bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C29: Periostin, a regulator of adhesion, is a novel effector of tumor invasion
Authors: Wong Gabrielle , Michaylira Carmen Z. , Miller Charles G. , Gutierrez Christie M. , Stairs Douglas B. , Kalabis Jiri , Nakagawa Hiroshi , Diehl Alan J. , Herlyn Meenhard , Rustgi Anil K. 
Published: May 2012

Abstract
Squamous cell cancers in aggregate comprise the most common forms of epithelial cancers, arising from the skin, head/neck, oral cavity, esophagus, lung and anogenital tract, and they share a number of environmental exposures and genomic alterations. A prototype of this cancer is esophageal squamous cell carcinoma (ESCC), which is associated with a high mortality rate worldwide. Local invasion and metastasis are important factors which influence patient survival. Amongst the frequent oncogene alterations are EGFR and cyclin D1 overexpression, and that in tumor suppressor genes are p53 mutation and p120-catenin loss or mislocalization. However, the functional interplay between these genetic alterations contributing to cancer progression remains unclear. Our previous studies have addressed this by presenting a tumor microenvironment model for tumor cell invasion using a 3D organotypic culture system and transformed human esophageal cells overexpressing EGFR and mutant p53 (Genes and Development 2007). From this, we have now utilized laser capture microdissection (LCM) and microarray analysis to identify novel targets of EGFR overexpression and mutant p53 by comparing gene expression of invading versus non-invading transformed cells. Results from these studies reveal a marked upregulation of periostin, a gene involved in cell adhesion, whose expression is restricted to invading tumor cells, as validated by qPCR, immunohistochemistry and Western blot. Furthermore, its expression was found to be upregulated in human esophageal cancer compared to normal esophagus. Using genetic approaches, gain-of-function of periostin fosters tumor cell invasion, whereas silencing of periostin markedly attenuates tumor cell invasion. Bioinformatic analyses reveal that periostin is upregulated in other human squamous cell cancers as well. Promoter studies assessing the transcriptional regulation of periostin upon EGFR overexpression and p53 mutation have been done. Our novel findings indicate periostin induction upon convergence of EGFR signaling and p53 mutation provides a cue for tumor cell invasion in the tumor microenvironment, and that it may be part of tumor invasion signature in squamous cell cancers in general.
This work was supported by P01-CA098101, NIH/NRSA F32-DK075230 and T32 CA115299.
Citation Information: Cancer Res 2009;69(23 Suppl):C29.
Abstract C32: Proteome analysis of pancreatic cancer tissue for identification of novel biomarkers
Authors: Ganepola Ganepola , Suman Paritosh , Gelber Cohava 
Published: May 2012

Abstract
Pancreatic cancer is the 4th largest cancer in US with mortality rate almost equal to incidence. The tumor usually presents at a late stage ruling out any curative surgery. Focus of pancreatic cancer research currently is mainly on early diagnosis and development of novel cancer therapeutics. Identifying sensitive, specific and reliable surrogate markers by genomic and proteomic methods1 in cancer tissue, blood or other bodily secretions can prove promising to reach this goal.
We are applying standard proteomic techniques like gel electrophoresis and MS (mass spectrometry) with a goal to identify potential biomarkers and new drug targets for the design and development of effective therapeutics in serum and pancreatic tissue samples.
Pancreatic cytosolic and membrane proteins were extracted from the 4 pairs of cancerous and adjacent normal tissue. Cytosolic protein fractions were run on PF-2D, traditional 1D and 2D SDS-PAGE. LC/MS/MS was used to identify differently expressed banding patterns. Multiple proteins were found to be either up (24) or downregulated (11). Compared to cytosolic proteins membrane proteins are priced for its accessibility on tumor tissue making these ideal for diagnosis and therapeutics. Isolating only plasma membrane proteins is very challenging due to low extraction efficiency, extremely low abundancy and poor solubility. Total cellular membrane protein was extracted and analyzed by SDS-PAGE and LC/MS/MS, and significant banding pattern differences were observed with 35 upregulated and 14 downregulated proteins with annexin 1, annexin A2 and annexin 5, tumor rejection antigen 1, prolyl 4-hydroxylase, calreticulin precursor, heat shock 70kDa protein 5, chaperonin and alpha 2 actin being the most significantly overexpressed. Findings were confirmed by probing western blots with anti-annexin 1 and 2 antibodies. Our findings suggest these differently expressed proteins can be explored as potential biomarkers after further validation. In contrast, analysis of serum samples by same techniques was futile due to exceedingly low abundance of protein and peptide fraction containing potential biomarkers due to masking by albumin and globulins as well as enzymatic degradation.
At present we are continuing the validation of our preliminary findings on larger sample size by using differential protein profiling technologies, immunohistochemistry and quantitative proteomics. Also we are planning to use affinity bait molecule with nanoparticles2 which can help overcome the limitations faced with serum samples in identification of de novo biomarkers.
Citation Information: Cancer Res 2009;69(23 Suppl):C32.
Abstract C71: Inhibition of polyisoprenylated methylated protein methylesterase by anticancer drugs
Authors: Schodlbauer Suzanne , Duverna Randolph , Lamango Nazarius S. 
Published: May 2012

