Diss. (sammanfattning) Uppsala : Uppsala universitet, 2008.

Cancer is the second leading cause of death among men and women after heart disease. Though our knowledge associated with the complexities of the cancer network has significantly improved over the past several decades, we have only recently started to get a more complete molecular understanding of the disease. To better comprehend signaling pathways that prevent disease development, we focused our efforts on investigating endogenous tumor suppression networks in controlling effectors of cancer cell survival and proliferation. Survivin is one such effector molecule that controls both cell proliferation and survival. In order to identify how this protein is overexpressed in cancer cells as opposed to normal cells, we looked at signaling molecules that negatively regulate this inhibitor of apoptosis protein. PTEN and caspase 2 are two of the identified proteins that utilize their enzymatic activity to suppress tumor growth by inhibiting downstream cell survival effectors, namely survivin. PTEN uses its phosphatase activity to suppress the PI3K/AKT pathway and maintain cellular homeostasis. In the absence of AKT activity, FOXO transcription factors are able to target downstream gene expression and regulate cell proliferation and survival. Here we have identified survivin as a novel gene target of FOXO, which binds to a specific promoter region of survivin and suppresses its transcription. Alternatively, caspase 2 uses its catalytic activity to suppress survivin gene expression by targeting the NFκB pathway. Caspase 2 acts by cleaving a novel substrate known as RIP1 that prevents NFκB from entering the nucleus, thus inhibiting target gene transcription. Interestingly, survivin is known to be a direct gene target of NFκB that controls cancer cell survival. In our investigation, we found that survivin is downregulated upon caspase 2 activation via the NFκB pathway, resulting in decreased cell cycle kinetics, increased apoptotic threshold and suppressed tumor growth in mice. These studies conclude that survivin is a common effector molecule that is regulated by tumor suppressors to maintain cellular homeostasis. However, upon deactivation of the tumor suppressor pathway, survivin is deregulated and contributes significantly to disease progression. These observations may lead to potential therapeutic implications and novel targeting strategies that will help eradicate harmful cancer cells and spare surrounding healthy cells; often the most persistent problem of most conventional chemotherapy.

No description available.

O melanoma é uma neoplasia maligna derivada de melanócitos, o qual tem uma letalidade elevada devido a sua característica altamente invasiva e agressiva. O caule da E. tirucalli produz um látex de coloração branca usado na medicina popular para o tratamento de neoplasias, que possui diversos constituintes ativos, incluindo o eufol, euforbol e isoeuforal. O objetivo do trabalho foi estudar os efeitos antineoplásicos in vitro e in vivo do látex da Euphorbia tirucalli em alguns modelos experimentais in vitro e in vivo. Células de melanoma B16/F10 foram tratadas com as seguintes diluições seriadas do látex a partir de uma concentração inicial de 0,1037ug/uL: 1/2, 1/4, 1/8, 1/16, 1/32, 1/64, 1/128, 1/256, 1/512, 1/1024, 1/2048, 1/5096, 1/11192. A viabilidade celular foi avaliada por MTT às 24, 48 e 72 horas. No experimento primeiro in vivo, células de melanoma foram inoculadas no tecido subcutâneo dorsal lombar de camundongos BALB/c e 10 dias após tratados, ou não, com 0,467ug/25g em volume de 200uL de látex de E. tirucalli por gavagem durante 14 dias. No segundo experimento, camundongos C57BL/6 foram inoculados com células de melanoma B16/F10 na veia da cauda para colonização pulmonar. No experimento in vitro, observou-se uma diminuição da viabilidade celular nas diluições de 1/1024 e 1/11192 no tempo de 24h e ás 48h houve uma diminuição da viabilidade celular nas diluições de 1/128, 1/256, 1/2048 e 1/11192. No experimento in vivo, observou-se que o látex da E. tirucalli foi capaz de reduzir o volume dos tumores subcutâneos em 53,5%, enquanto que o grupo não tratado o volume aumentou em 818,1%. No experimento de inoculação na veia da cauda com melanoma B16/F10 a administração de látex da E. tirucalli foi capaz de reduzir a fração de área pulmonar ocupada pelas colônias para 10,5% enquanto que no grupo não tratado, a fração de área pulmonar com colônias de melanoma aumentou para 35%. Não foram observadas alterações histopatológicas em nenhum dos grupos experimentais em outros órgãos. Os efeitos de redução de tumor, redução das colônias pulmonares e da viabilidade celular podem ser devidos à ação dos constituintes do látex que já demonstraram ter atividade antiproliferativa