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Introduction: Appendiceal neuroendocrine neoplasms are rare, clinically challenging tumours that are typically incidentally diagnosed, have a poorly understood biology and have controversy surrounding their management. Most are adequately treated with appendectomy, and although distant metastases are rare, the threat of disease dissemination remains and current guidelines possess poor accuracy in terms of selecting patients requiring more extensive surgery, i.e. oncological right-hemicolectomy. Areas covered: In this article, we discuss the presentation and diagnostic work-up of patients with appendiceal neuroendocrine neoplasms, and also examine the evidence base for existing management strategies. We highlight controversies within the management of these tumours, and anticipate avenues for further progress. Although no longer classified as neuroendocrine neoplasms, we also discuss two related forms of tumours with neuroendocrine features – goblet cell cancers and mixed adeno-neuroendocrine carcinomas. Expert commentary: Existing guidelines for the treatment of appendiceal neuroendocrine neoplasms are derived from a limited evidence base and are unable to accurately predict which patients require extensive attempts at surgical disease control. Future advances in the field of improved patient selection for more extensive surgery may be possible with multi-factorial tumour assessment integrating morphological and molecular analyses. [ABSTRACT FROM PUBLISHER]

Background & Aims Hepatocellular carcinoma ( HCC) is often associated with metastasis and recurrence leading to a poor prognosis. Therefore, development of novel treatment regimens is urgently needed to improve the survival of HCC patients. In this study, we aimed to investigate the in vitro and in vivo effects of anti- CD47 antibody alone and in combination with chemotherapy in HCC. Methods In this study, we examined the functional effects of anti- CD47 antibody ( B6 H12) on cell proliferation, sphere formation, migration and invasion, chemosensitivity, macrophage-mediated phagocytosis and tumourigenicity both in vitro and in vivo. The therapeutic efficacy of anti- CD47 antibody alone or in combination with doxorubicin was examined in patient-derived HCC xenograft. Results Blocking CD47 with anti- CD47 monoclonal antibody ( B6 H12) at 10 μg/ml could suppress self-renewal, tumourigenicity and migration and invasion abilities of MHCC-97 L and Huh-7 cells. Interestingly, anti- CD47 antibody synergized the effect of HCC cells to chemotherapeutic drugs including doxorubicin and cisplatin. Blockade of CD47 by anti- CD47 antibody induced macrophage-mediated phagocytosis. Using a patient-derived HCC xenograft mouse model, we found that anti- CD47 antibody (400 μg/mouse) in combination with doxorubicin (2 mg/kg) exerted maximal effects on tumour suppression, as compared with doxorubicin and anti- CD47 antibody alone. Conclusions Anti- CD47 antibody treatment could complement chemotherapy which may be a promising therapeutic strategy for the treatment of HCC patients. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cause of death among women. KIF3C, a member of kinesin superfamily, functions as a motor protein involved in axonal transport in neuronal cells. To explore the expression, regulation and mechanism of KIF3C in breast cancer, 4 breast cancer cell lines and 93 cases of primary breast cancer and paired adjacent tissues were examined. Immunohistochemistry, Real Time Polymerase Chain Reaction (RT-PCR), Western blot, flow cytometry, short hairpin RNA (shRNA) interference, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation techniques and xenograft mice model were used. We found that KIF3C was over-expressed in breast cancer tissues and such high KIF3C expression was also associated with tumor recurrence and lymph node metastasis. Silencing of KIF3C by shRNA inhibited epithelial-mesenchymal transition and metastasis by inhibiting TGF-β signaling and suppressed breast cancer cell proliferation through inducing G 2 /M phase arrest. The tumor size was smaller and the number of lung metastatic nodules was less in KIF3C depletion MDA-MB-231 cell xenograft mice than in negative control group. These results suggested that high expression of KIF3C in breast cancer may be associated with the tumor progression and metastasis. [ABSTRACT FROM AUTHOR]

ATPase inhibitory factor 1 (IF1) has recently been considered as a potential oncogene in human cancers. Recently, increasing evidences have shown that IF1 is overexpressed in human cancers and promotes tumor growth and metastasis. In this study, we found that the expression levels of IF1 protein and mRNA in gastric cancer tissues were significantly higher than those in matched adjacent nontumor tissues. Clinical association analysis revealed that the positive expression of IF1 was correlated with large tumor size, lymph node metastasis, venous infiltration and advanced TNM tumor stage in gastric cancer. Furthermore, IF1 was an independent prognostic marker for predicting 5-year overall survival and disease-free survival of gastric cancer patients. In vitro studies found that IF1 knockdown significantly inhibited cell proliferation and induced apoptosis in SGC-7901 cells. In a nude mouse xenograft model, IF1 knockdown prominently slowed down tumor growth with reduced number of Ki-67 positive cancer cells and elevated number of TUNEL positive cancer cells. Otherwise, IF1 knockdown evidently reduced SGC-7901 cell migration and invasion. In conclusion, these results indicate that IF1 may serve as a prognostic marker and promotes tumor growth and metastasis in gastric cancer. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common type of primary tumor of bone which mainly affects adolescents and young adults. Osteosarcoma causes large number of deaths because of its complex pathogenesis and resistance to conventional treatment. MicroRNAs are a class of small noncoding RNAs that function as critical gene regulators through targeting mRNAs, causing translational repression or degradation. In this study, we showed that miR-217 was down-regulated in osteosarcoma cell lines and tissues in comparison to that in normal bone cells or tissues. Meanwhile, the lower level of miR-217 was associated with metastasis in clinical osteosarcoma patients. Furthermore, we found that overexpession of miR-217 markedly suppressed cell proliferation, migration, and invasion of osteosarcoma cells. Conversely, the inhibition of miR-217 expression significantly accelerated the cell proliferation, migration, and invasion. Moreover, we identified WASF3 as a novel functional downstream target of miR-217. The ectopic expression of WASF3 can partially reverse the inhibition of cell proliferation and invasion caused by miR-217. Take together, our results demonstrate that miR-217 functions as a tumor-suppressive miRNA and inhibits the osteosarcoma tumorigenesis through targeting WASF3. [ABSTRACT FROM AUTHOR]