Abstract
Polyisoprenylated methylated protein methylesterase (PMPMEase) is a little explored enzyme of the polyisoprenylation (isoprenylation) pathway (PP). Polyisoprenylation is a post-translational modification that is important for the function of such proteins as the heterotrimeric G proteins, Ras and Rab families of proteins. PMPMEase hydrolyzes a methyl ester formed by the S-adenosyl-L-methionine (SAM)-dependent enzyme, polyisoprenylated protein methyltransferase (PPMTase). PMPMEase's regulatory role is suggested by the fact it hydrolyzes the ester products of PPMTase. PMPMEase is a serine hydrolase, a class of hydrolytic enzymes that attack electron-deficient carbons of amide and ester bonds with the alkoxide ion of their catalytic serines. Because alkylating agents function through an aziridinium ion with an electron-deficient carbon atom, it is hypothesized that they may inhibit PMPMEase through active site adduct formation. Alkylating agents have been suspected of having other mechanisms of action against cells besides impeding replication via the cross-linking of DNA strands. The crystal structure of the human form of PMPMEase, human carboxylesterase 1, with tamoxifen bound to its active site has been solved, also suggesting its possible inhibition. Polyisoprenylated proteins are involved in processes that regulate cell viability. Mutations and overexpression of such proteins are implicated in about 30% of cancers. This study considers the possibility that the agents also reduce malignant cell growth by disrupting growth signaling pathways. Cyclophosphamide is an organophosphorous alkylating agent. Organophosphorous compounds irreversibly inhibit PMPMEase and other serine esterases. Busulfan, cyclophosphamide, mechlorethamine and tamoxifen were tested for porcine liver PMPMEase inhibition. At 1 mM concentrations, cyclophosphamide, mechlorethamine and tamoxifen inhibited 62, 35 and 55% of the PMPMEase activity. The results show that the anticancer drugs may owe part of their pharmacological activity to their modulation of oncogenic polyisoprenylated protein function through their inhibition of PMPMEase.
Citation Information: Cancer Res 2009;69(23 Suppl):C71.
Abstract C75: Granulin-expressing bone marrow cells promote the outgrowth of indolent tumors
Authors: McAllister Sandra S. , Scheel Christina , Nilsson Björn , Gifford Ann M. , Reinhardt Ferenc , Bray Mark , Carpenter Ann E. , Ebert Benjamin L. , Weinberg Robert A. 
Published: May 2012

