bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4127: EGFR and K-Ras mutations and resistance of lung cancer to the IGF-1R tyrosine kinase inhibitors
Authors: Kim Woo-Young , Jin Quanri , Prudkin Ludmilla , Kim Jin-Soo , Morgillo Floriana , Feng Lei , Kim Edward S. , Hennessy Bryan , Lee Ju-Seog , Mills Gordon , Lee J. J. , Glisson Bonnie , Lippman Scott M. , Wistuba Ignacio I. , Lee Ho-Young 
Published: February 2011

Abstract
Background: The majority of patients with non-small cell lung cancer (NSCLC) has responded poorly to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We investigated (1) the involvement of insulin-like growth factor 1 receptor (IGF-1R) signaling in primary resistance to EGFR TKIs and (2) the molecular determinants of resistance to IGF-1R TKIs. Methods: Phosphorylated IGF-1R/insulin receptor (pIGF-1R/IR) was immunohistochemically evaluated in NSCLC tissue microarrays. The antitumor effects of IGF-1R TKIs (PQIP, OSI906), either alone or in combination with small-molecular inhibitors or siRNA targeting K-Ras or MAPK/extracellular signal-regulated kinase kinase (MEK) were analyzed in vitro and in vivo in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-transformed human bronchial epithelial (HBE) cells and in NSCLC cells with variable histologic features and mutations in EGFR or K-Ras. Results: pIGF-1R/IR expression in NSCLC specimens was positively correlated with presence of a history of tobacco smoking, squamous cell carcinoma, mutant (mut) K-Ras, and wild-type (wt) EGFR, all of which have been strongly associated with poor response to EGFR TKIs. IGF-1R TKIs exhibited significant antitumor activity in NNK-transformed HBE cells and in NSCLC cells harboring wt EGFR and wt K-Ras, but not those with mutations in these genes. Introduction of mut K-Ras attenuated the effects of IGF-1R TKIs on wt K-Ras-expressing NSCLC cells. Conversely, inactivation of MEK restored sensitivity to IGFR-TKI in cells carrying mut K-Ras. Conclusions: The mutation status of both EGFR and K-Ras could be a predictive marker for response to IGF-1R TKIs. Also, MEK antagonism can abrogate primary resistance of NSCLC to IGF-1R TKIs. This work was supported by NIH grants R01 CA-109520-01 and CA-100816 (all to H-YL.) and in part by DOD grant W81XWH-04-1-0142 VITAL and W8XWH-06-1-0303 BATTLE (W-K H.)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4127.
Abstract 4158: The p53 gain-of-function mutation p53R172H promotes oral cancer progression in response to DNA damage
Authors: Acin Sergio , Caulin Carlos 
Published: February 2011

Abstract
Oral cancer is one of the most common cancers worldwide, presenting high mortality rates and a severe impact on the quality of life of patients and survivors. Oral cancers arise from the accumulation of genetic alterations. Some of the most prevalent mutations found in patients with oral cancer involve mutations in Ras and p53 genes, although the mutation rates exhibit geographical variation, most likely as a result of different exposure to carcinogens. Most p53 mutations result in the expression of mutant forms of p53, rather than inactivation of the p53 gene. To determine the role of these mutations during oral cancer development we generated mice in which the endogenous K-rasG12D allele and p53 gain-of-function mutation p53R172H could be activated exclusively in the oral epithelium. We found that the p53R172H mutation, but not deletion of p53, cooperates with K-rasG12D to initiate oral tumor formation, accelerates oral tumor growth and promotes progression to squamous cell carcinoma. Expression profiling of the tumors that developed in these mice revealed that cyclin B1 was overexpressed in the oral tumors that expressed p53R172H compared to tumors with no p53. To expand the functional studies, we generated cell lines from these mouse oral tumors. Similar to the primary tumors, cell lines derived from the tumors expressing p53R172H generated tumors that grew faster upon injection in nude mice than cell lines that lacked p53. Using these cell lines we found that the expression of cyclin B1 was dramatically induced in the p53R172H cells in response to DNA damage, suggesting that cyclin B1 may contribute to the oncogenic properties p53R172H in oral tumor cells in response to DNA damage. Notably, we observed DNA damage in the oral tumors, as determined by staining for γ-H2AX. Since these tumors were initiated by oncogenic K-ras, we speculated that oncogene activation induced DNA damage in the tumors, thereby allowing the induction of cyclin B1 expression. Consistent with this hypothesis we found that suppressing K-ras in cells that express p53R172H resulted in significant reduction in cyclin B1 expression, indicating that p53R172H can induce the expression of cyclin B1 in response to oncogenic K-ras. In addition, we found increased DNA damage in the oral tumors that expressed p53R172H compared to tumors that lack p53, suggesting that p53R172H may modulate the DNA damage response. Together, these findings indicate that p53R172H may promote oral tumor progression in response to DNA damage, and suggest that attenuation of the DNA damage response may contribute to the oncogenic properties of mutant p53.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4158.
Abstract 4170: Primary Orthotopic Hepatocellular Carcinoma Models for Evaluation of Anticancer Drugs
Authors: Chen Dawei , Chen Taiping , Wery Jean-Pierre , Chen Yiyou 
Published: February 2011

