Cancer biology & therapy (Canc Biol Ther)

Publisher: Taylor & Francis

Journal description

Cancer, the second leading cause of death, is a heterogenous group of over 100 diseases. Cancer is characterized by disordered and deregulated cellular and stromal proliferation accompanied by reduced cell death with the ability to survive under stresses of nutrient and growth factor deprivation, hypoxia, and loss of cell-to-cell contacts. At the molecular level, cancer is a genetic disease that develops due to the accumulation of mutations over time in somatic cells. The phenotype includes genomic instability and chromosomal aneuploidy that allows for acceleration of genetic change. Malignant transformation and tumor progression of any cell requires immortalization, loss of checkpoint control, deregulation of growth, and survival. A tremendous amount has been learned about the numerous cellular and molecular genetic changes and the host-tumor interactions that accompany tumor development and progression. It is the goal of the field of Molecular Oncology to use this knowledge to understand cancer pathogenesis and drug action, as well as to develop more effective diagnostic and therapeutic strategies for cancer. This includes preventative strategies as well as approaches to treat metastases. With the availability of the human genome sequence and genomic and proteomic approaches, a wealth of tools and resources are generating even more information. The challenge will be to make biological sense out of the information, to develop appropriate models and hypotheses and to translate information for the clinicians and the benefit of their patients. Cancer Biology & Therapy aims to publish original research on the molecular basis of cancer, including articles with translational relevance to diagnosis or therapy. We will include timely reviews covering the broad scope of the journal. The journal will also publish op-ed pieces and meeting reports of interest. The goal is to foster communication and rapid exchange of information through timely publication of important results using traditional as well as electronic formats. The journal and the outstanding Editorial Board will strive to maintain the highest standards for excellence in all activities to generate a valuable resource.

Current impact factor: 3.29

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2011 Impact Factor 2.636

Additional details

5-year impact 3.33
Cited half-life 4.70
Immediacy index 0.39
Eigenfactor 0.02
Article influence 1.00
Website Cancer Biology and Therapy website
Other titles Cancer biology & therapy (Online), Cancer biology & therapy, Cancer biology and therapy
ISSN 1555-8576
OCLC 60037853
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Taylor & Francis

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    • STM: Science, Technology and Medicine
    • Publisher last contacted on 25/03/2014
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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Constitutive activation of AKT is a frequent occurrence in the development of human T-cell acute lymphocytic leukemia/lymphomas (T-ALLs), due largely to inactivation of PTEN. Up regulation of MYC is also commonly observed in human T-ALLs. We previously demonstrated that expression of a constitutively active form of Lck-Akt2 alone is sufficient to initiate T-cell lymphoma in mice, and that tumor formation typically requires up regulation of Myc or Dlx5 caused by specific chromosomal rearrangements. Furthermore, Lck-Dlx5 mice develop T-ALLs that consistently acquire overexpression of Myc and activation of Akt, the latter due to loss of Pten expression. Proliferation of T-ALL cells from Lck-Dlx5 mice was found to be highly sensitive to the Akt pathway inhibitors BEZ235 and RAD001, as well as to JQ1, an inhibitor of bromodomain proteins, one of which (BRD4) regulates Myc transcription. Additionally, low concentrations of BEZ235 were found to cooperate with JQ1 to enhance cell cycle arrest. Higher concentrations of BEZ235 (≥0.5 µM) promoted cell death, although the addition of JQ1 did not result in a further increase in apoptosis. In contrast, the specific Myc inhibitor 10058-F4 caused apoptosis, and when combined with BEZ235 (≥0.5 µM), an enhanced effect on apoptosis was consistently observed. In addition, BEZ235 and RAD001 potentiated vincristine-induced apoptosis when the cells were treated with both drugs simultaneously, whereas pretreatment with BEZ235 antagonized the cell-killing effect of vincristine. Collectively, these experimental findings provide rationale for the design of novel combination therapies for T-ALL that includes targeting of AKT and MYC.
