bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2390: Growth analysis of M-406 mammary adenocarcinoma in F1 and F2 generations of a cross between resistant and susceptible mice lines
Authors: Cáceres Juan M. , Pagura Lucas , Zacarías-Fluck Mariano F. , Scharovsky O Graciela , Di Masso Ricardo J. , Rico María J. , Rozados Viviana R. 
Published: June 2012

Abstract
Breast cancer is a complex, multifactor disease that affects about 10% of women in industrialized countries. Inbred mice models provide an interesting tool for identifying genes that control susceptibility to breast cancer. CBi- mice was artificially selected for body conformation from CBi. The mammary adenocarcinoma M-406 developed spontaneously in CBi female mouse and is maintained in vivo in mice of the same line. When CBi- mice are s.c. challenged with M-406 they show 100% take and 100% regression (resistance). In contrast, the tumor grows exponentially (susceptibility) in CBi mice. The aim of this study was to characterize the tumor behavior in both F1 reciprocal hybrids [(CBi × CBi-) and (CBi- × CBi) n=48], and in the four F2 combinations between them: F2A [(CBi- × CBi) × (CBi- × CBi)]; F2B [(CBi- × CBi) × (CBi × CBi-)]; F2C [(CBi × CBi-) X (CBi- × CBi)] and F2D [(CBi × CBi-) X (CBi × CBi-)] n=185. Adult female and male mice where challenged s.c. with M-406 by trocar, three tumor fragments (∼8 × 105cells). Tumors were measured three times/week and tumor volumes were calculated as follows: V = 0.4 (ab2), where V = volume (mm3), a = largest diameter (mm) and b = smallest diameter (mm). Tumor volume vs time data were fit to an exponential growth model Vt: S*e[k*t]. M-406 grew exponentially in 45/48 F1 mice. Non statistical differences were found in tumor growth rates between sexes on the reciprocal F1s. Significant differences in tumor volume doubling time (TvDT = 0.69/k) were observed between sexes in two of the four F2 combinations: F2A [females: 5.34 ± 0.44; males: 4.27 ± 0.26; t=2.154, P=0.038] and F2D [females: 4.04 ± 0.14; males: 4.85 ± 0.38; t=1.804, P=0.041]. When comparing females TvDT, F2D had a faster growth rate than F2A (P=0.0097), while non statistical differences were evident in males (P = 0.102). It is concluded that susceptibility to M-406 in CBi mice is inherited as a dominant trait. Genes involved in susceptibility inheritance would be autosomic, as the tumor behaviour in both F1 reciprocal hybrids is similar. The analysis of F2 alternative combinations allowed the identification of maternal effect as well as sexual dimorphism influencing tumor growth.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2390. doi:10.1158/1538-7445.AM2011-2390
Abstract 24: A genetic model of metastatic evolution: Driver and passenger mutations affect metastatic fitness
Authors: McFarland Christopher D. , Scott Jacob G. , Basanta David , Anderson Alexander R. A. , Mirny Leonid A. 
Published: June 2012

Abstract
Background: The metastatic process requires that cells accomplish two feats: 1) migrate from the primary tumor into the blood stream and arrest in foreign stroma, and 2) grow from a colony of only a few cells into a metastasis of macroscopic size. This second step is highly inefficient for reasons not well understood. Our previous research in tumorigenesis found that many mildly deleterious passenger mutations accumulate in cancer and can influence neoplastic progression, yet the effect of these mutations in metastatic evolution has not been studied.
Methods: We developed a model of somatic evolution of neoplastic progressions and metastatic growth. Using a modified Gillespie algorithm, individual cells in our model stochastically divide and die, occasionally acquiring advantageous driver mutations or mildly deleterious (for cancer) passenger mutations. The rate of cell division and death depend on the collective effect of accumulated passenger and driver mutations. Evolutionary pressures lead to clonal expansion and occasionally carcinogenesis. In our in silico experiments, aliquots of cells were taken from successful primary tumors and “injected” into a new micro-environment with new stromal interactions, where they were assayed for metastatic success. This allowed us to track the entire evolutionary history of metastatic cells and genomic determinants of their success.