Immunotherapy mediated by recombinant antibodies is an effective therapeutic strategy for a variety of cancers. In a previous study, we demonstrated that the fibroblast growth factor 1 ( FGF-1)-specific recombinant antibody scFv1C9 arrests the cell cycle at the G0/G1 transition by blocking the intracrine FGF-1 pathway in breast cancer cells. Here, we further show that the overexpression of scFv1C9 in MCF-7 and MDA- MB-231 breast cancer cells by lentiviral infection resulted in decreased tumourigenicity, tumour growth and lung metastasis through FGF-1 neutralization. We found that scFv1C9 resulted in the up-regulation of p21, which in turn inhibited the expression of CDK2 and blocked cell cycle progression. To explore the potential role of scFv1C9 in vivo, we delivered the gene into solid tumours by electroporation, which resulted in significant inhibition of tumour growth. In tumour tissue sections, immunohistochemical staining of the cellular proliferation marker Ki-67 and the microvessel marker CD31 showed a reduction in the proliferative index and microvessel density, respectively, upon expression of scFv1C9 compared with the appropriate controls. Thus, our data indicate a central role for scFv1C9 in blocking the intracrine pathway of FGF-1, therefore, scFv1C9 could be developed in an effective therapeutic for breast cancer. [ABSTRACT FROM AUTHOR]

Abstract: The tumor growth inhibition and anti-metastatic effects of peach polyphenolics were investigated in vivo using a xenograft model and MDA-MB-435 breast cancer cells. Results showed that tumor growth and lung metastasis were inhibited in vivo by peach polyphenolics in a dose range of 0.8–1.6 mg/day, and these effects were mediated by inhibition of metalloproteinases gene expression. Modulation of metalloproteinase-2, metalloproteinase-3 and metalloproteinase-13 gene expression may be some of the molecular targets for anti-metastatic activity of peach polyphenolics. Therefore, these compounds may constitute a novel chemopreventive tool to reduce the risk of metastasis in the combination therapy when primary cancer is diagnosed. Conversion to equivalent human intake for future clinical studies using the body surface area normalization method gave a dose of ~370.6 mg/day for a human adult of 60 kg, which can be supplied by consuming two to three peach fruit per day or alternatively using a dietary supplement peach polyphenol extract powder. [Copyright &y& Elsevier]

Abstract: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy. Nanosecond pulsed electric field (nsPEF) is a new technology destroying tumor cells with a non-thermal high voltage electric field using ultra-short pulses. The study’s aim was to evaluate the ablation efficacy of nsPEFs with human HCC cell lines and a highly metastatic potential HCC xenograft model on BALB/c nude mice. The in vivo study showed nsPEFs induced HCC cell death in a dose dependent manner. On the high metastatic hepatocellular carcinoma cell line (HCCLM3) xenograft mice model, tumor growth was inhibited significantly in nsPEF-treated- groups (single dose and multi-fractionated dose). Besides a local effect, the nsPEF treatment reduced pulmonary metastases. The nsPEFs also enhanced HCC cell phagocytosis by human macrophage cell (THP1) in vitro. The nsPEF is efficient in controlling HCC progression and reducing its metastasis. NsPEF treatment may elicit a host immune response against tumor cells. This study suggests nsPEF therapy could be used as a potential locoregional therapy for hepatocellular carcinoma. [Copyright &y& Elsevier]

Highlights: [•] JAK/STAT signaling is central to epithelial and hematopoietic tumors in Drosophila. [•] Unpaired is ectopically induced by loss of distinct tumor suppressors. [•] Ras and JAK/STAT pathways cooperate to induce metastatic tumors. [•] Dominant-active JAK mutations cause melanotic tumors, a fly leukemia. [•] Genetic screens have identified new pathway effectors in blood cell tumors. [Copyright &y& Elsevier]

Highlights: [•] miR-17 was increased in OS tissues and cell lines. [•] Inhibition of miR-17 suppressed OS cell proliferation. [•] Inhibition of miR-17 suppressed OS cell migration and invasion. [•] PTEN was a target of miR-17. [•] miR-17 was negatively correlated with PTEN in OS tissues. [ABSTRACT FROM AUTHOR]

For the most part, normal epithelial cells do not disseminate to other parts of the body and proliferate, as do metastatic cells. Presumably, a class of molecules-termed metastasis suppressors-are involved in this homeostatic control. Metastasis suppressors are, by definition, cellular factors that, when re-expressed in metastatic cells, functionally inhibit metastasis without significantly inhibiting tumor growth. In this brief review, we catalog known metastasis suppressors, what is known about their mechanism(s) of action, and experimental and clinical associations to date. [ABSTRACT FROM AUTHOR]

1,1-Bis(3-indolyl)-1-(p-substitutedphenyl)methane (C-DIM) compounds exhibit remarkable antitumor activity with low toxicity in various cancer cells including lung tumors. Two C-DIM analogs, DIM-C-pPhOCH3 (C-DIM-5) and DIM-C-pPhOH (C-DIM-8) while acting differentially on the orphan nuclear receptor, TR3/Nur77 inhibited cell cycle progression from G0/G1 to S-phase and induced apoptosis in A549 cells. Combinations of docetaxel (doc) with C-DIM-5 or C-DIM-8 showed synergistic anticancer activity in vitro and these results were consistent with their enhanced antitumor activities in vivo. Respirable aqueous formulations of C-DIM-5 (mass median aerodynamic diameter of 1.92±0.22μm and geometric standard deviation of 2.31±0.12) and C-DIM-8 (mass median aerodynamic diameter of 1.84±0.31μm and geometric standard deviation of 2.11±0.15) were successfully delivered by inhalation to athymic nude mice bearing A549 cells as metastatic tumors. This resulted in significant (p <0.05) lung tumor regression and an overall reduction in tumor burden. Analysis of lung tumors from mice treated with inhalational formulations of C-DIM-5 and C-DIM-8 showed decreased mRNA and protein expression of mediators of tumor initiation, metastasis, and angiogenesis including MMP2, MMP9, c-Myc, β-catenin, c-Met, c-Myc, and EGFR. Microvessel density assessment of lung tissue sections showed significant reduction (p <0.05) in angiogenesis and metastasis as evidenced by decreased distribution of immunohistochemical staining of VEGF, and CD31. Our studies demonstrate both C-DIM-5 and C-DIM-8 have similar anticancer profiles in treating metastatic lung cancer and possibly work as TR3 inactivators. [ABSTRACT FROM AUTHOR]