    Cancer biology & therapy 03/2015; DOI:10.1080/15384047.2015.1018495
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    ABSTRACT: Metastatic spread is the most common cause of cancer-related death in colorectal cancer (CRC) patients, with the liver being the mostly affected organ. Circulating tumor cells (CTCs) are a prognostic marker in stage IV CRC. We hypothesized that tumor burden in the liver correlates with CTC quantity. Blood (7.5 ml) was prospectively collected from 24 patients with novel stage IV CRC diagnosis. Baseline EpCAM+ CTCs were analyzed with the FDA-approved CellSearch(→) system. Clinicopathological data were collected, and hepatic tumor burden was determined by radiographic liver volumetry with contrast-enhanced CT scans. CRC primary tumors were immunohistochemically stained for EpCAM expression with BerEP4 monoclonal antibody. Statistical analyses were performed using two-sample T-test, non-parametric Wilcoxon Rank-Sum test, and Fisher's exact test. CTCs were detected n 17 (71%) of 24 patients. The overall mean CTC number as determined by EpCAM-based CellSearch(→) detection was 6.3 (SEM 2.9). High baseline CTC numbers (≥3) correlated significantly with a high tumor/liver ratio (≥30%), and with high serum CEA levels, as determined by two-sample T-test on log-transformed data and by Fisher's Exact test on categorical data analysis (p<0.05). The CRC primary tumors were consistently expressing EpCAM by immunostaining. High tumor burden in the liver and high baseline serum CEA levels are associated with high number of baseline CTCs in stage IV CRC patients. Future studies should further investigate the biological role and expression patterns of single CTCs in cancer patients to further improve personalized treatment strategies.
    Cancer biology & therapy 03/2015; DOI:10.1080/15384047.2015.1026508
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    ABSTRACT: Hes1 is one mammalian counterpart of the Hairy and Enhancer of split proteins that play a critical role in many physiological processes including cellular differentiation, cell cycle arrest, apoptosis and self-renewal ability. Recent studies have shown that Hes1 functions in the maintenance of cancer stem cells (CSCs), metastasis and antagonizing drug-induced apoptosis. Pathways that are involved in the up-regulation of Hes1 level canonically or non-canonically, such as the Hedgehog, Wnt and hypoxia pathways are frequently aberrant in cancer cells. Here, we summarize the recent data supporting the idea that Hes1 may have an important function in the maintenance of cancer stem cells self-renewal, cancer metastasis, and epithelial-mesenchymal transition (EMT) process induction, as well as chemotherapy resistance, and conclude with the possible mechanisms by which Hes1 functions have their effect, as well as their crosstalk with other carcinogenic signaling pathways.
    Cancer biology & therapy 03/2015; DOI:10.1080/15384047.2015.1016662
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    ABSTRACT: Recent studies indicate that post-translational protein neddylation is required for the maintenance of cell viability in several lymphoma cell lines, while inhibition of the neddylation pathway with an NEDD8-activating enzyme (NAE) inhibitor MLN4924 induces apoptosis in lymphoma cells. However, the mechanism by which neddylation inhibition induces apoptosis in lymphoma cells has not been fully elucidated. Moreover, it is unknown whether neddylation inhibition triggers non-apoptotic cell-killing responses, such as cell senescence, in lymphoma cells. Here, we report that MLN4924 specifically inhibited protein neddylation, inactivated cullin-RING E3 ligase (CRL), the best-known neddylation substrate, and induced the accumulation of tumor-suppressive CRL substrates in lymphoma cells. Moreover, MLN4924 potently suppressed the growth of lymphoma cells by inducing G2 cell-cycle arrest, followed by apoptosis or senescence in a cell-line dependent manner. MLN4924-induced apoptosis was mediated by intrinsic apoptotic signaling with substantial up-regulation of pro-apoptotic Bik and Noxa as well as down-regulation of anti-apoptotic XIAP, c-IAP1 and c-IAP2, while senescence induction upon neddylation inhibition seemed dependent on the expression of tumor suppressor p21/p27. Together, these findings expand our understanding on how lymphoma cells respond to neddylation inhibition and support the development of neddylation inhibitors (e.g. MLN4924) for the treatment of lymphoma.
