bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A53: Tumor suppressor microRNA miR-34 inhibits human pancreatic and gastric cancer stem cells
Authors: Xu Liang , Ji Qing , Hao Xinbao , Tang Wenhua , Li Ling , DeSano Jeffrey T. , Fearon Eric R. , Lawrence Theodore S. 
Published: June 2012

Abstract
MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34 family members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are Notch and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer stem cells.
We examined the roles of miR-34 in p53-mutant human pancreatic and gastric cancer cell lines and the potential link to cancer stem cells. Restoration of miR-34 expression in the cancer cells by miR-34 mimics or lentiviral miR-34 downregulated Bcl-2 and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and G2/M arrest in cell cycle, and sensitized the cancer cells to chemotherapy and radiation. We identified that CD44+/CD133+ cancer cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to a significant reduction of the tumor-initiating cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo. Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function of the p53 in p53-deficient human pancreatic and gastric cancer cells. Our data support that miR-34 may be involved in cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch, implying that miR-34 may play an important role in cancer stem cell self-renewal and/or cell fate determination. Currently, we are exploring the nanoparticle-targeted delivery of miR-34 to cancer stem cells as a novel molecular therapy for human pancreatic/gastric cancer, based on our patented nanobiotechnology which has been approved by FDA for clinical trials.
Taken together, our results demonstrate that restoration of miR-34 may hold significant promise as a novel molecular therapy for human pancreatic/gastric cancer with loss of p53-miR34, potentially via inhibiting cancer stem cells. The project is funded by NIH grants CA121830, CA128220 and CA134655 (to L. Xu.).
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A53.
Abstract A54: STAT3 as a novel therapeutic target in human breast cancer stem cells
Authors: Lin Li , Hutzen Brian , Peng Zhengang , Lin Huey-Jen , Li Pui-Kai , Li Chenglong , Wicha Max , Lin Jiayuh 
Published: June 2012

Abstract
The American Cancer Society estimates that over 200,000 new cases of invasive breast cancer and over 40,000 deaths are expected among women in United States each year. Despite advances in chemotherapy and hormonal treatment, at the present time, metastatic breast cancer remains an incurable disease. Although a large number of chemotherapeutic agents have been developed that are able to cause the regression of metastatic breast cancers, these tumors almost always recur following chemotherapy treatment. It is possible that breast cancer stem cells or breast cancer initiating cells are responsible for the drug-resistance, metastasis, and recurrence of cancer. Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in many types of cancers, including breast cancer, and has emerged as an attractive molecular target for cancer treatment. However, whether or not STAT3 is activated in breast cancer stem cells and what role STAT3 signaling plays in cancer stem cells is still unknown. If STAT3 is activated in breast cancer stem cells, targeting STAT3 may offer a promising opportunity to eliminate breast cancer stem cells and prevent the recurrence of cancer. We examined STAT3 activation in breast cancer stem cells, which are characterized by an aldehyde dehydrogenase (ALDH)-positive subpopulation. Interestingly, we observed that the ALDH-positive subpopulation of breast cancer cells expressed higher levels of phosphorylated STAT3, an active form of STAT3, as compared to the ALDH-negative subpopulation and un-separated breast cancer cells, suggesting that STAT3 is activated in breast cancer stem cells. We also demonstrated that a novel STAT3 inhibitor, LLL12, inhibited STAT3 phosphorylation, cell viability, STAT3 downstream target gene expression, and induced apoptosis in breast cancer stem cells. In addition, the STAT3 inhibitors Stattic and LLL12 reduced ALDH-positive subpopulation and inhibited their tumorsphere forming capacity. Furthermore, in our pilot study in a mouse tumor model using breast cancer stem cells, we demonstrated that LLL12 can suppress tumor growth in vivo. This is the first report to demonstrate that persistent STAT3 phosphorylation is expressed in breast cancer stem cells and that this subpopulation of breast cancer stem cells is sensitive to STAT3 inhibitors. Our results suggest that STAT3 is a novel therapeutic target in breast cancer stem cells and inhibition of activated STAT3 in cancer stem cells may offer a more effective treatment for breast cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A54.
Abstract A7: Targeting the tumor microenvironment via inhibition of VEGF and PDGF to improve liposomal drug delivery in human non-small cell lung cancer xenografts
Authors: Tailor Tina D. , Hanna Gabi , Yarmolenko Pavel S. , Dewhirst Mark W. 
Published: June 2012