e citotóxica em outros experimentos, como o eufol e o euforbol. Embora o látex seja uma substância tóxica, ela pode ter tido, nas maiores diluições utilizadas, um efeito positivo para o tratamento do tipo hormesis / Melanoma is a malignant neoplasm derived from melanocytes, which has a high lethality due to its highly invasive and aggressive trait. The E. tirucalli stem produces a white latex used in folk medicine for the treatment of cancer, this product has several active constituents, including euphol, euphorbol and isoeuphoral. The objective of this work was to study the antineoplastic effects of Euphorbia tirucalli latex in experimental models in vitro and in vivo. B16/F10 melanoma cells were treated with the following serial dilutions of the latex from an initial concentration of 0.1037ug/?l: 1/2, 1/4, 1/8, 1/16, 1/32, 1/64, 1/128, 1/256, 1/512, 1/1024, 1/2048, 1/5096, 1/11192. Cell viability was assessed by MTT at 24, 48 and 72 hours. In the first in vivo experiment, melanoma cells were inoculated into the lumbar dorsal subcutaneous tissue of BALB/c mice and 10 days later they were treated or not treated with 0.467ug/25g of body weight in of 200?L of E. tirucalli latex by gavage for 14 days. In the second experiment, C57BL/ 6 mice were inoculated with B16/F10 melanoma cells into the tail vein for lung colonization. In the in vitro experiment, a decrease in cell viability at 1/1024 and 1/11192 dilutions was observed at 24h, and at 48h there was a decrease in cell viability at the dilutions of 1/128, 1/256, 1/2048 and 1/11192. In the in vivo experiment it was observed that the latex of E. tirucalli could reduce the volume of the subcutaneous tumors in 53.5% while in the untreated group the volume increased 818.1%. In the experiment of inoculation into the tail vein with B16/F10 melanoma cells, E. tirucalli latex administration was able to reduce the fraction of lung area occupied by the colonies to 10.5% whereas in the untreated group, the fraction of lung area with colonies was 35%. No histopathological changes were observed in any of the experimental groups in other organs. The effects of tumor reduction, reduction of lung colonies and cell viability may be due to the action of latex constituents that have already demonstrated antiproliferative and cytotoxic activity in other experiments, such as euphol and euphorbol. Although latex is a toxic substance, it may have developed, at the low dilutions used, a positive effect for the treatment of the hormesis type

Os mecanismos moleculares relacionados ao desenvolvimento e à progressão de cânceres são extremamente complexos. A espectroscopia no infravermelho por transformada de Fourier (FTIR) é capaz de detectar alterações bioquímicas de materiais biológicos, permitindo a importante caracterização e diferenciação de células. Através da observação individual de bandas de absorção, é possível identificar semelhanças e diferenças entre células, através das quais é possível entender parte das alterações que ocorrem em linhagens celulares pertencentes à um mesmo grupo de doenças ou entre células sadias e neoplásicas. Neste trabalho foram caracterizados quatro conjuntos de células neoplásicas através da espectroscopia por FTIR. Cada conjunto foi composto por duas linhagens celulares: o primeiro conjunto foi composto por uma linhagem de melanoma murino (B16F10) e melanoma humano (C8161); o segundo conjunto continha uma linhagem de adenocarcinoma de cólon (HT-29) e outra de adenocarcinoma cérvix (HeLa); o terceiro conjunto foi composto por duas linhagens de câncer de mama humano (SKBr3 e MCF-7); por fim, o último conjunto possuía uma linhagem de leucemia humana do tipo T (JURKAT) e células mononucleares de sangue periférico (PBMC). Comparando-se todas as linhagens celulares, diferenças com relação à algumas bandas de absorção foram identificadas: 1084cm-1 (açúcar do DNA sugar e moléculas de PO2), 1236cm-1 (ligações fosfodiésteres), 1540cm-1 (estiramento da Amida II), 2851cm-1 e 2921cm-1 (estiramento do CH2). Alguns grupos revelaram diferenças nas bandas de absorção referentes ao estiramento das moléculas de C-C and C=O (967cm-1), configuração beta da Amida I e estrutura alfa-hélice (1650cm-1 e 1645cm-1, respectivamente), permitindo a caracterização destas doenças de forma eficiente por meio da área das bandas de absorção e deslocamento dos picos das mesmas. Através deste trabalho foi possível verificar o potencial de aplicação da espectroscopia por FTIR em estudos de base, visando a caracterização de células do ponto de vista bioquímico, buscando compreender quais fatores biológicos estão relacionados com as diferenças espectrais verificadas e, com isso, fornecer informações qualitativas referentes à ligações químicas relacionadas a determinados biomarcadores existentes em cada