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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  MicroRNA analysis of microdissected normal squamous esophageal epithelium and tumor cells 
Previous studies have identified several dysregulated microRNAs in esophageal squamous cell carcinoma (ESCC); however, to date there are no ex vivo analyses comparing expression levels of these regulatory molecules in esophageal squamous cell tumors versus patient-matched normal epithelium. We describe here a technical strategy to evaluate microRNAs in normal esophageal basal cells (NB), normal esophageal differentiated cells (ND), and tumor cells (T). Laser capture microdissection was used to procure target populations from five cases and 18 ESCC-associated microRNAs were measured by RT-qPCR. Five microRNAs (miR-25, miR-106b, miR-21, miR-203, and miR-145) demonstrated consistent differential expression in at least one of the three comparisons: T vs. NB, T vs. ND, or NB vs. ND. The potential regulatory role of the microRNAs in ESCC was further evaluated by correlating their expression with a matched mRNA dataset, which included the same five cases and cell populations. In conclusion, the present work demonstrates the feasibility of studying microRNA levels in precisely dissected cell populations from clinical samples, and sheds light on the molecular mechanisms associated with ESCC.
PMCID: PMC3142940  PMID: 21796275
Esophageal squamous cell carcinoma; laser capture microdissection; microRNA; basal layer; differentiated layer; miR-25; miR-106b; miR-21; miR-203; miR-145
9.  Akt signaling is required for glioblastoma maintenance in vivo 
Glioblastoma multiforme (GBM) can be induced in mice through the combined expression of activated forms of KRas and Akt in glial progenitor cells. We have previously demonstrated that KRas is required for the maintenance of these tumors in vivo as inhibition of KRas expression resulted in apoptotic tumor regression and significantly increased survival. To determine the reliance of these tumors on Akt signaling in vivo, we generated a viral vector that allows the expression of Akt to be controlled post-delivery. Survival rates were compared between those animals with continued Akt expression and animals in which expression of Akt was suppressed. Although a fifth of the tumors were refractory to treatment, inhibition of Akt significantly increased the survival of tumor-bearing mice and nearly a fourth of the mice remained in remission four months after the treatment period. These data suggest that Akt is required for glioblastoma maintenance in the context of activated Ras and that loss of Akt expression results in increased survival; therefore, the PI3K/AKT signaling pathway is a viable therapeutic target in this context.
PMCID: PMC3142953  PMID: 21796274
Akt; Ras; glioma; mouse model; tumor maintenance; somatic cell gene delivery; retroviral vector; RCAS; TVA
10.  Systematic review of pharmacogenetic testing for predicting clinical benefit to anti-EGFR therapy in metastatic colorectal cancer 
Pharmacogenetic testing can help identify patients with metastatic colorectal cancer more likely to respond to anti-EGFR therapy. We systematically reviewed the benefits and harms of EGFR-related pharmacogenetic testing of molecular targets downstream to KRAS in the treatment of metastatic colorectal cancer. We searched five electronic databases from January 2000 through November 2010, and conducted separate grey literature and conference abstracts searches. Two reviewers independently assessed all articles for relevance and quality. We identified 27 studies, primarily fair- to marginal-quality, small retrospective, and single-arm cohort studies with significant overlap in patient populations. We identified seven studies that studied BRAF in independent patient populations, one that studied NRAS, four that studied PIK3CA, eight that studied PTEN expression, and five that studied AKT expression. The best evidence for BRAF, NRAS, and PIK3CA comes from the largest retrospective study (n=649) of chemorefractory patients from seven European countries. In this study, BRAF mutation was present in 6.5% of KRAS wild-type tumors. Only 8.3% of persons with BRAF mutations, compared to 38% of persons without BRAF mutations (p=0.0012), responded to chemotherapy with cetuximab. Clinical sensitivity and the false positive fraction (1- specificity) were estimated at 9.8% (95% CI 6.3, 14.5) and 1.6% (95% CI 0.2, 5.6), respectively. BRAF mutation was also associated with worse median progression-free survival (absolute difference 18 weeks, p<0.0001), and overall survival (absolute difference 28 weeks, p<0.0001). In the only study comparing outcomes in persons who did (n=227) and did not (n=332) receive cetuximab with combination chemotherapy, those with BRAF mutation had worse survival outcomes regardless of whether or not they received cetuximab. Although NRAS and PIK3CA exon 20 mutations were also associated with worse outcomes compared to persons without these mutations, evidence is based on a small number of identified mutations. Evidence for protein expression of PTEN and AKT is more sparse and limited by variable methods for assessing protein expression. Low-quality evidence addressing clinical validity of pharmacogenetic testing in metastatic colorectal cancer patients suggests that BRAF mutations are associated with poorer treatment response and survival outcomes, although this association may be independent of treatment with EGFR inhibitors.