Abstract
We previously demonstrated that certain vigorously growing xenografted human carcinomas (“instigators”) stimulate the growth of otherwise-indolent carcinoma cells and metastases (“responders”) implanted at distant anatomical sites — a process we termed “systemic instigation” (S. McAllister, et al.; Cell, 2008). We showed that systemic instigation is largely the result of activation of bone marrow cells (BMCs) that subsequently contribute to the stroma of the responding tumors; however, the identity of the activated BMCs and their contribution to outgrowth of the once-indolent cells was unknown. Here, we demonstrate that Sca1+/cKit− BMCs of hosts bearing instigating tumors are activated prior to their mobilization into the circulation and are very potent in their ability to promote outgrowth of the responding tumors. Strikingly, responding tumors, which result from either the presence of a contralateral instigating tumor or the admixture of Sca1+/cKit− BMCs harvested from instigator-bearing mice, form with a desmoplastic stroma. Stromal desmoplasia, the accumulation of a myofibroblast-rich reactive connective tissue, is almost always observed in malignant human adenocarcinomas. The Sca1+/cKit− BMCs do not directly give rise to stromal myofibroblasts; instead, we found that factors secreted by these BMCs induce fibroblasts to express alpha-smooth muscle actin (ACTA2), a myofibroblast marker. Gene expression profiling of the Sca1+/cKit− BMCs from instigator- and non-instigator-bearing mice identified granulin, a pluripotent secreted growth factor, as the most highly upregulated gene in the activated BMCs. We found: i) that granulin is indeed expressed by bone marrow-derived cells that are recruited into the responding tumor stroma; ii) that treatment of human mammary fibroblasts with granulin induces ACTA2 expression; iii) that granulin treatment is sufficient to enhance responding tumor growth in vivo. Mining of existing microarray datasets revealed that high granulin expression is correlated with the expression of ACTA2 in human breast cancers and is associated with shorter disease-free survival of breast cancer patients. Our results indicate that the formation of desmoplastic stroma, a condition that is associated with invasive carcinomas, can be instigated systemically by certain tumors via activation of granulin-expressing Sca1+/cKit− in the bone marrow.
Citation Information: Cancer Res 2009;69(23 Suppl):C75.
Abstract IA-14: Molecular alterations that predict premalignancy in breast cancer
Authors: Tlsty Thea D. 
Published: May 2012

Abstract
Approximately 15–30% of women diagnosed with ductal carcinoma in situ (DCIS) develop a subsequent tumor event within 10 years after surgical lumpectomy. To date, little is known about the molecular pathways that confer this differential risk for developing subsequent disease. Since DCIS is non-obligate precursor of invasive carcinoma, the majority of DCIS lesions are not associated with subsequent invasive tumors. Likely, many women diagnosed with DCIS who opt for surgery, with or without adjuvant treatment, are being overtreated. Identification of characteristics of DCIS that predict subsequent tumor development would advance our understanding of breast cancer and allow us to stratify a woman's individual risk for subsequent invasive tumors and avoid over- and undertreatment of women with DCIS.
To address this clinical problem, we have recently identified biomarkers in DCIS biopsies that accurately predict future formation of tumors, years before it actually occurs. The overexpression of biological markers of stress activation, p16 and COX-2, reflect two biologically different processes that predict women with a better or worse prognosis. In the absence of proliferation, expression of these markers indicates activation of a senescence response and a low probability of tumor formation. In the presence of proliferation, these markers indicate abrogation of the pRb tumor suppressor pathway and are associated with a high likelihood of future tumor formation. We initially tested these markers in a pilot set of DCIS samples (32 cases and 38 controls) obtained from an extensively annotated population-based cohort of women diagnosed with DCIS, treated by lumpectomy alone, and followed for twenty years. These markers identified a highly aggressive subtype of DCIS that shares characteristics with basal-like invasive tumors. We have extended these studies to a larger retrospective cohort, 162 samples from the DCIS cohort (75 cases and 87 controls) and find that the prediction markers faithfully identify women at high and low risk for future tumor formation. Independent validation in a large retrospective cohort is ongoing. The finding that DCIS lesions with basal-like molecular characteristics have an increased risk of developing subsequent cancers suggest this phenotype can be assayed far in advance of the development of invasive disease and present clinical opportunities.
Citation Information: Cancer Res 2009;69(23 Suppl):IA-14.
Abstract IA-18: Mouse embryonic stem cells exist in a unique metabolic state
Authors: McKnight Steven L. 
Published: May 2012