amostra biológica. Outro ponto abordado foi a análise das razões entre as áreas de diversas bandas de absorção. A partir desta avaliação, foi possível definir bandas referentes a biomarcadores chaves na diferenciação celular. Foram comparadas as razões comumente utilizadas na literatura, assim como avaliadas novas combinações, visando uma diferenciação mais eficiente. As novas razões obtidas foram: (i) 1053cm-1 e 1084cm-1; (ii) 1540cm-1 e 10840cm-1; (iii) 1650cm-1 e 1084cm-1; (iv) 1395cm-1 e 1053cm-1; (v) 1453cm-1 e 1053cm-1; (vi) 1084cm-1 e 1646cm-1; (vii) 1084cm-1 e 2851cm-1 e, por fim, (viii) 1053cm-1 e 3060cm-1. Através das razões de tais bandas de absorção, referentes às proteínas, lipídeos, DNA e RNA, foi possível diferenciar não somente as linhagens celulares pertencentes à um mesmo grupo patológico e sim, adquirir valores distintos para cada uma das oito linhagens estudas. O deslocamento dos picos, alterações relacionadas à largura das bandas e variações relativas às razões de diversos componentes biológicos podem conter uma informação importante com relação aos biomarcadores envolvidos em diferentes tipos de doenças. Estes biomarcadores detectados através da espectroscopia com FTIR podem ser utilizados na diferenciação e classificação de células neoplásicas e sadias assim como levar a avanços relacionados ao desenvolvimento de protocolos clínicos. / The molecular mechanisms and changes leading to the development and progression of cancers are extremely complex. FTIR spectroscopy can detect biochemical features of biological materials, enabling the important characterization and differentiation of cells. By looking at the individual absorption bands, it is possible to spot similarities and differences between the cells, which help to understand the changes observed in the same disease cell line group or between healthy and diseases cells. In this work we characterized four sets of neoplastic cells with FTIR spectroscopy. Each cell set was composed of two cell lines: the first one was a set composed by murine melanoma (B16F10) and human melanoma (C8161), the second one was colorectal adenocarcinoma (HT-29), and adenocarcinoma of the cervix (HeLa), the third one two human breast cancers cell lines (SKBr3 cells and MCF-7), and the last one was human leukemia cell line (JURKAT) and peripheral blood mononuclear cell (PBMC). Comparing all cell lines, differences in the following absorption bands were identified: 1084cm-1 (DNA sugar and PO2), 1236cm-1 (phosphodiester bonds), 1540cm-1 (amide II stretching), 2851cm-1, and 2921cm-1 (CH2 stretching). Some groups revealed differences in the absorption bands related to C C and C O stretching (967cm-1), amide I beta sheet and alpha helix structure (1650cm-1 and 1742cm-1, respectively), allowing the characterization of these diseases, differentiating them efficiently through the area and peaks displacement of the absorption bands. Through this work it was possible to verify the FTIR spectroscopy potential for application on basic studies, aiming cells characterization from the biochemical point of view, trying to understand which biological factors are related to each spectral differences observed, and provide qualitative information concerning the chemical bonds associated with certain biomarkers in each biological sample. The ratio analysis between the areas of different absorption bands was another point discussed. By this analysis it was possible to define biomarkers key bands in cell differentiation. The ratios commonly used in the literature were compared and new combinations were evaluated, aiming more efficient differentiation. The new ratios defined were (i) 1053cm-1 and 1084cm-1; (ii) 1540cm-1 and 10840cm-1; (iii) 1650cm-1 and 1084cm-1; (iv) 1395cm-1 and 1053cm-1; (v) 1453cm-1 and 1053cm-1; (vi) 1084cm-1 and 1646cm-1; (vii) 1084cm-1 and 2851cm-1 and, finally, (viii) 1053cm-1 and 3060cm-1. Through these ratios, related to proteins, lipids, DNA and RNA it was possible to differentiate the cell lines not only belonging to the same pathology, but from every each other cell line. Advances related to the detection of biochemical alterations in cells and tissues will occur with the employment of new mathematical procedures for data analysis and the development of new technologies that will enable detection of weak and broad absorption bands with better accuracy. Peak displacement, alterations related to band width, and variations in the relative ratios of the main biological compounds, may carry important information with respect to biomarkers involved with different disease types. These biomarkers, detected by FTIR spectroscopy, will be used to differentiate and classify neoplastic and healthy cells as well as to lead to advances related to the development of clinical protocols.