Epidemiological and preclinical evidence supports that omega-3 dietary fatty acids (fish oil) reduce the risks of macular degeneration and cancers, but the mechanisms by which these omega-3 lipids inhibit angiogenesis and tumorigenesis are poorly understood. Here we show that epoxydocosapentaenoic acids (EDPs), which are lipid mediators produced by cytochrome P450 epoxygenases from omega-3 fatty acid docosahexaenoic acid, inhibit VEGFand fibroblast growth factor 2-induced angiogenesis in vivo, and suppress endothelial cell migration and protease production in vitro via a VEGF receptor 2-dependent mechanism. When EDP5 (0.05 mg kg-1d-1) are coadministered with a low-dose soluble epoxide hydrolase inhibitor, EDP5 are stabilized in circulation, causing ∼70% inhibition of primary tumor growth and metastasis. Contrary to the effects of EDPs, the corresponding metabolites derived from omega-6 arachidonic acid, epoxyeicosatrienoic acids, increase angiogenesis and tumor progression. These results designate epoxyeicosatrienoic acids and EDP5 as unique endogenous mediators of an angiogenic switch to regulate tumorigenesis and implicate a unique mechanistic linkage between omega-3 and omega-6 fatty acids and cancers. [ABSTRACT FROM AUTHOR]

The article discusses the molecule inhibitors of enzymes with the structural and chemical diversity of topoisomerase II modulators as anticancer agents. It mentions the development of chemical families of anticancer drugs which are classified as topoisomerase II poisons including epipodopodophyllotoxins, anthracyclines, and acridines. It says that potent cytotoxic agents are used to limit tumor growth and metastasis.

Objectives: Src family kinases (SFKs) are expressed in non-small cell lung cancer (NSCLC) and may be involved in tumor growth and metastases. Inhibition of SFK may also enhance radiation. The purpose of this study was to evaluate if a maximum dose of 100 mg of dasatinib could be safely administered with concurrent chemoradiation and then continued as maintenance for patients with newly diagnosed stage III NSCLC. Methods: Patients with stage III locally advanced NSCLC received paclitaxel, 50 mg/m2/week, with carboplatin area under the curve (AUC) = 2, weekly for 7 weeks, and concurrent radiotherapy, 64.8 Gy. Three dose levels of dasatinib 50, 70, and 100 mg/day were planned. Results: 11 patients with locally advanced NSCLC were entered. At the 70 mg dose level 1 patient had grade 5 pneumonitis not responsive to therapy, and one patient had reversible grade 3 pneumonitis and grade 3 pericardial effusion. Due to these toxicities the Brown University Oncology Group Data Safety Monitoring Board terminated the study. Conclusion: Dasatinib could not be safely combined with concurrent chemoradiation for stage 3 lung cancer due to pneumonitis. [ABSTRACT FROM AUTHOR]

Background and Aim: There has been little information about the long-term outcome and prognostic factors in patients with hepatocellular carcinoma (HCC) and extrahepatic metastases. The purpose of this study was to investigate the clinical factors affecting survival after extrahepatic metastasis and to determine the survival benefit of controlling intrahepatic HCC. Methods: Between 2004 and 2009, a total of 240 consecutive patients with HCC and extrahepatic metastasis were recruited. Based on tumor extent, performance, and hepatic function, the patients underwent locoregional and/or systemic treatments. The treatment response of the intrahepatic tumor after extrahepatic metastasis and other prognostic parameters were analyzed retrospectively. Results: During the mean follow up of 276 days, 222 patients died; the median survival time was 146 days. Multivariate analysis revealed that Child-Pugh class A, smaller hepatic tumor size, absence of portal venous invasion, single metastatic organ involvement, and objective treatment response of the intrahepatic tumor were the favorable prognostic factors for survival. Of the 183 evaluable patients, 24 achieved complete or partial response for intrahepatic tumors after treatment. The overall survival for the 24 responders was significantly improved, with a median of 521 days, as compared to 170 days for the remaining 159 patients without objective tumor response. The leading cause of death was progressive intrahepatic tumor. Conclusions: Intrahepatic tumor status and hepatic reserve are among the significant predictors of survival in patients with HCC and extrahepatic metastases. This study indicates that even in patients with metastases from advanced HCC, therapeutic approaches to control intrahepatic tumors are important in improving patient survival. [ABSTRACT FROM AUTHOR]