Results: Accumulation of passengers during tumorigenesis as well as metastatic progression frequently prevents initial colonies and micrometastases from developing into metastatic tumors. The population bottleneck experienced during colony formation accelerates the accumulation of deleterious passenger mutations in cancerous populations. We find that in the model, metastatic efficiency depends heavily on primary tumor size, age, and genetic diversity in a manner consistent with clinical observations. A favorable stromal environment was also critical for metastatic success. Surprisingly, we found that as the total number of mutations in neoplastic cells increased, metastatic efficiency, on average, decreased as many of these additional mutations were deleterious passengers.
Conclusions: Accumulation of deleterious passenger mutations helps explain metastatic inefficiency after extravasation, as well as many other features of metastasis. Our model makes several novel predictions testable in vivo_most notably that increased mutational load may prevent or impede metastasis. Cancer treatments exploiting the deleterious effects of passenger mutations may prevent metastatic disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 24. doi:10.1158/1538-7445.AM2011-24
Abstract 2406: Molecular characterization of ciclooxigenase-2 in canine proliferative inflammatory atrophy of the prostate
Authors: Amorim Renee L. , Rodrigues Marcela , Rosa Luciana , Drigo Sandra , Cirilo Priscila , Rogatto Silvia 
Published: June 2012

Abstract
Due to the importance and incidence of prostatic carcinoma in man, some animals are being used as a model in the investigation of the pathogenesis and development of this lesion. Similarly to men, the dog presents a spontaneous development of prostate cancer, which is locally invasive and can develop bone metastasis. Proliferative inflammatory atrophy (PIA) is considered a pre-neoplastic lesion in men. Overexpression of COX-2 has been associated with PIA, PIN and prostatic carcinoma playing a role in angiogenesis, apoptosis inhibition, increasing of invasive capacity, metastasis and inflammation in different prostatic affections. The aim of this study was to assess the protein and gene expression of COX-2 in laser capture microdissected stroma and epithelial cells of PIA foci in canine prostate by immunohistochemistry (IHC) and qRT-PCR. For IHC, 38 PIA lesions arranged in a tissue microarray were evaluated. Frozen fragments from 17 PIA and 3 normal prostatic tissues were used for COX2 gene expression. Our results showed increased COX2 gene expression in stromal cells compared to epithelial cells. High level of COX-2 protein expression was observed in 87% of PIA lesions, despite epithelial or stromal compartment. The In the present study, the stroma presented an important role, since the COX-2 gene expression in canine PIA lesions was increased in this cell compartment. To the best of our knowledge, this is the first report of COX2 gene expression in canine PIA. Since high levels of COX-2 have been associated to the risk of developing of prostate cancer in man, dog can be used as a natural model for this disease. The stroma can act as paracrine way in the epithelial cells, stimulating epithelial proliferation, reducing the apoptosis of this compartment and promoting angiogenesis in the microenvironment, factor that contribute to prostatic carcinogenesis and that the protein expression is increased in this lesion.
Sponcer: Fapesp (Fundação de Apoio a Pesqusia do Estado de São Paulo)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2406. doi:10.1158/1538-7445.AM2011-2406
Abstract 2417: A new mouse model for epithelial ear neoplasms based upon expression of mutant EGFRL858R/T790M
Authors: Kawabata Shigeru , Hollander M. Christine , Munasinghe Jeeva P. , Mercado Jose , Brinster Lauren R. , Butman John A. , Lonser Russell R. , Regales Lucia , Pao William , Janne Pasi A. , Wong Kwok-Kin , Dennis Phillip A. 