Abstract
Background: Pathological angiogenesis creates an abnormal microenvironment in tumors, characterized by elevated interstitial fluid pressure (IFP) and hypoxia. Judicious attenuation of angiogenic signals may “normalize” the vascular bed, making it more suitable for drug delivery and radiotherapy. In this work, we investigate the role of pazopanib, a small-molecule inhibitor of vascular endothelial growth factor (VEGF) receptors and platelet-derived growth factor (PDGF) receptors, on normalization parameters of IFP, vascular pericyte coverage, hypoxia, and liposomal drug delivery.
Methods: Nude mice bearing A549 human non-small cell lung cancer (NSCLC) xenografts were treated with pazopanib 100mg/kg (n=20) or control (n=20) for 8 days, followed by a single intravenous dose of Doxil (liposomal doxorubicin) 10mg/kg. 24 hours after Doxil delivery, tumor IFP was measured, and tumors were snap frozen and sectioned. In a second study, designed similarly to the previous (n=4 pazopanib 100mg/kg, n=4 control), EF5 (hypoxia marker) was delivered 3 hours prior to tumor harvest. Tissue sections were stained for vasculature and pericytes using anti-CD-31 (endothelial cell marker) and anti-alpha-smooth muscle actin, respectively. Hypoxia was assessed via immunostaining for CA-IX and EF5. High performance liquid chromatography was used to determine tumor doxorubicin concentration ([dox]), and the penetration distance of Doxil from CD-31 stained vessels was calculated using a MATLAB algorithm.
Results: Pazopanib treatment resulted in reduction of tumor IFP (116.571 ± 15.174 mmHg control vs. 61.000 ± 7.367 mmHg pazopanib, P = 0.0145) and decreased vessel density (251.228 ± 18.770 vessels/mm2 control vs. 101.313 ± 11.005 vessels/mm2 pazopanib, P &lt; 0.0001). No differences in tumor [dox] were observed between groups (10.849 ± 1.785 ng/kg control vs. 12.274 ± 1.013 ng/mg pazopanib, P = 0.5956), however Doxil penetration improved in pazopanib-treated tumors (18.980 ± 0.687 m control vs. 32.886 ± 1.741 m pazopanib, P = 0.0006). Despite these trends towards normalization, tumor hypoxia, evaluated by CA-IX and EF5 expression, was increased in the pazopanib group (% CA-IX staining, 7.034 ± 0.988% control vs. 16.720 ± 1.728% pazopanib, P = 0.0005;% EF5 staining, 15.992 ± 2.610% control vs. 36.554 ± 4.617% pazopanib, P = 0.0074). Additionally, the proportion of pericyte-coated vessels was decreased in the pazopanib group (0.840 ± 0.0362 control vs. 0.675 ± 0.0495 pazopanib, P = 0.0160).
Conclusions: Our results suggest a role for VEGF/PDGF inhibition in modulating functional parameters of the tumor microenvironment and improving drug distribution. However, these changes may be mediated by stromal changes in response to PDGF-receptor blockade, rather than normalization.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A7.
Abstract A75: Dual inhibition of EGFR and ErbB2 during androgen ablation prevent the progression of prostate cancer cells to androgen independence
Authors: Chen Liqun , Madhav Anisha , Ghosh Paramita M. 
Published: June 2012

