embelin significantly facilitates tumor suppression by radiation therapy both in vitro and in vivo in the prostate cancer model. This finding warrants embelin as a novel adjuvant therapeutic candidate for the treatment of hormone-refractory prostate cancer that is resistant to radiation therapy.
PMCID: PMC3144474  PMID: 21804946
IAP inhibitor; Embelin; prostate cancer; ionizing radiation therapy

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