Published: June 2012

Abstract
Epithelial neoplasms of the ear are rare and difficult to detect before the development of audiovestibular or facial nerve dysfunction. Complete resection is often difficult because of location and the late stage at diagnosis, so effective chemotherapy is required. No preclinical models exist for these tumors. During the generation of mice using CC10 or surfactant protein C (SP-C) promoters to drive expression of mutant EGFR (EGFRL858R/T790M) in lung tissues, we observed that no SP-C mice developed lung tumors, but approximately 30% of them developed head tilt and a circular gait by 25 wk. MRI scans showed bilateral ear tumors located in the tympanic cavity that partially invaded into temporal bone, which suggested the presence of middle ear tumors or endolymphatic sac tumors (ELSTs). Histology of the ear tumors showed well-differentiated adenocarcinomas with multiple papillary and microcystic structures. Immunohistochemical (IHC) analysis showed that the mutant EGFR was active and selectively expressed in the tumors, and that downstream components of EGFR signaling such as Akt, mTOR and ERK were activated. SP-C expression was also detected, suggesting that surfactant proteins are expressed in ear epithelium at specific times during tumor development. To determine if these tumors were addicted to EGFR signaling, EGFR-based therapies were tested in symptomatic mice. Consistent with the T790M mutation in EGFR conferring resistance to reversible EGFR tyrosine kinase inhibitors (TKI), erlotinib was ineffective. In contrast, the combination of an irreversible EGFR TKI (BIBW-2992) with an antibody against EGFR (cetuximab), or a chemically optimized analogue of BIBW-2992 (WZ4002) used alone, was highly effective. All mice treated with the combination or WZ4002 alone had normalization of gait and complete responses by MRI, suggesting that these tumors are dependent upon mutant EGFR. To assess the possible clinical relevance of this mouse model, 2 human middle ear adenocarcinomas and a human ELST were stained for active EGFR using IHC. 3/3 displayed increased EGFR activation. These studies describe a new mouse model for human epithelial ear tumors based on EGFR activation, and raise the possibility that EGFR-based therapies might have clinical efficacy in these rare neoplasms.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2417. doi:10.1158/1538-7445.AM2011-2417
Abstract 243: Functional dissection of hoxD genes in regulation of neuroblastoma cell proliferation and differentiation
Authors: Zha Yunhong , Ding Emily , Mao Ling , Ding Han-fei 
Published: June 2012

Abstract
Neuroblastoma is a common malignant tumor in children, arising in the sympathetic nervous system. The tumor cell differentiation state influences clinical outcome, and induction of differentiation has been considered as a promising therapeutic strategy for neuroblastoma. Retinoid acid (RA) is an effective inducer of neuroblastoma cell differentiation and has been used in clinic for treatment of high-risk neuroblastomas. However, resistance to RA presents a major obstacle to successful RA-based therapy. Therefore, identification of target genes that mediate the anti-neoplastic activity of RA is of paramout importance, as targeting these genes offers opportunities to bypass resistance to RA. A variety of experimental evidence has linked RA action to the activation of HOX genes, which function as master regulators of development and cell fate specification. Particularly, it has been shown that RA induces several HOXD genes in neuroblastoma cells including HOXD1, D8 and D9. Our microarray analysis confirmed the predominant upregulation of HOXD genes in the human neuroblastoma cell line BE(2)-C cells following RA treatment. To investigate the functional significance of the RA-induced upregulation of HOXD genes, we conducted a comprehensive functional analysis of HOXD genes in regulation of neuroblastoma cell proliferation and differentiation. The HOXD cluster contains 9 genes (HOXD1, D3, D4, and D9-13) that are positioned from 3’ to 5’ within the cluster, with HOXD1 at the 3’ end and HOXD13 the 5’ end. We established BE(2)-C-derived cell lines with inducible expression of individual HOXD genes. Induction of HOXD1, D12 or D13 had no significant effect on BE(2)-C cell growth and differentiation. By contrast, individual induction of other HOXD genes caused G1 arrest, which was associated with downregulation of cyclins and CDKs required for cell cycle progression through the S, G2 and M phases. Ectopic expression of HOXD3, D4, D8, D9, D10 or D11 also induced morphologic changes characteristic of neuronal differentiation. Interestingly, HOXD8 and D9 appeared to be most potent in the induction of G1 arrest and differentiation. These findings suggest that HOXD genes positioned in the middle of the cluster have higher differentiation-inducing activity compared to those positioned more 5’ and 3’ in the cluster. Thus, pharmacological activation of HOXD8 and HOXD9 may represent a therapeutic strategy for RA-resistant neuroblastomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 243. doi:10.1158/1538-7445.AM2011-243
Abstract 2441: CHI3L1 in allergic pulmonary inflammation promotes breast cancer metastasis by upregulation of MMP-9
Authors: Libreros Stephania , Garcia-Areas Ramon , Iragavarapu-Charyulu Vijaya L. 