    Cancer biology & therapy 03/2015; DOI:10.1080/15384047.2014.1003003
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    ABSTRACT: NCCN states that chemotherapies for advanced esophageal and gastric cancers may be used interchangeably. Biomarkers from gastroesophageal cancer patients were interrogated to identify actionable alterations with therapeutic implications. 666 gastric and 640 esophageal cancer cases referred to Caris Life Sciences between 2009 thru 2013 were evaluated. Specific testing was performed, which included a combination of sequencing (Sanger, NGS) and protein expression (IHC). In the complete cohort (n=1306), 30 of 45 genes tested harbored mutations; highest rates were seen in TP53 (54%), APC (10%), SMAD4 (5.9%), KRAS (5.9%), and PIK3CA (5.1%). IHC of TOP2A was high in 76% of cases, TOPO1 in 51% and SPARC in 25%; low IHC of ERCC1 was seen in 65%, RRM1 in 62%, TS in 61% and MGMT in 45%, indicating potential benefit from epirubicin, irinotecan, nab-paclitaxel, platinum-based agents, gemcitabine, 5FU/capecitabine and temozolomide, respectively. In the HER2+ cohort (n=88), 50% of patients demonstrated possible benefit from a combination of trastuzumab with 5FU/capecitabine based on concurrent low TS, 53% with irinotecan (high TOPO1), 63% with cisplatin (low ERCC1) and 55% with gemcitabine (low RRM1). Subgroup analysis by tumor origin demonstrated significant differences in actionable biomarker profiles with HER2 (13% vs. 4.6%), SPARC (34% vs. 15%), TOP2A (86% vs. 67%), and TOPO1 (55% vs. 46%) in esophageal and gastric adenocarcinoma cases respectively (p<0.05). A comprehensive multiplatform biomarker analysis suggested significant biomarker differences between gastric and esophageal cancers. These results can assist in the development of future clinical trials.
    Cancer biology & therapy 03/2015; DOI:10.1080/15384047.2015.1026479
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    ABSTRACT: Mitogen activated protein kinase phosphatase-1 (MKP-1) has emerged as an important protein mediating breast cancer oncogenesis and chemoresistance to cancer chemotherapies, especially proteasome inhibitors. In this in vitro study, we utilized the breast cancer epithelial cell lines MCF-7 and MDA-MB-231, in comparison to MCF-10A control cells, to examine the impact of MKP-1 on breast cancer cell growth and repression by proteasome inhibitors. We confirm that proteasome inhibitors MG-132 and bortezomib induce MKP-1 protein upregulation and we show that one of the ways in which bortezomib increases MKP-1 in breast cancer cells, in addition to inhibition of ubiquitin-proteasome system, is via upregulation of MKP-1 mRNA expression in p38 MAPK-mediated manner. Notably, these effects are specific to cancer cells, as bortezomib activated p38 MAPK and induced MKP-1 in MCF-7 and MDA-MB-231 breast cancer cells, but not in control cells (MCF-10A). We took a dual approach towards targeting MKP-1 to show that bortezomib-induced effects are enhanced. Firstly, treatment with the non-specific MKP-1 inhibitor triptolide reduces breast cancer cell growth and augments proteasome inhibitor-induced effects. Secondly, specific knock-down of MKP-1 with siRNA significantly repressed cell viability by reduced cyclin D1 expression, and enhanced repression of cancer cell growth by proteasome inhibitors. Taken together, these results indicate that removing the unwanted (MKP-1-inducing) effects of bortezomib significantly improves the efficacy of proteasome inhibition in breast cancer cells. Thus, future development of drugs targeting MKP-1 offer promise of combination therapies with reduced toxicity and enhanced cell death in breast cancer.
    Cancer biology & therapy 03/2015; DOI:10.1080/15384047.2015.1026465
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    ABSTRACT: Glucocorticoid (GC) resistance remains a major obstacle to successful treatment of lymphoid malignancies. Till now, the precise mechanism of GC resistance remains unclear. In the present study, dexamethasone (Dex) inhibited cell proliferation, arrested cell cycle in G0/G1-phase, and induced apoptosis in Dex-sensitive acute lymphoblastic leukemia cells. However, Dex failed to cause cell death in Dex-resistant lymphoid malignant cells. Intriguingly, we found that autophagy was induced by Dex in resistant cells, as indicated by autophagosomes formation, LC3-I to LC3-II conversion, p62 degradation, and formation of acidic autophagic vacuoles. Moreover, the results showed that Dex reduced the activity of mTOR pathway, as determined by decreased phosphorylation levels of mTOR, Akt, P70S6K and 4E-BP1 in resistant cells. Inhibition of autophagy by either chloroquine (CQ) or 3-methyladenine (3-MA) overcome Dex-resistance in lymphoid malignant cells by increasing apoptotic cell death in vitro. Consistently, inhibition of autophagy by stably knockdown of Beclin1 sensitized Dex-resistant lymphoid malignant cells to induction of apoptosis in vivo. Thus, inhibition of autophagy has the potential to improve lymphoid malignancy treatment by overcoming GC resistance.