Yuen Mong Ting. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 155-169). / Abstracts in English and Chinese. / Acknowledgements --- p.i / Abstract (English) --- p.ii / Abstract (Chinese) --- p.v / Contents --- p.vi / Chapter Chapter 1. --- Introduction --- p.1 / Chapter 1.1 --- Developmental biology of the prostate --- p.1 / Chapter 1.1.1 --- Development of the prostate gland in humans and rodents --- p.1 / Chapter 1.1.2 --- Mesenchymal-epithelial interaction --- p.2 / Chapter 1.2 --- Overview of the endocrinology of prostate --- p.3 / Chapter 1.3 --- Estrogen in male and prostate gland --- p.4 / Chapter 1.3.1 --- Stimulating effect of estrogen on prostate gland --- p.4 / Chapter 1.3.2 --- Inhibitory effect of estrogen on prostate gland --- p.5 / Chapter 1.4 --- Study of the role of estrogen receptors in prostate gland with the use of estrogen receptor knockout mice --- p.6 / Chapter 1.4.1 --- The two isoforms of estrogen receptors (ER): ERα and ERβ --- p.6 / Chapter 1.4.2 --- The use of estrogen receptor knockout mice for the study of ER --- p.7 / Chapter 1.5 --- Estrogen as a carcinogen --- p.8 / Chapter 1.5.1 --- Formation of DNA adducts --- p.8 / Chapter 1.5.2 --- Formation of oxidants --- p.9 / Chapter 1.5.3 --- Estrogen as a microtubule-disrupting agent --- p.10 / Chapter 1.6 --- Estrogen carcinogenicity in animal models --- p.11 / Chapter 1.6.1 --- Syrian golden hamster model --- p.11 / Chapter 1.6.2 --- Rat model --- p.12 / Chapter 1.7 --- Animal models of prostate cancer by hormonal induction --- p.12 / Chapter 1.7.1 --- Canine model --- p.13 / Chapter 1.7.2 --- Noble rat model --- p.13 / Chapter 1.7.3 --- Sprague-Dawley rat model --- p.15 / Chapter 1.7.4 --- Wistar and F344 rat model --- p.15 / Chapter 1.8 --- Perinatal estrogen exposure and prostate development --- p.16 / Chapter 1.8.1 --- Prenatal estrogen exposure --- p.15 / Chapter 1.8.2 --- Neonatal estrogen exposure --- p.17 / Chapter 1.9 --- Therapeutic use of synthetic estrogen --- p.18 / Chapter 1.9.1 --- Use of diethylstilbestrol in treating prostate cancer --- p.18 / Chapter 1.9.2 --- Use of diethylstilbestrol during pregnancy --- p.19 / Chapter 1.10 --- Estrogen contamination in food --- p.20 / Chapter 1.10.1 --- Estrogen in milk and dairy products --- p.20 / Chapter 1.10.2 --- Estrogen in meat --- p.21 / Figure 1.1 --- p.23 / Chapter Chapter 2. --- Materials and methods --- p.25 / Chapter 2.1 --- In vitro study of estrogen carcninogenicity in normal prostatic cell line --- p.25 / Chapter 2.1.1 --- NRP-152 cell line --- p.25 / Chapter 2.1.2 --- In vitro estrogen treatment on NRP-152 cells --- p.25 / Chapter 2.1.3 --- Colony formation by soft agar assay --- p.27 / Chapter 2.1.4 --- Determination of growth parameters of estrogen-treated and untreated NRP-152 cells --- p.29 / Chapter 2.1.5 --- Gene expression profiling in estrogen-transformed and untreated parental NRP-152 cells by cDNA microarray --- p.30 / Chapter 2.1.6 --- Immunohistochemistry of cultured cells --- p.34 / Chapter 2.1.7 --- Immunofluorescence on cultured cells --- p.36 / Chapter 2.1.8 --- Electron microscopy of the estrogen-transformed and untreated parental NRP-152 cells --- p.37 / Chapter 2.1.9 --- Tumorigenicity in nude mice --- p.38 / Chapter 2.1.10 --- Protein expressions and Western blottings in estrogen-transformed and untreated parental NRP-152 cells --- p.39 / Chapter 2.2 --- In vivo study of estrorgen carcinogenicity in rat protstate gland --- p.41 / Chapter 2.2.1 --- Origin and supply of Noble rats --- p.41 / Chapter 2.2.2 --- Perinatal estrogen imprinting on male Noble rats with diethylstilbestrol --- p.42 / Chapter 2.2.3 --- Long-term hormonal treatment with sex steroids on male Noble rats at adulthood --- p.43 / Chapter 2.2.4 --- Morphological study of Noble rat prostates --- p.44 / Chapter 2.2.5 --- Protein expressions by immunohistochemistry