Background:  Insulin-like growth factor II mRNA-binding protein 3 (IGF2BP3), an oncofetal RNA-binding protein, has been implicated in the enhancement of proliferation and invasion in various cancers. This study aimed to investigate the clinical significance and functional role of IGF2BP3 expression in oral squamous cell carcinoma (OSCC).Methods:  IGF2BP3 expression in 93 OSCC patients was investigated using immunohistochemical staining and correlated with clinical parameters and patients' survival. The effect of IGF2BP3 on cell invasion ability was evaluated by RNA interference in OSCC cell line.Results:  High expression of IGF2BP3 in OSCC was significantly correlated with large tumor size and lymph node metastasis. Kaplan-Meier analysis revealed that oral cancer patients with high IGF2BP3 expression had a significantly lower 5-year survival (P = 0.0017). Multivariate analysis of clinical samples demonstrated IGF2BP3 to be an independent prognosis factor (P = 0.003). Moreover, the IGF2BP3 shRNA significantly suppressed the invasion ability of OSCC in vitro, and the knockdown of endogenous IGF2BP3 expression also inhibited tumor formation in vivo.Conclusions:   IGF2BP3 enhances cell invasion ability and tumorigenicity in human OSCC in vitro and in vivo. IGF2BP3 is an independent prognostic factor in patients with OSCC. Targeting of IGF2BP3 could potentially suppress the tumor growth and metastasis to improve the outcome of patients with OSCC. [ABSTRACT FROM AUTHOR]

We investigated the effects of caloric restriction (CR) on growth of tumors and metastases in the 4T1 mammary tumor model and found that CR, compared with normal diet, reduced the growth of mammary tumors and metastases and the total number of metastases that originated both spontaneously from the primary tumor and also experimentally from i.v. injection of the tumor cells. CR also decreased proliferation and angiogenesis and increased apoptosis in tumors. CR reduced levels of insulin, leptin, insulin-like growth factor 1, insulin-like growth factor binding protein 3 and increased adiponectin in tumors. We also demonstrated that tumors from CR mice possessed lower levels of transforming growth factor-β, lower intratumor deposition of collagen IV and reduced invasiveness due to a decrease in tumor secretion of active matrix metalloproteinase 9. Our results suggest that CR-induced metabolic and signaling changes affect the stroma and the tumor cells resulting in a microenvironment that prevents proliferation of breast tumors and their metastases. [ABSTRACT FROM AUTHOR]

Abstract: Surgery is currently the best approach for treating either primary or metastatic hepatic malignancies. Because only 20% of hepatic cancers are operable in patients, several types of regional therapy (RT) are emerging as alternate treatment modalities. However, RTs can have their own limitations at controlling tumor growth or may lack the ability to detect such metastases. Additional strategies can be implemented to enhance their efficacy. An animal model of hepatic metastases coupled with a gastroduodenal artery (GDA) cannulation technique may provide a site to apply such therapies. In our study, splenic injections were performed with CC531 adenocarcinoma cells, which generated metastatic hepatic tumors in WAG/RijHsd rats. Cannulation of GDA was achieved via a polyethylene catheter. Infusion of generation 3 polyamidoamine 4-amino-1,8-naphthalimide dendrimer containing 8 europium ions (Eu-G3P4A18N) via the GDA resulted in luminescence of the hepatic metastatic nodules. Imaging of the metastatic hepatic nodules was obtained with the help of a cooled charge coupled device (CCD) camera. From the Clinical Editor: Hepatic malignancies represent a major therapeutic challenge, despite the available surgical and oncologic treatment modalities. In this paper, an animal model of hepatic adenocarcinoma is used in demonstrating successful targeting of spleen metastases with generation 3 polyamidoamine 4-amino-1,8-naphthalimide dendrimer containing 8 europium ions (Eu-G3P4A18N) for luminescence imaging. [Copyright &y& Elsevier]

The article analyzes the role and mechanism of vascular endothelial growth factor-B (VEGF-B) in the progression of human choriocarcinoma. Based on a study using complementary DNA microaray technique, VEGF-B gene specific short hairpin RNA (shRNA) was able to decrease the expression of VEGF-B messenger RNA (mRNA). It also concludes that VEGF-B shRNA transfection has a significant role in regulating the invasion level of metastatic cells and weakening the invasion ability of choriocarcinoma.

Purpose: It was to assess antiangiogenic effect of β-elemene in vitro and in vivo, and it was involved in inhibiting melanoma growth and metastasis, as well as to elucidate its intrinsic mechanism. Methods: Inhibitive effect of β-elemene on B16F10 cells was performed by cell proliferation assay. Angiogenesis assays in vitro including rat aortic ring and chick embryo chorioallantoic membrane were used, as well as melanoma growth and metastasis assay in C57BL/6 mice. Vascular endothelial growth factor (VEGF) expression in vitro and in vivo was measured respectively by western blot analysis and enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry analysis of CD34 and VEGF expression in primary melanoma was also presented. Results: β-Elemene inhibited B16BF10 cell proliferation starting from 200 μM, but VEGF from 20 μM. Both 20 and 50 μM β-elemene in vitro inhibited VEGF-induced sprouting vessel of rat aortic ring and microvessel formation of chick embryo chorioallantoic membrane. In vivo, tumor size of primary melanoma in mice intraperitoneally treated with β-elemene was significantly smaller than that of the control; CD34 expression of primary melanoma was also suppressed; and the metastatic melanoma colonies and content of melanin in lung were detected obviously decreased in mice of β-elemene-treated groups. Furthermore, results of VEGF expressing in primary melanoma, serum and lung of mice also disclosed that VEGF was inhibited in vivo. Conclusions: β-Elemene inhibited melanoma growth and metastasis through suppressing VEGF-mediated angiogenesis. It is a natural potential antiangiogenic agent. [ABSTRACT FROM AUTHOR]