    Cancer biology & therapy 03/2015; DOI:10.1080/15384047.2015.1016658
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    ABSTRACT: Lung cancers express non-neuronal, cholinergic autoparacrine loop, which facilitates tumor growth. Interruption of M3 muscarinic cholinergic signaling has been reported to inhibit small cell lung cancer (SCLC) growth. The purpose of this study is to investigate if blocking autoparacrine muscarinic cholinergic signaling could inhibit non-small cell lung cancer (NSCLC) growth and possible underlying mechanisms. Our results showed that PC9 and A549 cells expressed all five subtypes of muscarinic receptor (mAChR) and blocking M2 mAChR (M2R) signaling using selective antagonist methoctramine or short hairpin RNA (shRNA) inhibited tumor cell proliferation in vitro and in vivo. Consistent with AChR agonists stimulating p44/42 MAPK (Erk1/2) and Akt phosphorylation, blocking M2R signaling decreased MAPK and Akt phosphorylation, indicating that non-neuronal ACh functions as an autoparacrine growth factor signaling in part through activation of M2R and downstream MAPK and Akt pathways. Importantly, further studies revealed that blocking M2R signaling also reversed epithelial-mesenchymal transition (EMT) in vitro and in vivo, indicating that non-neuronal ACh promotes EMT partially through activation of M2R. These findings demonstrate that M2R plays a role in the growth and progression of NSCLC and suggest M2R antagonists may be an efficacious adjuvant therapy for NSCLC.
    Cancer biology & therapy 03/2015; DOI:10.1080/15384047.2015.1029835
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    ABSTRACT: Arginine auxotrophy constitutes a weak point of several tumors, among them glioblastoma multiforme (GBM). Hence, those tumors are supposed to be sensitive for arginine-depleting substances, such as arginine deiminase (ADI). Here we elucidated the sensitivity of patient-individual GBM cell lines towards Streptococcus pyogenes-derived ADI. To improve therapy, ADI was combined with currently established and pre-clinical cytostatic drugs. Additionally, effectiveness of local ADI therapy was determined in xenopatients. Half of the GBM cell lines tested responded well towards ADI monotherapy. In those cell lines, viability decreased significantly (up to 50%). Responding cell lines were subjected to combination therapy experiments to test if any additive or even synergistic effects may be achieved. Such promising results were obtained in 2/3 cases. In cell lines HROG02, HROG05 and HROG10, ADI and Palomid 529 combinations were most effective yielding more than 70% killing after two rounds of treatment. Comparable boosted antitumoral effects were observed after adding chloroquine to ADI (> 60 % killing). Apoptosis, as well as cell cycle dysregulation were found to play a minor role. In some, but clearly not all cases, (epi-) genetic silencing of arginine synthesis pathway genes (argininosuccinate synthetase 1 and argininosuccinate lyase) explained obtained results. In vivo, ADI as well as the combination of ADI and SAHA efficiently controlled HROG05 xenograft growth, whereas adding Palomid 529 to ADI did not further increase the strong antitumoral effect of ADI. The cumulative in vitro and in vivo results proved ADI as a very promising candidate therapeutic, especially for development of adjuvant GBM combination treatments.
    Cancer biology & therapy 03/2015; DOI:10.1080/15384047.2015.1026478
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    ABSTRACT: In the present study, we examined the mechanisms of oxaliplatin-induced drug resistance in human colorectal cancer cell lines HT29 and HCT116. Our results demonstrate a significant autophagy expression in CRC cells after an oxaliplatin treatment. Administration of oxaliplatin to human CRC cells significantly enhanced the expression of HMGB1, which regulated the autophagy response and negatively regulate the cell apoptosis. Moreover, a decreased oxaliplatin -induced autophagy response and an increased apoptosis level were detected in stable CRC cells harboring HMGB1 shRNA. Then we noted that HMGB1 significantly induced extracellular signal-regulated kinase (ERK) / Extracellular signal-regulated kinase kinase (MEK) phosphorylation. Taken together, these data suggest that HMGB1-mediated autophagy modulates sensitivity of colorectal cancer cells to oxaliplatin via MEK/ERK signaling pathway.