PMCID: PMC3139487  PMID: 21779535
BRAF; NRAS; PTEN; AKT; metastatic colorectal cancer; anti-EGFR monoclonal antibodies; cetuximab; panitumumab; pharmacogenetic test; systematic review
11.  Signal transducer and activator of transcription-3 and breast cancer prognosis 
Signal transducer and activator of transcription-3 (Stat3) is frequently activated in breast cancer and multiple lines of evidence suggest that Stat3 promotes tumor progression. However, the prognostic value of Stat3 in human breast cancer remains controversial and associations range from favorable to unfavorable based on four outcome studies of 62, 102, 255 and 517 patients. Cellular Stat3 protein expression was measured in three studies whereas nuclear localized, tyrosine phosphorylated Stat3 (Nuc-pYStat3) was used as the readout in only one study. We therefore retrospectively analyzed the prognostic value of Nuc-pYStat3 in a larger material of 721 breast cancer specimens. Overall, patients whose tumors were positive for Nuc-pYStat3 tended to have improved survival, but the trend did not reach statistical significance (P=0.08). When specimens were stratified by tumor grade, patients with low grade but not high grade tumors that were positive for Nuc-pYStat3 had significantly prolonged overall survival in univariate analysis (P=0.014) but not in multivariate analyses. Unexpectedly, quantitative immunofluoresence detection revealed highest levels of Nuc-pYStat3 in normal breast epithelia and gradual loss of Nuc-pYStat3 during progression from DCIS, invasive ductal carcinoma, and lymph node metastases. Levels of Nuc-pYStat3 correlated positively with levels of Nuc-pYStat5, a favorable prognostic marker, in invasive ductal carcinomas. Furthermore, NucpYStat3 levels correlated strongly with protein levels of nuclear localized Stat5a (r=0.633, P<0.001) but not Stat5b. Our data does not support the notion that Nuc-pYStat3 is an independent marker of prognosis in breast cancer, although future studies may reveal prognostic utility within molecularly characterized subtypes of breast cancer.
PMCID: PMC3138712  PMID: 21776434
Stat3; breast cancer; biomarker; prognosis; survival; immunohistochemistry
12.  Systemic activation of K-ras rapidly induces gastric hyperplasia and metaplasia in mice 
Mouse models with conditional activation of K-ras (K-rasG12D) are used widely to investigate the role of oncogenic K-ras in a tissue-specific manner. However, the effect of ubiquitous activation of K-ras in adult mice has not been well studied. Herein, we report that systemic activation of K-ras in mice leads to rapid changes in gastric cellular homeostasis. Conditional activation of K-ras results in activation of the MAPK pathway and hyperproliferation of squamous epithelium in the forestomach and metaplasia in the glandular stomach. Parietal cells almost completely disappear from the upper part of the stomach adjacent to forestomach of K-ras activated mice. CDX2, a caudal-related homeobox transcription factor normally expressed in the intestine, is upregulated in parts of the stomach, following activation of K-ras in mice. Cyclooxygenase 2 (COX-2), a mediator of inflammation, is also upregulated in parts of the stomach of the K-ras activated mice with concomitant infiltration of hematopoietic cells in the hyperplastic tissue. Moreover, in K-ras activated mice, the expression of putative progenitor cell marker Dcamkl1 is upregulated in the glandular stomach. Expression of CD44, a candidate stomach cancer stem cell marker, is also increased in forestomach and the glandular stomach. These results suggest that cells of the stomach, potentially stem or progenitor cells, are highly susceptible to K-ras activation-induced initiation of gastric precancerous lesions. The histological changes in the K-ras activated mice resemble the pre-neoplastic changes that take place during gastric carcinogenesis in humans. Thus, a mouse model with systemic K-rasG12D activation could be useful for studying the early molecular events leading to gastric carcinogenesis.
PMCID: PMC3134228  PMID: 21761008
K-ras; intestinal metaplasia; gastric stem cells; Dcamkl1; CD44
13.  FHIT gene expression is repressed by mitogenic signaling through the PI3K/AKT/FOXO pathway 
The Fragile Histidine Triad gene or FHIT functions as tumor suppressor in many epithelial cell types. Although its tumor suppressive mechanism is the subject of intense study, less is known about how FHIT gene expression itself is regulated. Here we show that PI3 kinase and its downstream target AKT suppress FHIT gene expression in response to growth factor stimulation in actively cycling cells. Upon removal of mitogens from the culture environment, FHIT mRNA and protein levels are observed to increase as a result of derepression from these protooncogenic kinases. AKT signaling through the FOXO transcription factors appears to be the basis for FHIT gene regulation. Increases in FHIT gene expression are directly dependent on endogenous FOXO3a in MCF7 breast carcinoma cells as evidenced by experiments with RNAi targeting FOXO transcription factor family members. Thus, this is the first report demonstrating that FHIT gene expression is normally repressed in actively cycling cells through the PI3K/AKT/FOXO3a axis.