Summary: Cancer is a leading cause of death worldwide. Tumor cells exploit various signaling pathways to promote their growth and metastasis. To our knowledge, the role of angiopoietin-like 4 protein (ANGPTL4) in cancer remains undefined. Here, we found that elevated ANGPTL4 expression is widespread in tumors, and its suppression impairs tumor growth associated with enhanced apoptosis. Tumor-derived ANGPTL4 interacts with integrins to stimulate NADPH oxidase-dependent production of O2 − . A high ratio of O2 − :H2O2 oxidizes/activates Src, triggering the PI3K/PKBα and ERK prosurvival pathways to confer anoikis resistance, thus promoting tumor growth. ANGPTL4 deficiency results in diminished O2 − production and a reduced O2 − :H2O2 ratio, creating a cellular environment conducive to apoptosis. ANGPTL4 is an important redox player in cancer and a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Abstract: The chemokine granulocyte chemotactic protein (GCP)-2/CXCL6 promotes tumor growth as angiogenesis inducer and neutrophil chemoattractant. The neutralizing capacity and specificity of monoclonal mouse anti-murine (mu)GCP-2/CXCL6 antibodies were evidenced by granulocyte chemotaxis and signaling assays. The half-life of the non-antigenic antibody in the blood circulation was approximately 15days. The titers remained constant upon weekly injection. Tumor growth and lymphogenic metastases of human melanoma over-expressing muGCP-2 were reduced in mice treated with anti-muGCP-2. Moreover, the drop in muGCP-2 antibody titer correlated with the melanoma tumor size. Taken together, we show that functional blocking of GCP-2 inhibits tumor growth and metastases. [Copyright &y& Elsevier]

Abstract: A series of new 4β-anilino-4′-O-demethyl-4-desoxypodophyllotoxin derivatives were prepared and evaluated for their cytotoxicities against four human cancer cell lines including KB, KB/VCR, A549 and 95D. Most compounds showed better growth-inhibition activities against tested cell lines than that of etoposide (VP-16). Preliminary structure–activity relationships (SARs) were concluded and it indicated that the side chains substituted at 4β position of podophyllotoxin significantly influenced the cytotoxic activity, especially for the drug resistance profile. In vivo studies of compound 26c on highly metastatic human lung cancer xenograft in nude mice showed that it can significantly inhibit tumor growth with administrating by oral route. [Copyright &y& Elsevier]

Abstract: Both vascular endothelial growth factor A (VEGF) and osteopontin (OPN) can directly induce tumor angiogenesis, which is essential for the growth and metastasis of solid tumors. Here we engineered a bispecific antibody (VEGF/OPN-BsAb) using the anti-VEGF-A antibody bevacizumab and the anti-OPN antibody hu1A12. Compared with hu1A12 alone and bevacizumab alone, VEGF/OPN-BsAb was significantly more effective in inhibiting tumor angiogenesis in a highly metastatic human hepatocellular carcinoma nude mouse model. Further study demonstrated that VEGF/OPN-BsAb could effectively suppress primary tumor growth and metastasis to lungs, suggesting that it might be a promising therapeutic agent for treatment of metastatic cancer. [ABSTRACT FROM AUTHOR]

Thrombospondin 1 (TSP1) has been shown to play a critical role in inhibiting angiogenesis, resulting in inhibition of tumor growth and metastases. To figure out TSP1's regulators will lead to reveal its biological function mechanistically. In this study, we show that E2F-1 could activate the transcription of TSP1 by both promoter assays and Northern blot. Analysis of various TSP1 promoter mutant constructs showed that a sequence located -144/-137 up-stream of the transcriptional initiation site, related to the consensus E2F-responsive sequence, is necessary for the activation. In consistence with upregulation of TSP-1 activity by over-expression of E2F-1, the knockdown of endogenous E2F-1 inhibited TSP-1 promoter activity significantly, implying that E2F-1 mediated regulation of TSP-1 is relevant in vivo. In addition, E2F-1 could also directly bind to the TSP1 promoter region covering -144/-137 region as revealed by ChIP assays. Furthermore, the E2F-1- induced activation of TSP1 gene transcription is suppressed by pRB1 in a dose-dependent manner. Taken together, the results demonstrate that TSP1 is a novel target for E2F1, which might imply that E2F-1 can affect angiogenesis by modulating TSP1 expression. [ABSTRACT FROM AUTHOR]

The article focuses on a study which evaluated the effect of portal branch ligation (PBL) on angiogenesis, growth factor expression and tumour growth in a mouse model of hepatic colorectal metastases. Angiogenesis, microcirculatlon, growth factor expression, cell proliferation and tumour growth were assessed in the mice that underwent PBL of the left liver lobe or sham. Study authors concluded that PBL initially reduced vascular perfusion and tumour growth.

Abstract: Cytotoxic T lymphocytes (CTL) are critical effector cells in tumor immunity. Adoptive transfer therapy with in vitro-expanded tumor-specific CTL is a promising approach for preventing cancer metastasis and recurrence. Transferred CTL are not effective in clinical trials, however, due to inadequate tumor-infiltration. Therefore, the development of functionally modified CTL, such as tumor-targeting CTL, is widely desired. Here, we designed the tumor-targeting CTL expressing a single-chain antibody fragment (scFv-CTL) specific for vascular endothelial growth factor receptor 2 (VEGFR2/flk1) by transducing the CTL with a retroviral vector. The scFv-CTL bound to VEGFR2/flk1-expressing cells and retained their cytotoxic activity against tumor cells. In addition, adoptive transfer of scFv-CTL into tumor-bearing mice effectively suppressed tumor growth due to the augmented accumulation of the transferred CTL in the tumor tissue. These findings indicate that the creation of CTL capable of targeting tumor vascular endothelial cells by scFv-expression technique is considerably promising for improvement of efficacy in adoptive immunotherapy. [Copyright &y& Elsevier]

Multidrug transporter proteins are best known for their contributions to chemoresistance through the efflux of anticancer drugs from cancer cells. However, a considerable body of evidence also points to their importance in cancer extending beyond drug transport to fundamental roles in tumour biology. Currently, much of the evidence for these additional roles is correlative and definitive studies are needed to confirm causality. We propose that delineating the precise roles of these transporters in tumorigenesis and treatment response will be important for the development of more effective targeted therapies. [ABSTRACT FROM AUTHOR]