Abstract
Human primary tumor model represents better alternatives for preclinical drug evaluation than cell lined derived xenograft models, due to its preservation of tumor tissue organization and pathology. At the same time, orthotopic xenograft models have also been used to better mimic the human patho-physiologic conditions such as vascularization, tumor expansion, and local microenvironmental factors. Here we combined the orthotopic transplantation method with our primary HCC models. The initial tumor inoculate was derived from a HCC patient tumor which was maintained subcutaneously in nude mice with limited passages. Tumor fragment was then anchored to the anterior hepatic lobe of nude mice. The Plasma AFP level of the orthotopic tumor bearing mice were determined once per week in order to correlate with the tumor volume. We have applied several standard care anticancer drugs to evaluate this model. Cisplatin (5mg/kg, q3d x 4) and Sorafinib (50mg/kg, qd x14), were dosed for 2 weeks after randomized grouping based upon the serum AFP levels of tumor bearing mice. The procedure of HCC fragments inoculation for this orthotopic model was successful and efficient. The tumor take rate of transplantation is over 90%. AFP level in tumor bearding mice plasma could be used as a biomarker to monitor tumor burden. These results indicated that primary orthotopic HCC model is a powerful tool for the evaluation of the drugs targeting heptocellular carcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4170.
Abstract 4171: The role of the Src kinase family in determining three-dimensional epithelial cell morphology of colorectal cancer cell lines
Authors: Hellwig Sabine , Smithgall Thomas E. 
Published: February 2011

Abstract
Members of the Src kinase family are involved in numerous cellular signaling pathways that regulate cellular growth, survival, differentiation, adhesion and migration. Src family kinases (SFKs) associate with cellular membranes and function as molecular switches at the interface of various extracellular input signals (e.g., growth factors, cell-matrix adhesion) and intracellular signaling cascades. Deregulation of SFK expression levels and activity is implicated in a variety of human pathologies, including cancer, neurodegeneration, epilepsy and progression of HIV/AIDS. Elevation of c-Src activity is a common event in human colon cancer, and increases in c-Src activity are often associated with disease progression. In addition, upregulation of other Src-family members has been observed in colon cancer (e.g., c-Yes, Lck), suggesting that deregulation of SFKs may contribute to colorectal cancer progression.
The three-dimensional culture of epithelial cells in a laminin-rich extracellular matrix (lrECM) has become increasingly popular in investigating the integration of cellular signaling pathways. Because the growth of cells in lrECM more closely recapitulates the microenvironment encountered by cells in vivo, three-dimensional cell culture is particularly useful in elucidating the biological roles of molecular components, such as SFKs, that function at the interface of extracellular and intracellular signals.
In this study we use a three-dimensional culture system to study the role of SFKs in determining epithelial cell morphology of colorectal cancer cells. We tested a panel of ten commonly studied colorectal cancer cell lines for their ability to form organized cysts with established apical-basal polarity when grown in Matrigel in the presence or absence of broad-spectrum SFK inhibitors. We observed that Caco-2 and T84 cells, two lines capable of polarized cyst formation, show distinct sensitivity to SFK inhibition in three-dimensional culture but not in monolayer growth. Surprisingly, in Caco-2 cells, but not in T84 cells, global inhibition of SFK activity appears to interfere with cyst polarization, suggesting that one or more SFKs contribute to epithelial cell polarity. In addition, using RT-PCR and immunoblot techniques we demonstrate that SFK expression profiles are altered in Matrigel culture compared to monolayer culture. By comparing SFK expression profiles in cell lines displaying polarized versus unpolarized cell morphology we seek to identify individual members of the SFK family that contribute to three-dimensional epithelial morphology.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4171.
Abstract 4177: Inhibition of tumor malignancy by anti-angiogenic therapies in orthotopic mouse models of hepatocellular carcinoma
Authors: Li Gang , Hu-Lowe Dana , Christensen James , Pocalyko David 
Published: February 2011