Published: June 2012

Abstract
Disseminated metastasis is one of the main causes of malignancy related deaths in breast cancer patients. Murine mammary tumors cells metastasize to the lung 5 weeks post tumor-implantation. However, in the presence of asthma, metastasis is seen at an earlier time point. In this study, we investigated the molecule(s) contributing to early metastasis. One of the common molecules among asthma and breast cancer is a glycoprotein known as chitinase-3-like-1 (CHI3L1) which induces TH2 proinflammatory cytokines and matrix degrading enzymes. The expression of CHI3L1 is elevated in the lungs and serum of asthmatic patients and correlates with disease severity. Interestingly, this glycoprotein is also elevated in plasma of patients with metastatic breast cancer. Using murine mammary cancer models, we show the link between increased metastasis and asthma. The pathways that tumor cells use for metastasis have significant similarities with the mechanisms mediating allergen-induced leukocyte recruitment. Thus, leukocyte recruitment to the site of inflammation and tumor cell metastasis involves extracellular matrix degradation. Matrix metalloproteinase-9 (MMP-9) is one such enzyme that can degrade all aspects of the extracellular matrix. Our previous studies have shown increased levels of MMP-9 in mammary tumor-bearing mice. MMP-9 has been reported to be upregulated in the presence of CHI3L1. In this report, we show that the levels of CHI3L1 are higher in asthmatic tumor bearers compared to either tumor controls or asthma controls. We hypothesize that the elevated CHI3L1 expression causes increased MMP-9 production leading to higher metastasis. To answer this hypothesis, a mouse model of allergic pulmonary inflammation and two types of well-established metastatic mammary tumor models were used. Analysis of serum, bronchioalveolar lavage (BAL), lung and spleen by RT-PCR and ELISA revealed higher expression of CHI3L1 in asthmatic tumor bearers. In summary, these studies implicate a relationship between allergic pulmonary inflammation and increased breast cancer metastasis to the lung. As CHI3L1 is involved in both of these diseases, this molecule may be a novel target for suppressing/preventing metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2441. doi:10.1158/1538-7445.AM2011-2441
Abstract 245: KIF1Bβ interacts with YME1L1, resulting in apoptosis accompanied by the alteration of mitochondrial morphology
Authors: Ando Koji , Tokochi Tomoki , Mukai Akira , Maehara Yoshihiko , Nakagawara Akira 
Published: June 2012

Abstract
We previously reported that KIF1Bβ is a tumor suppressor gene mapped to chromosome 1p36.2, and is related to apoptosis (JBC, 2008). It is known that cell survival and apoptosis have a close relationship with mitochondrial morphology, such as fusion and fragmentation. Cell survival and resistance to pro-apoptotic stimuli is related to mitochondrial fusion. On the other hand, apoptosis is frequently associated with mitochondrial fragmentation. Considering these facts, we hypothesized that KIF1Bβ might play an important role in the morphological change in mitochondria.
The mitochondrial morphology was examined by indirect immunofluoresence using MitoTracker Red® and anti-cytochrome c antibody. To quantify the degree of mitochondrial fusion, we used JC-1 probe. Yeast two hybrid screening was performed to identify the interacting proteins of KIF1Bβ.