Extracellular adenosine is a potent immunosuppressor that accumulates during tumor growth. We performed proof-of-concept studies investigating the therapeutic potential and mechanism of action of monoclonal antibody (mAb)-based therapy against CD73. an ecto-enzyme overexpressed on breast-cancer cells that catalyzes the dephosphorylation of adenosine monophosphates into adenosine. We showed that anti-CD73 mAb therapy significantly delayed primary 4T1 .2 and E0771 tumor growth in immune-competent mice and significantly inhibited the development of spontaneous 4T1.2 lung metastases. Notably, anti-CD73 mAb therapy was essentially dependent on the induction of adaptive anti-tumor immune responses. Knockdown of CD73 in 4T1.2 tumor cells confirmed the tumor-promoting effects of CD73. In addition to its immunosuppressive effect, CD73 enhanced tumor-cell chemotaxis, suggesting a role for CD73-derived adenosine in tumor metastasis. Accordingly, administration of adenosine-5'-N-ethylcarboxamide to tumorbearing mice significantly enhanced spontaneous 4T1 .2 lung metastasis. Using selective adenosine-receptor antagonists, we showed that activation of A2B adenosine receptors promoted 411.2 tumorcell chemotaxis in vitro and metastasis in vivo. In condusion, our study identified tumor-derived CD73 as a mechanism of tumor immune escape and tumor metastasis, and it also established the proof of concept that targeted therapy against CD73 can trigger adaptive anti-tumor immunity and inhibit metastasis of breast cancer. [ABSTRACT FROM AUTHOR]

Abstract: Lifestyle and nutritional factors have been recognized to influence breast cancer survival, irrespective of genomic alterations that are the hallmarks of the disease. The biological and molecular mechanisms involved in the effects of dietary polyunsaturated fatty acids and breast cancer response to treatments in clinical and preclinical studies have been reviewed. Among nutrients, rumenic acid, a naturally occurring CLA isomer and n-3 docosahexaenoic acid (DHA) a highly unsaturated fatty acid, have emerged due to their potential to increase cancer treatment efficacy without additional side effects. In this review, we analyze the literature evidence that breast cancer treatment and outcome could be improved through an adjuvant dietary supplementation. Such an original approach would involve two successive phases of breast cancer treatment: an initial sensitization of residual tumor cells to chemotherapy and to radiation therapy with dietary DHA; then a prevention of metastatic re-growth with a prolonged rumenic acid supplementation. Safety is not anticipated to be a critical issue, although it has to be assessed in the long term. Dietary supplements, used in combination to anti-cancer agents, should be provided under medical prescription. Such an original use of fatty acids in breast cancer treatment could provide the lipid field with a new avenue to impact public health. [Copyright &y& Elsevier]

Multiple observations in preclinical and clinical studies support a role for the immune system in controlling tumor growth and progression. Various components of the innate and adaptive immune response are able tomediate tumor cell destruction; however, certain immune cell populations can also induce a protumor environment that favors tumor growth and the development of metastasis. Moreover, tumor cells themselves are equipped with various mechanisms that allow them to evade surveillance by the immune system. The goal of cancer vaccines is to induce a tumor-specific immune response that ultimately will reduce tumor burden by tipping the balance from a protumor to an antitumor immune environment. This review discusses common mechanisms that govern immune cell activation and tumor immune escape, and some of the current strategies employed in the field of cancer vaccines aimed at enhancing activation of tumor-specific T-cells with concurrent reduction of immunosuppression. [ABSTRACT FROM AUTHOR]

The article presents a study on the relation of sperm-associated antigen 9 (SPAG9) in carcinogenesis of cervical squamous cell carcinoma (SCC). The study used a small interfering RNA approach to knock down SPAG9 expression in SiHa cells obtained from cervical SCC. The study found that small interfering RNA silencing of SPAG9 inhibits tumor growth of cervical SCC. It suggests that SPAG9 expression may also lead to early spread of cervical cancer.

Background: CXCL12/CXCR4 signaling may be involved in tumor growth and angiogenesis, and homing of cancer cells to bone and other organs. Our purpose was to determine whether inhibition of CXCR4 with a peptide-based antagonist would reduce tumor growth and metastasis of breast cancer. Methods: We used two mouse models of breast cancer. In the first model, 1 × 106 MDA-MB-231 breast cancer cells transfected with luciferase were implanted into the inguinal mammary fat pad to produce primary tumors. In the second model, 1 × 105 MDA-231-BSC12 cells were injected into the left cardiac ventricle to produce bone metastases. CTCE-9908, a peptide analog of CXCL12 that competitively binds to CXCR4, was used to test the effect of inhibiting CXCR4. Five mice from each mouse model were treated with CTCE-9908 (25 mg/kg, injected subcutaneously 5 d/wk). All mice were assessed weekly using bioluminescent imaging to quantify relative volumes of tumor burden. Results: Bioluminescencent imaging showed that the mice treated with CTCE-9908 had significantly less primary tumor burden than the control mice. At 5 and 6 wk, the mice treated with CTCE-9908 had a 7-fold reduction and 5-fold reduction in primary tumor burden, respectively. Treatment with CTCE-9908 also significantly inhibited the rate of metastases compared with the control group. At 5 and 6 wk, the mice treated with CTCE-9908 demonstrated a 9-fold reduction and 20-fold reduction in metastatic tumor burden, respectively. Conclusion: Treatment with the CXCR4 antagonist CTCE-9908 significantly reduced metastasis as well as primary tumor growth in mouse models of breast cancer. [Copyright &y& Elsevier]