Abstract
Hepatocellular carcinoma (HCC) is the most common liver malignancy, and the third most common cause of cancer-related mortalities worldwide. Most cases occur in Asia, and in China alone an estimated 251,000 male and 95,000 female patients are diagnosed annually. Although significant advances have been made with the use of certain chemotherapeutic and targeted therapeutic agents in HCC treatment, the prognosis for most liver cancer patients remains poor. To address this significant unmet medical need, Pfizer Oncology has set out to strengthen its research and drug discovery activities targeting HCC. Here we report the establishment of two series (cell line-derived and primary human tumor-derived) of orthotopic mouse models of HCC, and their validation with anti-angiogenic compounds sutent and axitinib. In both series of models, tumor fragments obtained from in vivo expansion were surgically implanted into the left lobe of mouse liver to mimic the natural microenvironment and preserve the interaction between tumor cells and the stroma components. Both sutent and axitinib demonstrated significant anti-tumor activity, as well as metastatic potential at therapeutic doses. The anti-tumor activity of these agents are associated with reduction of CD31 in the tumor. Both sutent and axitinib were well tolerated by the animals during the course of the studies. In addition, plasma samples were collected at different time points for α-feto-protein (AFP) measurement. A significant correlation between tumor size (or weight) and serum AFP level was demonstrated, which indicated that circulating AFP can be utilized as a non-invasive biomarker for HCC burden. These results support anti-angiogenesis as a valid approach for effective treatment of HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4177.
Abstract 42: Biological significance of the lipogenic enzyme acetyl-CoA carboxylase in the control of metastatic properties of murine and human transformed cells
Authors: Scott Kristen E. , Wheeler Frances B. , Ntambi James M. , Seals Darren F. , Kridel Steven J. 
Published: February 2011

Abstract
In recent years, it has been determined that the fatty acid synthesis pathway is upregulated in several types of cancers of epithelial origin at both transcriptional and translational levels. Unlike normal cells, cancer cells rely on this pathway to provide the fatty acid precursors needed for synthesizing lipids that preferentially segregate into the liquid ordered microdomains of the plasma membrane. Acetyl-CoA carboxylase (ACC) is the ATP dependent and rate limiting step of fatty acid synthesis and catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. Interestingly, overexpression of this enzyme increases with severity of breast cancer patient samples and cell lines, indicating a possible role for ACC in the metastatic process. Preliminary findings from our lab indicate that ACC is important for the proteolytic invasion and migration of transformed cells independently of cell death. Moreover, ACC is critical for formation of F-actin rich membrane structures known as podosomes, which have been implicated in the metastatic process in recent years. Restoration of podosomes in cells with ACC inhibition was achieved with the addition of the soluble fatty acid, C18:1 (oleate). In contrast, inhibition of the fatty acid synthetic enzyme, fatty acid synthase (FASN), or the Δ9 desaturase, stearoyl-CoA desaturase 1 (SCD-1), does not affect podosome formation. However, inhibition of FASN resulted in attenuated proteolytic invasion and migration of transformed cells with a phenotype similar to cells with ACC inhibition although not quite to the same degree. In addition to regulation at transcriptional and translational levels, ACC activity is also regulated by phosphorylation/dephosphorylation by AMP activated protein kinase (AMPK). Decreased ACC phosphorylation at serine 79 (S79) has been shown to correlate with increased disease severity and reduced disease free survival of lung adenocarcinoma patients. This indicates that the phosphorylation status of ACC may be an important mechanism that cancer cells manipulate to successfully achieve metastasis. Therefore, induction of phosphorylation, and inactivation of ACC, either by activation of AMPK or by direct mutation of S79 may be sufficient to reduce invasion and migration of cancer cells. Taken together, investigating ACC phosphorylation status and analyzing the resulting phenotype will advance the mechanistic understanding of how cancer cells metastasize and possibly provide new therapeutic avenues to explore in the treatment of disseminated disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 42.
Abstract 4206: Utilizing a Drosophila high throughput screening technology for cancer drug discovery
Authors: Gracheva Elena M. , Martinez Eduardo J. , Thompson Jill , Thompson Dominick , Cagan Ross L. 
Published: February 2011

Abstract
MEDROS has developed unique high-throughput 96-well drug screening methods to model human diseases in the context of a whole organism, the fruit fly Drosophila melanogaster. Our approach is designed to address disease complexity and whole animal drug pharmacology, aspects poorly addressed by in vitro or cell screening methods.
Here we focus on cancer, a complex disease that will benefit from the powerful tools available in Drosophila. We have designed a cancer fly model where the human oncogenes Ras and Src, centrally important in a variety of major human cancers, are targeted together to the retinal epithelium. We utilize inducible systems to calibrate their activation, generating reliably metastatic tumors that progress in a manner that is readily screened. In one iteration, these ‘tumors’ lead to organismal lethality that we have developed into a robust high-throughput screen. The kinase inhibitor Sorafenib rescued this phenotype, allowing flies to survive to adulthood and providing important validation of our screening platform. In a second iteration we permit Ras and Src to more mildly transform the eye epithelium to generate a ‘rough’ or ‘tumorous’ eye. We demonstrate that these phenotypes provide a second, more sensitive assay of Ras/Src oncogenic activity; again, Sorafenib rescued these cancer-like phenotypes. This work has important implications regarding novel drug screening methods for cancer and provides useful insights about the metastatic process.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4206.
Abstract 4216: Activation of Akt and β-catenin pathways are required for the sustention of cancer stem cell-like characteristics generated by epithelial-mesenchymal transition
Authors: Li Junlin , Evers Mark B. , Zhou Binhua P. 
Published: February 2011

