Cancer Letters

Editorial Board

2012-04-01

Sleeping Beauty – A mouse model for all cancers?

Viive M. Howell — 2011-12-09

Abstract: Sleeping Beauty (SB) is a genetically engineered insertional mutagenesis system. Its ability to rapidly induce cancer in SB-transgenic mice as well as the ease of identification of the mutated genes suggest important roles for SB in the discovery of novel cancer genes as well as the generation of models of human cancers where none currently exist. The range of SB-related tumors extends from haematopoietic to solid cancers such as hepatocellular carcinoma. This review follows the refinement of SB for different cancers and assesses its potential as a model for all cancers and a tool for cancer gene discovery.

Bortezomib enhances radiation-induced apoptosis in solid tumors by inhibiting CIP2A

2011-12-02

Abstract: Previously, we demonstrated that cancerous inhibitor of protein phosphatase 2A (CIP2A) mediates bortezomib-induced apoptosis in hepatocellular carcinoma cells. Herein, we report that bortezomib sensitizes solid tumor cells to radiation-induced apoptosis. Treatment with a combination of bortezomib and radiation downregulated CIP2A in a dose-dependent manner in solid tumor cells. Knockdown of CIP2A enhanced radiation-induced apoptosis in cancer cells, and ectopic expression of CIP2A in cancer cells abolished radiation-induced apoptosis. Finally, our in vivo data showed that bortezomib and radiation combination treatment decreased tumor growth significantly. Thus, bortezomib sensitized solid tumor cells to radiation through the inhibition of CIP2A.

Irreversible electroporation shows efficacy against pancreatic carcinoma without systemic toxicity in mouse models

Anabel José, Luciano Sobrevals, Antoni Ivorra, Cristina Fillat — 2011-11-30

Abstract: Pancreatic ductal adenocarcinoma (PDAC) therapies show limited success. Irreversible electroporation (IRE) is an innovative loco-regional therapy in which high-voltage pulses are applied to induce plasma membrane defects leading to cellular death. In the present study we evaluated the feasibility of IRE against PDAC. IRE treatment exhibited significant antitumor effects and prolonged survival in mice with orthotopic xenografts. Extensive tumor necrosis, reduced tumor cell proliferation and disruption of microvessels were observed at different days post-IRE. Animals had transient increases in transaminases, amylase and lipase enzymes that normalized at 24h post-IRE. These results suggest that IRE could be an effective treatment for locally advanced pancreatic tumors.

LCH-7749944, a novel and potent p21-activated kinase 4 inhibitor, suppresses proliferation and invasion in human gastric cancer cells

2011-12-02

Abstract: P21-activated kinase 4 (PAK4), a serine/threonine protein kinase, has involved in the regulation of cytoskeletal reorganization, cell proliferation, gene transcription, oncogenic transformation and cell invasion. Moreover, PAK4 overexpression, genetic amplification and mutations were detected in a variety of human tumors, which make it potential therapeutic target. In this paper we found that LCH-7749944, a novel and potent PAK4 inhibitor, effectively suppressed the proliferation of human gastric cancer cells through downregulation of PAK4/c-Src/EGFR/cyclin D1 pathway. In addition, LCH-7749944 significantly inhibited the migration and invasion of human gastric cancer cells in conjunction with concomitant blockage of PAK4/LIMK1/cofilin and PAK4/MEK-1/ERK1/2/MMP2 pathways. Interestingly, LCH-7749944 also inhibited the formation of filopodia and induced cell elongation in SGC7901 cells. Importantly, LCH-7749944 caused successful inhibition of EGFR activity due to its inhibitory effect on PAK4. Taken together, these results provided novel insights into the development of PAK4 inhibitor and potential therapeutic strategies for gastric cancer.

Overexpression of BMI1 confers clonal cells resistance to apoptosis and contributes to adverse prognosis in myelodysplastic syndrome

2011-12-12

Abstract: The polycomb group (PcG) protein BMI1 plays a critical role in regulating self renewal capacity of both normal and leukemic stem cells. BMI1 is frequently overexpressed in several types of cancer, which is associated with poor prognosis. However, there are few researches on BMI1 in myelodysplastic syndromes (MDS). In this study, we reported that overexpression of BMI1 protein was detected in MDS patients, and inversely correlated with the apoptosis of CD34+ cells. In vitro overexpression of BMI1 facilitated proliferation and inhibited apoptosis of MDS-L cells. The overexpression of BMI1 could downregulate apoptosis sensitivity to cytotoxic agents in MDS-L cells; on the contrary, MDS-L cells could be rendered apoptosis-sensitive by BMI1 knockdown. Overexpression of BMI1 antagonised apoptosis by downregulating several apoptosis-related proteins, such as p16INK4a, phospho-p53 (Ser46) and caspase 3/9. In addition, overexpression of BMI1 was correlated with an elevated IPSS score and a shorter survival. Collectively, overexpression of BMI1 induces resistance to apoptosis and contributes to adverse prognosis in MDS. BMI1 could serve as a therapeutic target for patients with MDS.