Abstract: Chitooligosaccharides (COS) are hydrolyzed products of chitosan and have been proven to exhibit various biological functions. The objectives of this study were to evaluate the anti-tumor growth, anti-metastatic potency and related pathways of COS extracted from fungi. In in vitro studies, we found that COS significantly inhibited human hepatocellular carcinoma (HepG2) cell proliferation, reduced the percentage of S-phase and decreased DNA synthesis rate in COS-treated HepG2 cells. Expressions of cell cycle-related genes were analyzed and the results indicated that p21 was up-regulated, while PCNA, cyclin A and cdk-2 were down-regulated. Moreover, we also found that the activity of metastatic related protein (MMP-9) could be inhibited by COS in Lewis lung carcinoma (LLC) cells. In in vivo studies, we found that COS inhibited the tumor growth of HepG2 xenografts in severe combined immune deficient (SCID) mice. In a LLC-bearing mouse tumor growth and lung metastasis model, COS inhibited tumor growth and the number of lung colonies in LLC-bearing mice as well as the lung metastasis, and it prolonged the survival time of the LLC-mice. These results suggest a potential anti-tumor growth and anti-metastatic potency of COS in cancer chemoprevention. [Copyright &y& Elsevier]

Although there are numerous reports of carbohydrates enriched in cancer cells, very few studies have addressed the functions of carbohydrates present in normal cells that decrease in cancer cells. It has been reported that core3 O-glycans are synthesized in normal gastrointestinal cells but are down-regulated in cancer cells. To determine the roles of core3 O-glycans, we transfected PC3 and LNCaP prostate cancer cells with β3-Nacetylglucosaminyltransferase-6 (core3 synthase) required to synthesize core3 O-glycans. Both engineered cell lines exhibited reduced migration and invasion through extracellular matrix components compared with mock-transfected cells. Moreover we found that α2β1 integrin acquired core3 O-glycans in cells expressing core3 synthase with decreased maturation of β1 integrin, leading to decreased levels of the α2β1 integrin complex, decreased activation of focal adhesion kinase, and reduced lamellipodia formation. Upon inoculation into the prostate of. nude mice, PC3 cells expressing core3 O-glycans produced much smaller tumors without metastasis to the surrounding lymph nodes in contrast to robust tumor formation and metastasis seen in mock-transfected PC3 cells. Similarly LNCaP cells expressing core3 O-glycans barely produced subcutaneous tumors in contrast to robust tumor formation by mock-transfected LNCaP cells. These findings indicate that addition of core3 O-glycans to β1 and α2 integrin subunits in prostate cancer cells suppresses tumor formation and tumor metastasis. [ABSTRACT FROM AUTHOR]

Abstract: Angiogenesis is known to be required for tumour growth and metastasis. Recent reports indicated that phosphatidylinositol 3-kinase (PI3K) promoted angiogenesis by inducing expressions of HIF-1α and vascular endothelial growth factor (VEGF). The present study aims to investigate the antiangiogenic effect of ZSTK474, a novel pan-PI3K inhibitor. ZSTK474 significantly inhibited tumour growth in the RXF-631L xenograft model. Immunohistochemical staining of the tumour tissue with anti-von Willebrand Factor antibody showed a significantly reduced number of microvessels in the ZSTK474-treated mice, suggesting the highly promising antiangiogenic activity in vivo. In human umbilical vein endothelial cells (HUVECs), submicromolar concentrations of ZSTK474 inhibited cell growth, blocked VEGF-induced cell migration and the tube formation, and thus revealed potent in vitro antiangiogenic activity. Furthermore, ZSTK474 inhibited phosphorylation of Akt at submicromolar concentrations. In RXF-631L cancer cells, on the other hand, ZSTK474 treatment inhibited the expression of HIF-1α and secretion of VEGF. Together, these results suggest that ZSTK474 has potent antiangiogenic activity, which could be attributed to dual-target inhibitory properties: inhibition of VEGF secretion by cancer cells and inhibition of PI3K in endothelial cells. [Copyright &y& Elsevier]

Summary: Epithelial-mesenchymal transition (EMT) is a key step toward cancer metastasis, and Snail is a major transcription factor governing EMT. Here, we demonstrate that Snail-induced EMT accelerates cancer metastasis through not only enhanced invasion but also induction of immunosuppression. Murine and human melanoma cells with typical EMT features after snail transduction induced regulatory T cells and impaired dendritic cells in vitro and in vivo partly through TSP1 production. Although Snail+ melanoma did not respond to immunotherapy, intratumoral injection with snail-specific siRNA or anti-TSP1 monoclonal antibody significantly inhibited tumor growth and metastasis following increase of tumor-specific tumor-infiltrating lymphocytes and systemic immune responses. These results suggest that inhibition of Snail-induced EMT could simultaneously suppress both tumor metastasis and immunosuppression in cancer patients. [Copyright &y& Elsevier]

Clinical practice reveals that therapy with angiogenesis inhibitors often does not prolong survival of cancer patients for more than months, because tumors elicit evasive resistance. In this issue of Cancer Cell, two papers report that VEGF inhibitors reduce primary tumor growth but promote tumor invasiveness and metastasis. These perplexing findings help to explain resistance to these drugs but raise pertinent questions of how to best treat cancer patients with antiangiogenic medicine in the future. We discuss here how VEGF inhibitors can induce such divergent effects on primary tumor growth and metastasis. [Copyright &y& Elsevier]

Abstract: Objectives: Clear-cell renal cell carcinoma (RCC) is the most prevalent form of kidney cancer and is frequently associated with loss of von Hippel-Lindau (VHL) gene function, resulting in the aberrant transcriptional activation of genes that contribute to tumor growth and metastasis, including transforming growth factor-α (TGF-α), a ligand of the epidermal growth factor receptor (EGFR) tyrosine kinase. To determine the functional impact of EGFR activation on RCC, we suppressed critical components of this pathway: EGFR, Akt-1, and MEK-1. Methods: Stable transfection of RCC cells with plasmids bearing shRNA directed against each of these genes was used to individually suppress their expression. Transfectants were characterized for growth and invasiveness in vitro and tumorigenesis in vivo. Results: RCC cell transfectants displayed significantly reduced growth rate and matrix invasion in vitro and RCC tumor xenograft growth rate in vivo. Analysis of tumor cells that emerged after extended periods in each model showed that significant EGFR suppression was sustained, whereas Akt-1 and MEK-1 knock-down cells had escaped shRNA suppression. Conclusions: EGFR, Akt-1, and MEK-1 are individually critical for RCC cell invasiveness in vitro and tumorigenicity in vivo, and even partial suppression of each can have a significant impact on tumor progression. The emergence of transfectants that had escaped Akt-1 and MEK-1 suppression during tumorigenicity experiments suggests that these effectors may each be more critical than EGFR for RCC tumorigenesis, consistent with results from clinical trials of EGFR inhibitors for RCC, where durable clinical responses have not been seen. [Copyright &y& Elsevier]