    Cancer biology & therapy 03/2015; DOI:10.1080/15384047.2015.1017691
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    ABSTRACT: Natural compound schweinfurthins are of considerable interest for novel therapy development because of their selective anti-proliferative activity against human cancer cells. We previously reported the isolation of highly active schweinfurthins E-H, and in the present study, mechanisms of the potent and selective anti-proliferation were investigated. We found that schweinfurthins preferentially inhibited the proliferation of PTEN deficient cancer cells by indirect inhibition of AKT phosphorylation. Mechanistically, schweinfurthins and their analogs arrested trans-Golgi-network trafficking, an intracellular vesicular trafficking system, resulting in the induction of endoplasmic reticulum stress and the suppression of both lipid raft-mediated PI3K activation and mTOR/RheB complex formation, which collectively led to an effective inhibition of mTOR/AKT signaling. The trans-Golgi-network traffic arresting effect of schweinfurthins was associated with their in vitro binding activity to oxysterol-binding proteins that are known to regulate intracellular vesicular trafficking. Moreover, schweinfurthins were found to be highly toxic toward PTEN-deficient B cell lymphoma cells, and displayed two orders of magnitude lower activity toward normal human peripheral blood mononuclear cells and primary fibroblasts in vitro. These results revealed a previously unrecognized role of schweinfurthins in regulating trans-Golgi-network trafficking, and linked mechanistically this cellular effect with mTOR/AKT signaling and with cancer cell survival and growth. Our findings suggest the schweinfurthin class of compounds as a novel approach to modulate oncogenic mTOR/AKT signaling for cancer treatment.
    Cancer biology & therapy 03/2015; DOI:10.1080/15384047.2015.1019184
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    ABSTRACT: Background RACK1 is known to be involved in tumor progression, and its prognostic value on many kinds of tumors has been identified. However, there are limited studies about the functional role of RACK1 in esophageal squamous cell carcinoma (ESCC). Patients and methods RACK1 expression was examined in 100 ESCC tissue samples using immunohistochemistry staining. RACK1 was knocked-down in ESCC cell lines by shRNA. The effects on cell proliferation, invasion and migration were examined in ESCC cell lines and nude mouse model. Vimentin and E-cadherin were introduced to further study the association between RACK1 and EMT. Results RACK1 expression was significantly associated with the tumor length(P=0.012), diameter<3cm (P=0.047), T stage (P=0.032), and lymph node metastasis (P= 0.038), respectively. Kaplan-Meier survival analysis and Cox analyses revealed RACK1 expression was an independent predictor for OS (P=0.030) and DFS (P=0.027) in ESCC. Down-regulation of RACK1 inhibited cell proliferation, along with invasion and migration in vitro and in vivo. A significant positive correlation between RACK1 expression and vimentin (P=0.0190) and an inverse correlation between RACK1 expression and E-cadherin (P=0.0047) were found. Conclusions RACK1 predicted poor prognosis in ESCC, promoted tumor progression, and was involved in EMT of ESCC.
    Cancer biology & therapy 02/2015; DOI:10.1080/15384047.2015.1016687
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    ABSTRACT: Accumulating evidence suggests that changes in methylation patterns may help mediate the sensitivity or resistance of cancer cells to ionizing radiation. The present study provides evidence for the involvement of radioresistance-induced DNA methylation changes in tumor radioresistance. We established radioresistant laryngeal cancer cells via long-term fractionated irradiation, and examined differences in DNA methylation between control and radioresistant laryngeal cancer cells. Interestingly, we found that the promoter-CpG islands of five previously identified radioresistance-related genes (TOPO2A, PLXDC2, ETNK2, GFI1, and IL12B) were significantly altered in the radioresistant laryngeal cancer cells. Furthermore, the demethylation of these gene promoters with a DNA methyltransferase inhibitor (5-aza-2'-deoxycytidine) increased their transcription levels. Treatment with 5-aza-2'-deoxycytidine also sensitized the radioresistant laryngeal cancer cells to irradiation, indicating that changes in DNA methylation contributed to their radioresistance. Of the tested genes, the expression and activity levels of TOPO2A were tightly associated with the radioresistant phenotype in our system, suggesting that the hypermethylation of TOPO2A might be involved in this radioresistance. Collectively, our data suggest that radiation-induced epigenetic changes can modulate the radioresistance of laryngeal cancer cells, and thus may prove useful as prognostic indicators for radiotherapy.