Mitochondrial fusion was facilitated in both NB1 (neuroblastoma cell line which KIF1Bβ is homozygously deleted) and HeLa in which KIF1Bβ was knocked down. This result suggests that KIF1Bβ takes part in the process of morphological change in mitochondria. Those cells were resistant to doxorubicin treatment, demonstrating that apoptosis was prevented accompanied by mitochondrial fusion. Overexpression of KIF1Bβ induced mitochondrial fragmentation, enhanced cytochrome c release into the cytoplasm, and resulted in apoptosis. These results are consistent with the properties of KIF1Bβ as a tumor suppressor described previously. On the other hand, overexpression of KIF1Bβ lacking the death inducing region neither induced mitochondrial fragmentation nor apoptosis, indicating that the death inducing region is essential for the alteration of mitochondrial morphology and induction of apoptosis. Utilizing yeast two hybrid screening, we found several proteins physically interacting with KIF1Bβ. We identified YME1L1, the mitochondrial metalloprotease, which is known to cleave mitochondrial fusion protein OPA1. Overexpression of YME1L1 cleaved OPA1 in the presence of KIF1Bβ. However, OPA1 cleavage was partially inhibited in the absence of KIF1Bβ, suggesting that KIF1Bβ enhances the activity of YME1L1 as a protease to cleave OPA1. Interestingly, high expression of YME1L1 was associated with better survival of neuroblastoma patients (n=101; p=0.046), while high expression of OPA1 was correlated with poor outcome (n=101; p=0.04).
These results suggest that the tumor suppressor KIF1Bβ takes part in the alteration of mitochondrial morphology collaborating with an interacting partner YME1L1.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 245. doi:10.1158/1538-7445.AM2011-245
Abstract 2454: Pancreatic cancer stem cells (CSCs) express MUC1 and MUC1-expressing pancreatic cancers encompass higher levels of CSCs
Authors: Curry Jennifer M. , Thompson Kyle J. , Rao Shanti , Ahrens William A. , McKillop Iain H. , Sindram David , Iannitti David A. , Martinie John B. , Mukherjee Pinku 
Published: June 2012

Abstract
Introduction: Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis of all cancers and is the fourth leading cause of cancer-related deaths in the United States. Cancer stem cells (CSCs), which are a small population of tumor cells that have the ability to self-renew and differentiate into the diverse cells that comprise the tumor, have been identified in pancreatic cancer patients as lineage-negative, CD133 (prominin-1)-expressing cells. In pancreatic cancer, MUC1 is a protein expressed with a high frequency and its expression correlates with high metastasis and poor prognosis. Recent reports from our lab have demonstrated the ability of MUC1 to drive epithelial-to-mesenchymal transition thus producing a cell with ‘stem-like’ properties. We therefore investigated the correlation between MUC1 expression and CSCs. Methods: Primary tumor tissues surgically resected from patients diagnosed with pancreatic adenocarcinoma (n=8) and human pancreatic cancer cell lines were assessed for CD133 and MUC1 expression by flow cytometry. Results: In pancreatic cancer patients, tumor MUC1 levels correlated with a higher percentage of CD133-expressing cells (R=0.76). Similarly, in MiaPaCa2, Capan-1, BxPC3 WT, BxPC3 MUC1, Su86.86 WT and Su86.86 MUC1 cells lines, MUC1 levels correlated with increased CD133 expression (R=0.83). The majority of CD133+ cells isolated from primary human pancreatic tumors (82.6 ± 12.7%) expressed MUC1. Similar results were obtained using cell lines, as 83.22 ± 30.9% of CD133-expressing cells were MUC1-positive. Conclusion: MUC1 is present on the majority of CSCs and its expression correlates with higher levels of cancer stem cells. This study demonstrates yet another oncogenic role of MUC1 in pancreatic cancer progression and suggests MUC1 as a novel marker for CSCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2454. doi:10.1158/1538-7445.AM2011-2454