Abstract
The cell division cycle of mouse embryonic stem (ES) cells is considerably more rapid than that of even the most aggressively growing cancer cells. In order to investigate whether mouse ES cells might exist in a unique metabolic state supportive of rapid growth, organic extracts were prepared and analyzed by liquid chromatography/mass spectrometry. Upon comparison of mouse ES cells with differentiating embryoid bodies, such assays revealed profound differences in the abundance of metabolites associated with one-carbon metabolism and purine biosynthesis. It was also noted that the abundance of both threonine and acetyl-CoA changed markedly as ES cells were cued to differentiate into embryoid bodies. These differences in metabolite abundance were traced to the copious, ES cell specific expression of the gene encoding threonine dehydrogenase (TDH). TDH gene expression was 1,000-fold higher in ES cells than any of 7 tissues assayed from adult mice. The TDH enzyme catalyzes the mitochondrial breakdown of threonine into glycine and acetyl-CoA. Glycine is further catabolized by mitochondrial enzymes associated with the glycine cleavage system to foster the charging (methylation) of tetrahydrofolate, a key intermediate in purine synthesis. The acetyl-CoA produced from TDH-mediated breakdown of threonine is fed into the TCA cycle. This TDH-dependent metabolic pathway is used in rapidly growing microbial organisms, including bacteria and yeast — and is a component of what has been termed the high flux backbone of microbial metabolism. “Drop-out” culture media were prepared individually missing each of the 20 amino acids. It was observed that mouse ES cells grow fine in all drop-out media except that lacking threonine. Cell division and DNA synthesis of mouse ES cells were abruptly impeded in threonine-deficient culture medium. Threonine dependence was not observed for any of a number of other cell lines that do not express the TDH gene, including HeLa cells, mouse embryonic fibroblast (MEF) cells, or NIH 3T3 cells. These studies provide evidence that mouse ES cells are unique in using threonine as a metabolic fuel.
Citation Information: Cancer Res 2009;69(23 Suppl):IA-18.
Abstract IA-21: Malignant progression and the stem-cell state
Authors: Weinberg Robert A. 
Published: May 2012

Abstract
The process of invasion and metastasis represents a complex, multi-step succession of events that, when completed, enables a cancer cell to spawn a macroscopic, clinically detectable tumor. Given the complexity of this process, much effort has been expended in attempting to elucidate how cancer cells acquire the entire spectrum of cell-biological phenotypes that in aggregate are needed to negotiate the steps of the invasion-metastasis cascade, as it is often called. The discovery of the epithelial-mesenchymal transition (EMT) program and its importance in conferring multiple malignancy-associated traits provides one solution to this puzzle, as the expression of one or more EMT-inducing transcription factors can serve to pleiotropically induce many of these cellular phenotypes. Indeed, the expression of these transcription factors may occur in primary tumors through the actions of paracrine signals that are received by carcinoma cells from the nearby tumor-associated stroma.
Several years ago, we and others discovered that the product of the EMT program is not, as we had anticipated, a mesenchymal cell, but instead is a cell exhibiting many stem-cell properties and concomitantly expressing a variety of mesenchymal markers. Indeed, extension of this work now suggests that similar dynamics operate in both immortalized mammary epithelial cells and their transformed derivatives. This indicates that the EMT program not only enables cancer cells to physically disseminate, but in addition, because of the self-renewal potential associated with the stem-cell state, confers on these disseminated cells an ability to spawn the large number of cells forming a metastasis.
Recent research has revealed that stem-like cells can also be found in cultures of mammary epithelial cells that have undergone various degrees of transformation. Of interest is the fact that these cells retain stem-cell-like properties for extended periods of time in culture. Moreover, non-stem-like cells in culture appear to be able to spontaneously convert into stem-cell-like derivatives, a process that appears to be accelerated by cell transformation. This raises the possibility that the typically depicted hierarchy of stem cells generating non-stem cells may need to be revised to accommodate the reversal of this process, that is a bidirectional trafficking between cells in the stem-cell and non-stem-cell compartments of a normal or neoplastic tissue.
Citation Information: Cancer Res 2009;69(23 Suppl):IA-21.
Abstract IA-23: TERT, senescence, and transformation
Authors: Maida Yoshiko , Hayashizaki Yoshihide , Masutomi Kenkichi , Hahn William C. 
Published: May 2012