Summary: Cited research papers support the main hypothesis that selected publications supply sufficient information for a combined multi-level treatment strategy against cancer that will also strengthen the host. The three major elements of the proposal are: (A) metastasis being separate from tumor growth requires specific antimetastatic treatments. For this, manipulation of the composition of phospholipids will alter cellular charge characteristics which are instrumental in adhesion. (B) Formate metabolism is at the center of many activities that are controlling tumor growth. The rational and consequences of this are as follows. Supply of formate depends mainly on serine, and consumption on conversion to CO2 yielding needed NADPH. The remainder is used to complete IMP configuration with 5-aminoimidazole-4-carboxamide ribonucleotide (ZMP). At homeostasis residual ZMP activates AMP-activated protein kinase (AMPK) to curb growth promoting phosphatidylinositol-3-kinase (PI3PK). Residual ZMP also activates the oxidation of choline to betaine supplying methyl groups needed for global methylation of DNA while increased oxidation of choline also alters cellular phospholipid composition (refer to metastasis). At low formate level, increased accumulated ZMP becomes pyrophosporylated to ZTP. AMPK activation shifts to PI3PK activity for insulin action restoring formate supplied by serine derived from glycolysis. Increased NADPH-generating glucose-6-phosphate dehydrogenase is diminishing NADP+ required for dehydrogenation of formate. This is restoring the formate balance while lowering ZMP levels to that of homeostasis. Evidence suggests that transformed cells exceed up-regulation of formate thus suppressing all ZMP accumulations resulting in limited AMPK activation, cessation of choline oxidation to betaine and loss of global methylation of DNA. This scenario appears to be tied to tumor survival, a state that could be altered by metabolic interventions using mild agents as described in the research reports cited. (C) Because of a preponderance of pyrimidines in cancer supporting UTP requiring immune evasion, exogenous IMP may offset this imbalance and thus hinder tumor anti-immune activities while strengthen host immune functions. For studies to confirm the proposal, the overall expected result is that a combined administration of all these agents cited here will outperform any single agent considered so far for anticancer treatment. [Copyright &y& Elsevier]

A prospective nonrandomised trial was performed in order to evaluate tumour control and toxicity of low-dose adjuvant radiotherapy in stage I seminoma with treatment portals confined to the para-aortic lymph nodes. Between April 1991 and March 1994, 721 patients were enrolled for the trial by 48 centres in Germany. Patients with pure seminoma and no evidence of lymph node involvement or distant metastases received 26?Gy prophylactic limited para-aortic radiotherapy. Disease-free survival at 5 years was the primary end point. With a median follow-up of 61 months, 675 patients with follow-up investigations were evaluable for this analysis. Kaplan-Meier estimates of disease-free and disease-specific survival were 95.8% (95% CI: 94.2-97.4) and 99.6% (95% CI: 99.2-100%) at 5 years and 94.9% (95% CI: 92.5-97.4%) and 99.6% (95% CI: 99.2-100%) at 8 years, respectively. A total of 26 patients relapsed. All except two were salvaged from relapse. In all, 21 recurrences were located in infradiaphragmatic lymph nodes without any ‘in-field’ relapse. Nausea and diarrhoea grade 3 were observed in 4.0 and 1.0% of the patients, respectively. Grade 3 late effects have not been observed so far. The results of our trial lend further support to the concept of limited para-aortic irradiation as the recently defined new standard of radiotherapy in stage I seminoma. There is no obvious compromise in disease-specific or disease-free survival compared to more extensive hockey-stick portals, which were used as standard portals at the time this study was initiated.British Journal of Cancer (2004) 90, 2305-2311. doi:10.1038/sj.bjc.6601867 www.bjcancer.com Published online 11 May 2004 [ABSTRACT FROM AUTHOR]

The article reports on the ability of microRNA to decrease the expression of the adhesion molecule CD44 in prostate cancer stem cells (CSCs) in the U.S. It states that microRNA has also the ability to block tumor growth and metastasis. It notes that the systematic delivery of negative regulator may also open new avenues for targeting CSCs to halt cancer.

The article reports on the findings of the studies conducted by the groups of Meenhard Herlyn and Jean-Pierre Abastado regarding the treatment for melanoma, a tumor that is highly metastastic. Studies found that melanoma can be treated by controlling the growth of primary tumors and metastases. They also discovered the need to target slow cycling populations of melanoma cells and increase immune response to target these cells.

This article discusses the development of an oral antiangiogenic drug, which could disrupt the process of cancer metastasis. This drug, called Lodamin, works by interrupting the integration of cancer cells within the circulatory system of the patient. Lodamin is compared to the antiangiogenic drug TNP-470, which also uses a synthetic analog of fumagillin as an active ingredient. These two drugs differ in their delivery methods and their bioavailability. These medications are also compared to the angiogenesis inhibitor bevacizumab, also known as Avastin. The possibility that Lodamin could make certain types of cancer chronic rather than terminal is noted.

The article provides information on the discovery of protein that inhibits metastatic tumors. It notes that metastasis is the leading cause of death from cancer which can be inhibited by using a protein called prosaposin. Prosaposin can inhibit metastasis by producing factors that blocks the growth of blood vessels. It discusses how prosaposin suppress the metastatic tumors in the connective tissue.