Abstract
Introduction: Patients with metastatic prostate cancer are treated with androgen ablation therapy which is initially effective, but most patients on this therapy ultimately become refractory to this treatment. Studies show that androgen withdrawal does not result in cell death, but simply cell growth arrest, whereas the development of androgen independence allows them to come out of the growth arrest and undergo cell cycle progression. Hence, induction of apoptosis during androgen ablation will prevent progression to androgen independence. The goal of the present project is to determine whether dual inhibition of EGFR and ErbB2 in prostate cancer cells during androgen withdrawal prevent their progression to androgen independence. EGFR, ErbB2, ErbB3 and ErbB4 constitute a family of receptor tyrosine kinases that require dimerization for complete activation.
Experimental Procedures: Androgen dependent LNCaP prostate cancer cells and its androgen-independent subline LNCaP-AI were treated with combinations of the EGFR inhibitors AG1478 or Erlotinib (Tarceva), and the ErbB2 inhibitors AG879 or Trastuzumab (Herceptin), either in the presence of androgens, or together with androgen withdrawal. These experiments were also conducteds in androgen receptor (AR)-null pRNS-1-1 cells transfected with vector only, wild type AR or mutant AR(T877A).
Results: Dual inhibition of EGFR and ErbB2 was more effective in inhibiting cell growth compared to single inhibition of either kinase. This effect was more pronounced in the absence of androgens compared to its presence, and was also more effective in androgen-dependent than in androgen-independent cells. Investigation of the mechanism of this effect demonstrated that dual inhibition of EGFR and ErbB2 also inhibited ErbB3 phosphorylation, likely by preventing its dimerization. Androgen withdrawal results in increased Akt phosphorylation, and we show here that dual EGFR/ErbB2 inhibition, but not single inhibition, prevented this effect and induced apoptosis. This effect is most pronounced in androgen sensitive cells undergoing androgen ablation, whereas in androgen-independent cells where Akt phosphorylation is already increased, the effect of the dual inhibition was less pronounced.
Conclusions: Our results indicate that cell survival during androgen withdrawal caused by an increase in Akt phosphorylation may be prevented by dual use of EGFR and ErbB2 inhibitors. If the cells can be killed during androgen ablation, then no cells will remain to progress to androgen independence. Hence, the effect of the dual inhibition prevents the development of androgen-independence in prostate cancer cells. The significance of these results is that they suggest that the use of dual EGFR/ErbB2 inhibitors during androgen ablation may prevent the development of androgen independence in patients undergoing androgen ablation therapy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A75.
Abstract A84: Role of Akt pathway in the response of cetuximab in a resistant head and neck cell line
Authors: Rebucci Magali , Peixoto Paul , De Witte Amelie , Dewas Claire , Lartigau Eric , Lansiaux Amelie 
Published: June 2012

Abstract
The Epidermal Growth Factor Receptor (EGFR) is a central regulator of cell proliferation and differentiation in human cancers and is frequently overexpressed in many types of tumors. Cetuximab is a monoclonal antibody designed to block the EGFR activation, to induce the internalization of the receptor and to reduce the signaling pathway. However many tumors exert resistance to EGFR inhibitors. Accumulating evidence indicates that the response of cancer cells to cetuximab is a complex process that can be affected by multiple intrinsic and extrinsic resistance mechanisms. The aim of this study was to investigate the mechanisms of resistance to cetuximab treatment in vitro. We investigated the EGFR pathway and the receptor internalization after cetuximab treatment, alone or combined, and we compared results in CAL33 (HNSCC) and A431 (epidermoïd cancer) cell lines which overexpressed EGFR and present different sensitivities to cetuximab and to EGF (EGFR natural ligand).
Cetuximab induced a high growth inhibition and a high inhibition of ERK and AKT phosphorylation in A431. By contrast, cetuximab induced a lower growth inhibition, an ERK phosphorylation inhibition but any inhibition of the AKT pathway. The cetuximab sensitivity of these cell lines was thus different and the difference would be based on the AKT pathway. To verify this hypothesis, we used an EGFR tyrosine kinase inhibitor and an AKT inhibitor. Results have shown that the AKT pathway can be inhibited in CAL33 cell line by an EGFR tyrosine kinase inhibitor and an AKT inhibitor. While the cetuximab induced a strong growth inhibition in A431, this growth inhibition was weakly increased by the combination. In contrast, cetuximab induced a weak growth inhibition in CAL33 while the growth inhibition was much stronger with the combination than in A431. According to the central role of the EGFR internalization in the AKT pathway activation, we investigated the EGFR internalization role in these models. Preliminary results showed significant differences between these two cell lines. In conclusion, this study had shown some explanations to the limited efficacy to cetuximab in CAL33. Firstly, we have shown a persistent activation of AKT in CAL33 which might prevent the antitumor effect of cetuximab. Secondly, we have shown that the EGFR internalization and signal transduction mediation were different in CAL33 and A431 and this difference might contribute to the response to cetuximab. The AKT pathway appears as a central element in the cetuximab sensitivity in these models and the combination of cetuximab with an AKT inhibitor could be a good therapeutic option in HNSCC
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A84.
Abstract A87: Synthesis and structure-activity relationships of a series of epipodophyllotoxin polyamine conjugated derivatives vectorized for active polyamine transporter system in tumor cells, leading to the selection of F14512 for clinical trials
Authors: Imbert Thierry , Guminski Yves , Cugnasse Sandrine , Grousseaud Martial , Barret Jean-Marc , Kruczynski Anna , Vispe Stéphane , Gras Stéphane , Annereau Jean-Philippe , Vandenberghe Isabelle , Stennevin Aline , Lacastaignaratte Laurence , Novosad Natacha , Pourtau Sandrine , Roy Sabine , Castano Caroline , Blanchet Jean-Christophe , Guilbaud Nicolas , Bailly Christian 
Published: June 2012