Insulin-like growth factor binding protein-3 inhibits migration of endometrial cancer cells

Lujia Gribben, Robert C. Baxter, Deborah J. Marsh — 2011-12-02

Abstract: Cell migration and invasion leading to metastasis is a major cause of death from endometrial cancer (EC). We have shown that the rate of EC cell migration is inversely related to the level of insulin-like growth factor protein-3 (IGFBP-3). Down-regulation of IGFBP-3 by siRNA in EC cells accelerated migration without affecting proliferation and cells displayed a more migratory phenotype, with co-localization of migration-associated markers at the leading edge of cell membranes. Opposite effects were seen with either the addition of recombinant IGFBP-3 or overexpression of IGFBP-3. Cells with mutated PTEN had the highest IGFBP-3 expression and the slowest migration rates. This study demonstrates that endogenous IGFBP-3 modulates adhesion–migration dynamics in EC cells, implying that it may be important in regulating metastasis in this disease.

Transplacental carcinogenesis with dibenzo[def,p]chrysene (DBC): Timing of maternal exposures determines target tissue response in offspring

2011-12-02

Abstract: Dibenzo[def,p]chrysene (DBC) is a transplacental carcinogen in mice (15mg/kg; gestation day (GD) 17). To mimic residual exposure throughout pregnancy, dams received four smaller doses of DBC (3.75mg/kg) on GD 5, 9, 13 and 17. This regimen alleviated the previously established carcinogenic responses in the thymus, lung, and liver. However, there was a marked increase in ovarian tumors (females) and hyperplastic testes (males). [14C]-DBC (GD 17) dosing revealed transplacental distribution to fetal tissues at 10-fold lower concentrations than in paired maternal tissue and residual [14C] 3weeks post-dose. This study highlights the importance of developmental stage in susceptibility to environmental carcinogens.

Newcastle disease virus induces apoptosis in cisplatin-resistant human lung adenocarcinoma A549 cells in vitro and in vivo

2011-12-02

Abstract: Cisplatin (DDP) is widely used in lung cancer chemotherapy. However, cisplatin resistance represents a major obstacle in effective clinical treatment. This study aims to investigate whether Newcastle disease virus (NDV) exhibits an oncolytic effect on cisplatin-resistant A549 lung cancer cells. We found that NDV induced A549/DDP cell apoptosis via the caspase pathway, particularly involving caspase-9, while the mitogen-activated protein kinase (MAPK) and Akt pathways also contributed to apoptotic induction. Furthermore, NDV displayed oncolytic effects in a mouse A549/DDP lung cancer model. Collectively, our data indicate that NDV could overcome the cisplatin resistance in lung cancer cells in vitro and in vivo.

P-21 activated kinase 1 knockdown inhibits β-catenin signalling and blocks colorectal cancer growth

2011-11-30

Abstract: The p21-activated kinase 1 (PAK1) plays important roles in cell growth, motility, and transformation. The aims of this study were to delineate the signalling mechanisms downstream of PAK1, and to investigate the importance of PAK1 for colorectal cancer (CRC) growth and metastasis in vivo. PAK1 knockdown in human CRC cell lines inhibited β-catenin expression, β-catenin/TCF4 transcriptional activity, and the expression of c-Myc. In mouse models PAK1 knockdown suppressed the growth and metastasis of human CRC cells by decreasing proliferation and increasing apoptosis. Our findings demonstrate for the first time the crucial role of PAK1 in CRC progression in vivo.

Copy number status and mutation analyses of anaplastic lymphoma kinase (ALK) gene in 90 sporadic neuroblastoma tumors

Ozkan Bagci, Sait Tumer, Nur Olgun, Oguz Altungoz — 2011-12-09

Abstract: Somatic and germline mutations of the anaplastic lymphoma kinase (ALK) gene were recently described in neuroblastoma (NB). In this study, we investigated the association of ALK copy number alterations with copy number status 2p24.1 amplicon harboring DEAD box polypeptide 1 (DDX1), MYCN and neuroblastoma-amplified (NAG) genes in 90 primary tumors of sporadic NB cases by multiplex ligation-dependent probe amplification (MLPA). We also performed mutation analysis of ALK gene by directly sequencing the exons 20–28 which cover the region that encodes juxtamembrane and kinase domains. A total of 39 (43.3%) NB cases revealed copy numbers alterations of ALK gene. There was highly significant association of ALK copy number gains with gains of one or more of the genes at 2p24.1 (DDX1, MYCN or NAG) in MYCN unamplified tumors (P<0.000). In addition, 15 of 17 MYCN amplified cases (88.2%) had aberrant ALK status. Solitary gain of ALK with normal copy number status of all other genes was observed only in one case. DNA sequencing of exons 20–28 of ALK revealed two different nucleotide changes in three cases leading to amino acid substitutions of F1245V and R1275Q in tyrosine kinase domain. In conclusion, the frequency of ALK mutations in NB is low and solitary copy number change of it is rarely observed.