Abstract
Constitutive expression of telomerase in human cells prevents the onset of senescence and crisis by maintaining telomere homeostasis. However, accumulating evidence suggests that the human telomerase catalytic subunit (hTERT) contributes to cell physiology independent of its ability to elongate telomeres. We have recently found that hTERT interacts with the RNA component of mitochondrial RNA processing endoribonuclease (RMRP), a gene that is mutated in the inherited pleiotropic syndrome Cartilage-Hair Hypoplasia (CHH). hTERT and RMRP form a distinct ribonucleoprotein complex that exhibits RNA dependent RNA polymerase (RdRP) activity and produces double-stranded RNAs that can be processed into small interfering RNA in a Dicer-dependent manner. These observations identify a mammalian RdRP composed of hTERT in complex with RMRP. Since mutations in RMRP are found in CHH, these findings suggest that perturbation of the hTERT-RMRP complex is involved in the pathogenesis of this disorder. The involvement of hTERT in two syndromes characterized by stem cell failure (CHH and dyskeratosis congenita) suggests that ribonucleoprotein complexes containing hTERT play a critical role in stem cell biology.
Citation Information: Cancer Res 2009;69(23 Suppl):IA-23.
Abstract IA-8: p53: From structure to drug discovery
Authors: Fersht Alan R. 
Published: May 2012

Abstract
The ability to produce quantities of stable p53 and the use of new biophysical methods are giving novel insights into the oligomerization of p53 and how this may be important in its regulation. We have discovered that the association and dissociation of p53 is extremely slow and can take more time than the half-life of p53 in the cell. The rate of association equilibria can be catalyzed by the binding to DNA and proteins and also be regulated by the binding to proteins, such as members of the S100 family, for example. I will discuss these phenomena and the latest developments in rescuing unstable oncogenic mutants of p53 by lead compounds for novel anti-cancer drugs.
Citation Information: Cancer Res 2009;69(23 Suppl):IA-8.
Abstract IA-9: Using switchable mouse genetic models to validate therapeutic cancer targets
Authors: Evan Gerard I. 
Published: May 2012

Abstract
Cancers are lethal diseases in desperate need of new therapeutic approaches: despite dramatic advances in the use of conventional chemo and radiotherapy and the growth of more “targeted” drugs, many cancers are still incurable. The principal problem is that we have no systematic or informed way of predicting which, out of the legion of aberrant processes in pancreatic cancer cells, is the best to target with drugs or where, within that process, the most effective molecular targets lie. To address this problem, we employ a novel class of genetically engineered mouse (GEM) in which individual oncogenes and/or tumor suppressor genes may be systemically toggled off and on, reversibly and at will, in vivo. In this way we can identify the most effective therapeutic targets irrespective of contemporary (and ephemeral) prejudices as to their “druggability.” This approach will be illustrated by two such GEMs: one mouse that models pharmacological inhibition of Myc, a core component of the replicative machinery of all tumor and normal cells and a downstream conduit for many (perhaps all) oncogenic growth signals, and a second mouse that models pharmacological restoration of the p53 tumor suppressor that is functionally inactivated in most human cancers. Since it is the endogenous oncogene or tumor suppressor that is toggled in such GEMs, they can be easily applied to any existing or new preclinical mouse cancer model. Using these two GEMs, we have directly ascertained the therapeutic impact, efficacy, and side effects of Myc inhibition and p53 restoration — establishing both mechanism of action and therapeutic index.
Citation Information: Cancer Res 2009;69(23 Suppl):IA-9.