Abstract
One of the major concerns for chemotherapy is the selective targeting of drugs into highly proliferative cancer cells. Natural polyamines (spermine, spermidine, putrescine) are essential for the regulation of cellular growth and differentiation. Due to their highly proliferative nature, cancer cells have a pronounced need to import polyamines from their external environment, through the polyamine transporter system (PTS). On the basis of this biological mechanism, we vectorized the new cytotoxic anticancer compound F14512, a epipodophyllotoxin — spermine conjugate, into tumor cells.1 Here we present the synthesis and the structure-activity relationships of a new series of compounds constituted by an podophyllotoxin core tethered with a polyamine moiety with a variable spacer. Two synthetic strategies with protected polyamines, and a direct 3 steps synthesis of F14512 from natural podophyllotoxin and spermine without any protection are presented.2 This series of topoisomerase II inhibitors were checked for their cytotoxicity on A549 lung cancer cell line, displaying marked potency up to nM range. Cancer cell internalization through PTS was assessed by selective cytotoxicity on different PTS expressing cell lines, and by competition experiments. Our results displayed a potent specificity for the conjugated tetramine (spermine) compounds, which were more recognized than the triamine (spermidine) ones, while mono and diamines showed no selectivity. Lead compounds were also tested in vivo and proved potent antitumor activity. This series of new water-soluble cytotoxic compounds culminates with the selection of F14512 for clinical trials.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A87.
Abstract B103: Integrative genomic and proteomic analyses identify novel targets for Lkb1 deficient metastatic lung tumors
Authors: Carretero Julian , Shimamura Takeshi , Rikova Klarisa , Gu Ting-Lei , Borgman Christa L. , Buttarazzi S. , McNamara Kate L. , Brandstetter Kathleyn A. , Silva Jeffrey C. , Shapiro Geoffrey I. , Castrillon Diego H. , Maira Michel , García-Echeverría Carlos , Kim Carla F. , Bardeesy Nabeel , Sharpless Norman E. , Kim William Y. , Engelman Jeffrey A. , Wong Kwok K. 
Published: June 2012

Abstract
Lung cancer is the leading cause of cancer related mortality worldwide. Gene expression profiling of primary human lung tumors has successfully led to the identification of aberrant signalling pathways involved in the initiation of non-small cell lung cancer (NSCLC). However, advances in defining the pathways deregulated in lung cancer progression and metastases have been limited. The process of tumor metastasis is a complex, multistage process that involves both metastasis initiation functions, such as invasion and angiogenesis, as well as metastasis progression functions such as extravasation and survival. In mice, lung-specific deletion of the Lkb1 tumor suppressor gene and activation of mutant Kras results in lung tumors with a high penetrance of lymph node and distant metastases. However, which of the several candidate pathways are responsible for the pro-metastatic effects of Lkb1 loss has yet to be defined. To identify altered signal transduction pathways involved in the progression and metastases of Lkb1 deficient lung tumors we have integrated genomic and phosphoproteomic signatures of primary and metastastic, Lkb1 deficient lung tumors to identify differentially activated signal transduction pathways. These studies revealed a number of signatures associated with the process of metastasis such as EMT, stem cell phenotype, growth factor signaling and focal adhesion. Moreover, several tyrosine kinases, including the non-receptor tyrosine kinase Src and the focal adhesion kinase, are activated in Lkb1 deficient primary and metastatic lung tumors, resulting in increased motility and Src-dependent adhesion of LKB1 deficient cells. Collectively, these results point towards a mechanism behind the increased propensity for metastases seen in Lkb1 deficient lung tumors and identify molecularly targetable pathways for the treatment of LKB1 deficient NSCLC in humans.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B103.
Abstract B109: Modulation of tumor-associated lymphatic function by the VEGF-C axis
Authors: Caunt Maresa , Gogineni Alvin , Weimer Robby , Bagri Anil 
Published: June 2012