Identification of heat shock protein 90 inhibitors to sensitize drug resistant side population tumor cells using a cell based assay platform

2011-12-21

Abstract: Current cancer therapeutics are identified based on initial tumor regression screens that mostly kill differentiated tumor cells, sparing the rare cancer stem cells (CSCs). Being rare and difficult to characterize, it remains a challenge to identify compounds active against them. Side population (SP) cells identified in multiple cancer cell line panels expressing mitochondrial Cytochrome C-EGFP were evaluated for identifying possible drug candidates utilizing high-throughput imaging. We identified heat shock protein 90 inhibitors as potential agents to sensitize SP cells to anticancer drugs. Hsp90 inhibitors induced down regulation of Akt leading to proteasomal degradation of survivin and consequent mitochondrial apoptosis. A successful screening platform for identifying compounds targeting drug resistant side population cells was developed.

Targeting cathepsin S induces tumor cell autophagy via the EGFR–ERK signaling pathway

2011-12-06

Abstract: Cathepsin S is a cellular cysteine protease, which is frequently over-expressed in human cancer cells and plays important role in tumor metastasis. However, the role of cathepsin S in regulating cancer cell survival and death remains undefined. The aim of this study was to determine whether targeting cathepsin S could induce autophagy/apoptosis in cancer cells. In this study, we demonstrated that targeting cathepsin S by either specific small molecular inhibitors or cathepsin S siRNA induced autophagy and subsequent apoptosis in human cancer cells, and the induction of autophagy was dependent on the phosphorylation of EGFR and activation of the EGFR-related ERK/MAPK-signaling pathway. In conclusion, the current study reveals that cathepsin S plays an important role in the regulation of cell autophagy through interference with the EGFR–ERK/MAPK-signaling pathway.

Induced expression of B7-H4 on the surface of lung cancer cell by the tumor-associated macrophages: A potential mechanism of immune escape

2011-12-29

Abstract: B7-homolog 4 (B7-H4), a recently identified homolog of B7.1/2 (CD80/86), has been described to exert co-stimulatory and immune regulatory functions. We investigated the expression and the functional activity of B7-H4 in lung cancer in vitro and in vivo. Although a lung cancer cell line constitutively expressed B7-H4 mRNA and protein in plasma, primary tumor cell isolated from the transplanted lung carcinoma model expressed B7-H4 on the surface. Interestingly, in transplanted lung carcinoma model, the expression of membrane-bound B7-H4 in tumor cells was increased as prolonging of tumor transformation. Exposure to tumor-associated macrophages strongly induced membrane-bound B7-H4 expression on the lung cancer cell line. To elucidate the functional significance of lung cancer-related B7-H4 expression, we performed co-culture experiments of lung cancer cell with allo-reactive T cells. Lung cancer-related B7-H4 was identified as a strong inhibitor of T-cell effect. Furthermore, B7-H4 mAb had an ability to inhibit tumor growth in vivo. B7-H4 expression may thus significantly influence the outcome of T-cell tumor cell interactions and TAM induced membrane-bound B7-H4 on the lung cancer cell represents a novel mechanism by which lung cancer cells evade immune recognition and destruction.

p65-Dependent production of interleukin-1β by osteolytic prostate cancer cells causes an induction of chemokine expression in osteoblasts

2011-12-06

Abstract: Skeletal metastases are a frequent complication of prostate, breast and lung cancer, and the interactions of tumor cells with bone-forming osteoblasts and bone-resorbing osteoclasts have been suggested to play critical roles in disease progression. We have previously shown that treatment of primary murine osteoblasts with conditioned medium of the human osteolytic prostate cancer cell line PC-3 results in a rapid induction of chemokine expression, thereby providing further evidence for a molecular crosstalk between bone and tumor cells. The aim of our current study was to identify PC-3-derived molecules mediating this effect. Using Affymetrix Gene Chip hybridization followed by qRT-PCR we were able to confirm that the expression of chemokine-encoding genes is markedly induced in human primary osteoblasts following incubation with PC-3-conditioned medium. Since this induction was significantly affected upon alteration of p65-levels in PC-3 cells, we performed a second genome-wide expression analysis to identify p65-regulated cytokines, which were then tested for their ability to induce chemokine expression. Here we observed that interleukin-1β (IL-1B) did not only increase the expression of chemokines in osteoblasts, but also the phosphorylation of p65 and thereby its own expression. Since immunohistochemistry on bone biopsy sections from prostate cancer metastases demonstrated IL-1B expression in both, tumor cells and osteoblasts, our data suggest that IL-1B is one of the relevant cytokines involved in the skeletal complications of cancer metastases.