PMCID: PMC3130617  PMID: 21743838
FHIT; mitogen signaling; PI3K; AKT; FOXO
14.  Role of the WWOX tumor suppressor gene in bone homeostasis and the pathogenesis of osteosarcoma 
Osteosarcoma is the most common primary bone malignancy in children with unknown etiology and often with poor clinical outcome. In recent years, a critical role has emerged for the WW domain-containing oxidoreductase (WWOX) in osteosarcoma and bone biology. WWOX is a tumor suppressor that is deleted or attenuated in most human tumors. Wwox-deficient mice develop osteosarcoma and a bone metabolic disease characterized by hypocalcemia and osteopenia. Studies of human osteosarcomas have revealed that the WWOX gene is deleted in 30% of cases and WWOX protein is absent or reduced in ~60% of tumors. Further, WWOX levels are attenuated in the majority of osteosarcoma cells, in which ectopic expression is associated with reduced proliferation, migration, invasion and tumorigenicity. At the molecular level, WWOX associates with RUNX2 and suppresses its transcriptional activity in osteoblasts and in cancer cells. This review provides new insights on the current knowledge of the spectrum of WWOX activities and future directions for the role of WWOX in bone biology and osteosarcoma.
PMCID: PMC3124638  PMID: 21731849
Tumor suppressor; WWOX; osteosarcoma; WW domain; RUNX2; osteoblast
15.  Genomic profiling of genes contributing to metastasis in a mouse model of thyroid follicular carcinoma 
Metastasis is the major cause of thyroid cancer-related death. However, little is known about the genes involved in the metastatic spread of thyroid carcinomas. We have created a mouse that spontaneously develops metastatic follicular thyroid carcinoma (FTC). This mouse harbors a targeted mutation (denoted TRβPV) in the thyroid hormone receptor β gene (ThrbPV/PV mice). Our recent studies show that the highly elevated level of thyroid stimulating hormone (TSH) in ThrbPV/PV mice promotes proliferation of thyroid tumor cells, but requires the collaboration of the oncogenic action of TRβPV to empower the tumor cells to undergo distant metastasis. To uncover genes destined to drive the metastatic process, we used cDNA microarrays to compare the genomic expression profile of laser capture microdissected thyroid tumor lesions of ThrbPV/PV mice with that of hyperplastic thyroid cells of wild-type mice having elevated TSH induced by treatment with the anti-thyroid drug propylthiouracil (WT-PTU mice). Analyses of microarray data indicated that the expressions of 150 genes were significantly altered between ThrbPV/PV and WT-PTU mice (87 genes had higher expression and 63 genes had lower expression in ThrbPV/PV mice than in WT-PTU mice). Thirty-six percent of genes with altered expression function as key regulators in metastasis. The remaining genes were involved in various cellular processes including metabolism, intracellular trafficking, transcriptional regulation, post-transcriptional modification, and cell-cell/extracellular matrix signaling. The present studies have uncovered novel genes responsible for the metastatic spread of FTC and, furthermore, have shown that the metastatic process of thyroid cancer requires effective collaboration among genes with diverse cellular functions. Importantly, the present studies indicate that the tumor cells in the primary lesions are endowed with the genes destined to promote metastasis. Thus, our study has provided new insights into the understanding of the metastatic spread of human thyroid cancer.
PMCID: PMC3090007  PMID: 21562609
Metastasis; thyroid cancer; mouse model; microarray; gene expression
16.  Global expression profiling reveals gain-of-function oncogenic activity of a mutated thyroid hormone receptor in thyroid carcinogenesis 
Thyroid hormone receptors (TRs) are critical in regulating gene expression in normal physiological processes. Decreased expression and/or somatic mutations of TRs have been shown to be associated several types of human cancers including liver, breast, lung, and thyroid. To understand the molecular mechanisms by which mutated TRs promote carcinogenesis, an animal model of follicular thyroid carcinoma (FTC) (ThrbPV/PV mice) was used in the present study. The ThrbPV/PV mouse harbors a knockin dominant negative PV mutation, identified in a patient with resistance to thyroid hormone. To understand whether oncogenic actions of PV involve not only the loss of normal TR functions but also gain-of-function activities, we compared the gene expression profiles of thyroid lesions in ThrbPV/PV mice and Thra1−/−Thrb−/− mice that also spontaneously develop FTC, but with less severe malignancy. Analysis of the cDNA microarray data derived from microdissected thyroid tumor cells of these two mice showed contrasting global gene expression profiles. With stringent selection using 2.5-fold change (p<0.01) in cDNA microarray analysis, 241 genes with altered gene expression were identified. Nearly half of the genes (n=103: 42.7% of total) with altered gene expression in thyroid tumor cells of ThrbPV/PV mice were associated with tumorigenesis and metastasis; some of these genes function as oncogenes in human thyroid cancers. The remaining genes were found to function in transcriptional regulation, RNA processing, cell proliferation, apoptosis, angiogenesis, and cytoskeleton modification. These results indicate that the more aggressive thyroid tumor progression in ThrbPV/PV mice was not due simply to the loss of tumor suppressor functions of TR via mutation but also, importantly, to gain-of-function in the oncogenic activities of PV to drive thyroid carcinogenesis. Thus, the present study identifies a novel mechanism by which a mutated TRβ evolves with an oncogenic advantage to promote thyroid carcinogenesis.
PMCID: PMC3086765  PMID: 21547001
Mutant TR; thyroid cancer; mouse model; microarray; gene expression

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