Abstract
Lymph vasculature associated with solid tumors provides an exit route for disseminating metastatic cells. VEGF-C, a member of the vascular endothelial growth factor family, is upregulated in a range of metastatic tumor types. VEGF-C is known to mediate lymphatic development and is implicated in modulating lymph vessel function. These observations have lead to the hypothesis that VEGF-C expression in tumors may promote metastatic cell dissemination by augmenting lymph morphology or function. To explore this hypothesis we have developed longitudinal assays based on near-infrared fluorescence imaging technologies to study lymphatics associated with primary tumors. In preliminary experiments we observe a ∼ 50% increase in bulk transport through lymph beds draining VEGF-C(+) primary tumors. This increase in transport correlates with a ∼50% increase in contractile events along the draining vessels, suggesting that chronic production of VEGF-C promotes lymph transport in part by stimulating contractility. We are currently testing agents which block VEGF-C-mediated signaling pathways to determine if reduced signaling correlates with reduced transport and rates of metastatic events.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B109.
Abstract B113: Role of I-TAC-binding receptors CXCR3 and CXCR7 in biology of various tumor cell lines
Authors: Miekus Katarzyna , Jarocha Danuta , Trzyna Elzbieta , Majka Marcin 
Published: June 2012

Abstract
Introduction: Chemokines and its receptors stimulate tumor growth, migration and invasion. SDF-1-CXCR4 axis plays a major role in these processes. However, other chemokines and their receptors are also important for tumor biology. Recently, SDF-1 was shown to bind with high affinity to the orphan receptor RDC1, later renamed CXCR7. In human tissues, CXCR7 expression has been described on endothelial cells and on some tumor cell lines. Recent studies confirmed a critical role for CXCR7/RDC1 in tumor vascular formation, angiogenesis and promotion of growth of breast and lung cancer in vivo.
Objectives: In this study we evaluated the expression and function of CXCR3 and CXCR7 receptors in cervical carcinoma, rhabdomyosarcoma and glioblastoma cell lines. The main goal of this study was to explore the role of CXCR7 in biology of rhabdomyosarcoma, cervical carcinoma and glioblastoma.
Material and Methods: Several cell lines were used in the study: rhabdomyosarcoma (SMS-CTR, RD, RH18, RH28, CW9019, RH30), cervical carcinoma (HeLa, HTB-34, HTB-35) and glioblastoma (LN18, LN229, T98G). To study the expression and function of CXCR3 and CXCR7 receptor real-time PCR, flow cytometry, western blot and chemotaxis assays were used.
Results: We tested 12 different cell lines and found that all of them expressed CXCR7 and CXCR3 at mRNA and protein level. We noticed higher expression of CXCR7 on more aggressive tumor cell lines (e.g. CXCR7 expression differed between rhabdomyosarcoma subtypes and it was highly expressed by alveolar rhabdomyosarcoma and expressed at the low level by embryonal rhabdomyosarcoma). Since I-TAC binds CXCR3 receptor as well, its expression was also examined by flow cytometry. We observed expression of CXCR3 receptor on all tested cell lines except HeLa and CW9019 and these cell lines were chosen to check functionality of the CXCR7 receptor. Upon I-TAC stimulation the phosphorylation of AKT and MAPK was observed. We did not observed the migration of tumor cells toward I-TAC gradient. However, at the low dose I-TAC sensitized tumor cells toward SDF-1 gradient and synergized with SDF-1 in activation of intracellular pathways.
Conclusions: We found that CXCR7 is expressed on various cell lines and its expression might correlate with aggressiveness of tumor. I-TAC, the ligand for CXCR7, was able to activate signaling transduction pathways responsible for tumor growth and survival.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B113.