    Cancer biology & therapy 02/2015; DOI:10.1080/15384047.2015.1017154
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    ABSTRACT: Phosphoglycerate dehydrogenase (PHGDH) is the key enzyme of de novo serine biosynthesis. Previous reports have demonstrated that PHGDH plays an important role in some malignancies. However, the biological role of PHGDH in human cervical adenocarcinoma has not been explored. We examined the expression of PHGDH in 54 cervical adenocarcinoma samples by immunohistochemistry and evaluated the association with clinicopathological parameters and prognosis. We performed shRNA transfection to knock down PHGDH gene expression in HeLa cells. A cell proliferation test, cisplatin cytotoxicity test and apoptosis test examined the HeLa cell line after PHGDH knockdown in vitro. In vivo tumorigenesis was assessed using a mouse xenograft model. Moreover, we examined the effects on Bcl-2 and cleaved caspase-3 expression after knockdown of PHGDH and treatment of cisplatin for 48h by Western blot. In this study, we demonstrated that elevated PHGDH expression was found in cervical adenocarcinoma and was associated with tumor size and prognosis. Knocking down PHGDH in HeLa cells significantly inhibited cell proliferation and increased cisplatin chemotherapy sensitivity. Silencing PHGDH resulted in inhibition of tumorigenesis in vivo. Furthermore, PHGDH knockdown reduced Bcl-2 and increased cleaved caspase-3 expression. Collectively, our study indicates the novel roles of PHGDH in cervical adenocarcinoma and identifies PHGDH as a new anticancer target.
    Cancer biology & therapy 02/2015; DOI:10.1080/15384047.2015.1017690
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    ABSTRACT: Glioblastomas multiforme (GBM) are the most frequently occurring malignant brain cancers. Treatment for GBM consists of surgical resection and subsequent adjuvant radiation therapy and chemotherapy. Despite this, GBM patient survival is limited to 12-15 months, and researchers are continually trying to develop improved therapy options. Insulin-like growth factor 2 mRNA-binding protein 2 (Imp2) is known to be upregulated in many cancers and is known to regulate the signaling activity of insulin-like growth factor 2 (IGF2). However, relatively little is known about its role in malignant development of GBM. In this study, we first found Imp2 is upregulated in GBM tissues by using clinical samples and public database search. Studies with loss and gain of Imp2 expression in in vitro GBM cell culture system demonstrated the role of Imp2 in promoting GBM cell proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT). Additionally, our results show that Imp2 regulates the activity of IGF2, which further activates PI3K/Akt signaling, thereby to promote GBM malignancy. Inhibition of Imp2 was also found to sensitize GBM to temozolomide treatment. These observations add to the current knowledge of GBM biology, and may prove useful in development of more effective GBM therapy.
    Cancer biology & therapy 02/2015; DOI:10.1080/15384047.2015.1019185
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    ABSTRACT: Bevacizumab and Tamoxifen are valid therapeutic options for metastatic breast cancer (mBC) patients. In this report, we describe a 47 year old woman with mBC successfully treated with a maintenance therapy with Bevacizumab+Tamoxifen. A maintenance approach using two different drugs with different targets and mechanism of action, such as anti-angiogenic and anti-hormonal treatment is particularly intriguing because they affect different pathways involved in mBC progression. Further studies including a large number of patients are needed, in order to select women who could benefit from this maintenance approach.
    Cancer biology & therapy 02/2015; DOI:10.1080/15384047.2015.1017692
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    ABSTRACT: Inadequate delivery of therapeutics into tumors has been suggested as a reason for poor response. We hypothesize that bevacizumab, an antibody to vascular endothelial growth factor (VEGF), can improve cetuximab uptake in squamous cell carcinoma tumors. Athymic nude mice were implanted with OSC19 and SCC1 human cancer lines in a subcutaneous flank model. Mice were imaged daily for 14 days after intravenous tail vein injections of the following groups: IgG-IRDye800 (Control), cetuximab-IRDye800 (CTX800 Only), bevacizumab-IRDye800 (BVZ800 Only), cetuximab-IRDye800 + bevacuzimuab-IRDye800 (Simultaneous), and unlabeled bevacizumab followed by cetuximab-IRDye800 3 days later (Neoadjuvant). Within single-agent groups, the CTX800 Only tumor-specific uptake (TSU) was significantly higher than BVZ800 Only at Day 13 (TSU 8.6 vs 2.8, p<0.001). The Simultaneous treatment with BVZ800 and CTX800 demonstrated no increase in antibody delivery. However, administration of unlabeled bevacizumab 3 days prior to CTX800 (Neoadjuvant group) resulted in significantly higher tumor specific delivery than administration of both antibodies at the same time (11.8 vs Simultaneous 5.0, p<0.001). This difference can be attributed to a slower decline in tumor fluorescence intensity (-6.8% vs. Simultaneous -11.5% per day, respectively). Structural changes in pericyte coverage and functional vessel changes demonstrating decreased proliferation and tumor growth corroborate these fluorescence results. Although simultaneous administration of bevacizumab with cetuximab failed to increase antibody delivery to the tumor, pretreatment with bevacizumab improved TSU reflecting an increase in tumor-specific uptake of cetuximab as a result of vessel normalization.