Abstract
Approximately 90% of cancer deaths are caused by metastasis. The increased motility and invasiveness of tumor cells is reminiscent of the processes at the epithelial-mesenchymal transition (EMT), which is essential for morphogenetic events in embryonic development, tissue remodeling, and wound healing. EMT not only confers tumor cells with a distinct advantage for metastatic dissemination but also provides cancer stem cell-like characteristics for their proliferation and survival. However, the molecular mechanism for maintenance of these cancer stem cell-like traits by EMT remains unclear. In this study, we generated two stable transfectants in breast cancer MCF7 and cervical cancer Hela cell lines with expression of Twist, a key transcriptional factor of EMT. We found that expression of Twist induced a morphological EMT changes in these cells by downregulating the expression of E-cadherin and ZO-1 and by increasing vimentin and N-cadherin expression. We also showed that the CD44highCD24low subpopulation in these stable transfectants, which is associated with cancer stem cells properties, was significantly increased. Consistent with these findings, expression of stem cell marker ALDH1 was also elevated in these cells. The increased stem cell-like traits in Twist expression clones correlated with the tumorsphere formation in these cells. Strikingly, we found that β-catenin and Akt pathways were activated in these Twist-expressing transfectants. The nuclear accumulation of β-catenin correlated with the expression of CD44. Knockdown of β-catenin expression or inhibition of the Akt pathway significantly decreased the expression of CD44. Together, our results indicate that the activation of β-catenin and Akt pathway are required for the sustention of cancer stem cell-like traits generated by EMT.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4216.
Abstract 4218: Potential roles of NF-kappa B pathways in breast cancer-initiating cells
Authors: Hinohara Kunihiko , Murohashi Michiko , Kuroda Masahiko , Isagawa Takayuki , Tsuji Shingo , Kobayashi Seiichiro , Umezawa Kazuo , Tojo Arinobu , Aburatani Hiroyuki , Gotoh Noriko 
Published: February 2011

Abstract
Accumulating evidence suggests that Tumor-initiating cells (TICs) or cancer stem cells_which make up only a small proportion of heterogeneous tumor cells_possess a greater ability to maintain tumor formation than other tumor cell types. In human breast cancers, a population characterized by the expression of cell surface markers, CD24−/low/CD44+, was reported to be highly enriched in TICs as compared to CD24+/CD44+ cell populations. However, the signaling pathways activated in TICs that contribute to tumorigenesis are not fully understood. We observed various expression levels of CD24 and CD44 among 8 human breast cancer cell lines. The CD24−/low/CD44+ cell populations of HCC1954 and MCF7, breast cancer cell lines, generated significantly larger tumors than the CD24+/CD44+ cell populations in a xenograft model, suggesting that the CD24−/low/CD44+ cell populations have the properties of TICs at some extent. To identify expressed genes that were highly enriched in CD24−/low/CD44+ cell populations, we next performed DNA microarray analysis using HCC1954, MCF7, and HCC70 cell lines that have small populations of CD24−/low/CD44+ cells. We then applied a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. GSEA revealed that the CD24−/low/CD44+ cell populations are enriched for genes involved in a tumor necrosis factor (TNF) or interferon (IFN) response pathway. TNF or IFN response pathway is involved in the expression of many inflammatory cytokines/chemokines, including IL8 and CCL5. We measured expression levels of IL8 and CCL5 by quantitative RT-PCR (qRT-PCR) and confirmed that they were expressed at significantly higher levels in CD24−/low/CD44+ cell populations compared with the CD24+/CD44+ cell populations. Moreover, we found the relatively high nuclear factor kappa B (NF-kappa B) activity in the CD24−/low/CD44+ cell populations. In addition, NF-kappa B inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) prevented tumorigenesis of CD24−/low/CD44+ cell populations in vivo. Our findings suggest that NF-kappa B play a crucial role for orchestration of transcription factors regulating breast cancer stem cell biology. Further studies will be presented about the mechanism of NF-kappa B activation and its role in breast TICs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4218.