    Cancer biology & therapy 02/2015; DOI:10.1080/15384047.2015.1016664
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    ABSTRACT: Pancreatic cancer has a dismal prognosis. A technically perfect surgical operation may still not provide a survival advantage for patients with technically resectable pancreatic cancer. Appropriate selection of patients for surgical resections is an imminent issue. Recent studies have provided an important clue on what serum biomarkers may be used to select out the patients who would unlikely benefit from the surgical resection.
    Cancer biology & therapy 02/2015; DOI:10.1080/15384047.2014.1002699
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    ABSTRACT: The ability of living cells to exert physical forces upon their surrounding is the necessary prerequisite for diverse biological processes, such as local cellular migrations in wound healing to metastatic-invasion of cancer. How forces are coopted in metastasis has remained unclear, however, because the mechanical interplay between cancer cells and the various stromal components has not been experimentally accessible. Current dogma implicates inflammation in these mechanical processes. Using Fourier transform traction microscopy, we measured the force-generating capacity of human breast cancer cells occupying a spectrum of invasiveness as well as basal and inducible COX-2 expression (MCF-7<SUM-149<MDA-MB-231). Compared with non-invasive MCF-7 and moderately-invasive SUM-149, poorly-differentiated MDA-MB-231 cells showed increased cellular dispersion on collagen matrix that was accompanied by emergent distribution of contractile stresses at the interface between the adherent cell and its substrate, defined herein as the traction field. In metastatic MDA-MB-231 cells, the local tractions were precisely tuned to the surrounding matrix rigidity in a physiologic range with the concomitant expression of mechanosensitive integrin β1. These discrete responses at the single-cell resolution were correlated with PGE2 secretion and were ablated by shRNA-mediated knockdown of COX-2. Both COX-2-silenced and COX-2-expressing cells expressed EP2 and EP4 receptors, but not EP1 and EP3. Exogenous addition of PGE2 increased cell tractions and stiffened the underlying cytoskeletal network. To our knowledge this is the first report linking the expression of COX-2 with mechanotransduction of human breast cancer cells, and the regulation of COX-2-PGE2-EP signaling with physical properties of the tumor microenvironment. Drug treatments aimed at reducing this mechanical interplay may have therapeutic potential in the treatment of breast cancer.
    Cancer biology & therapy 02/2015; DOI:10.1080/15384047.2014.1003004
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    ABSTRACT: Methionine enkephalin (MENK), an endogenous neuropeptide, plays an crucial role in both neuroendocrine and immune systems. CD4+Foxp3+ regulatory T cells (Tregs) are identified as a major subpopulation of T lymphocytes in suppressing immune system to keep balanced immunity. The aim of this research work was to elucidate the mechanisms via which MENK interacts with Tregs in cancer situation. The influence of MENK on transforming growth factor-β (TGF-β) mediated conversion from naïve CD4+CD25- T cells to CD4+CD25+ Tregs was determined and the data from flow cytometry (FCM) analysis indicated that MENK effectively inhibited the expression of Foxp3 during the process of TGF-βinduction. Furthermore, this inhibiting process was accompanied by diminishing phosphorylation and nuclear translocation of Smad2/3, confirmed by western blot (WB) analysis and immunofluorescence (IF) at molecular level. We established sarcoma mice model with S180 to investigate whether MENK could modulate Tregs in tumor circumstance. Our findings showed that MENK delayed the development of tumor in S180 tumor bearing mice and down-regulated level of Tregs. Together, these novel findings reached a conclusion that MENK could inhibit Tregs activity directly and retard tumor development through down-regulating Tregs in mice. This work advances the deepening understanding of the influence of MENK on Tregs in cancer situation, and relation of MENK with immune system, supporting the implication of MENK as a new strategy for cancer immunotherapy.
    Cancer biology & therapy 02/2015; DOI:10.1080/15384047.2014.1003006