in estrogen-primed and hormone-treated Noble rat prostates --- p.45 / Tables 2.1 -2.2 --- p.48 / Chapter Chapter 3. --- Results --- p.50 / Chapter 3.1 --- In vitro study --- p.50 / Chapter 3.1.1 --- Dose selection for estrogen treatment of NRP-152 cells from cell proliferation assay --- p.50 / Chapter 3.1.2 --- Colony formation in soft agar --- p.50 / Chapter 3.1.3 --- Morphology of NRP-152 cells and the estrogen-transformed clones --- p.51 / Chapter 3.1.4 --- Study of growth parameters --- p.52 / Chapter 3.1.5 --- CDNA array analysis of differentia] gene pattern --- p.53 / Chapter 3.1.6 --- Immunohistochemistry of untreated parental and estrogen- transformed NRP-152 cells --- p.55 / Chapter 3.1.7 --- Electron microscopy --- p.58 / Chapter 3.1.8 --- Tumorigenicity of NRP-152 cells and the estrogen-transformed clones --- p.59 / Chapter 3.1.9 --- Western blottings --- p.59 / Chapter 3.2 --- In vivo study --- p.52 / Chapter 3.2.1 --- Survival of male Nobel rats during perinatal and long-term hormone treatment --- p.62 / Chapter 3.2.2 --- Histological studies of Noble rat prostates --- p.63 / Chapter 3.2.3 --- Immunohistochemistry of the hormone-treated and control Noble rat prostates --- p.65 / Figure 3.1.1 -3.1.44 --- p.73 / Figure 3.2.1 - 3.2.50 --- p.97 / Table 3.1 -3.4 --- p.117 / Chapter Chapter 4. --- Discussions --- p.121 / Chapter 4.1 --- The study on the transformation of cells and soft agar assay --- p.121 / Chapter 4.2 --- Growth patterns of the estrogen-transformed clones --- p.123 / Chapter 4.3 --- Altered differential gene expression --- p.124 / Chapter 4.3.1 --- TUBA --- p.124 / Chapter 4.3.2 --- PTEN --- p.125 / Chapter 4.3.3 --- RAP 1A --- p.126 / Chapter 4.3.4 --- BRCA2 --- p.126 / Chapter 4.4 --- Ultrastructural study in the estrogen-transformed and untreated parental NRP-152 cells --- p.127 / Chapter 4.5 --- Neoplastic lesions induced in prostates of estrogen-imprinted and long-term combined hormone treated Noble rats --- p.129 / Chapter 4.6 --- Altered protein expressions in estrogen-transformed NRP-152 cells and estrogen-imprinted and hormone-treated Noble rat prostates --- p.132 / Chapter 4.6.1 --- Alteration in steroid hormone receptors --- p.132 / Chapter 4.6.2 --- Alternation in cytoskeleton (tubulin-α) --- p.138 / Chapter 4.6.3 --- Alternation in PTEN --- p.141 / Chapter 4.6.4 --- Alternation in Rap1 --- p.143 / Chapter 4.6.5 --- Alternation in BRCA2 --- p.145 / Chapter 4.6.6 --- "Altered in scavenger enzyme (Superoxide dismutase, SOD-1)" --- p.147 / Chapter Chapter 5. --- Summary --- p.150 / Reference --- p.155

by Yang Lei. / Publication date from spine. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1995. / Includes bibliographical references (leaves 110-126). / Acknowledgement --- p.i / Abstract --- p.ii / Abbreviations --- p.v / Table of Contents --- p.vi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter Chapter 2 --- Literature Review --- p.4 / Chapter Chapter 3 --- Materials and Methods --- p.41 / Chapter Chapter 4 --- Results --- p.58 / Chapter Chapter 5 --- Discussion --- p.86 / References --- p.110 / Appendix --- p.120 / Publications --- p.125 / Illustrations --- p.127

Introducão. A perda da resposta aos mecanismos que regulam o crescimento da população celular em tecidos normais, as alterações em níveis genéticos e epigenéticos, induzem a carcinogênese. Durante o crescimento, seja tumor primário ou metástase, ge- ralmente há uma fase avascular, caracterizada por tumores pequenos onde os recursos necessário para proliferação da população são oriundos dos tecidos adjacentes. Ade- mais, um aspecto marcante é a heterogeneidade intratumoral, que é desencadeada por fatores intrínseco e ambientais às células, desempenhando papeis importante no cresci- mento e resposta ao tratamento. Métodos. Foi proposto um modelo estocástico espacial em termos de Cadeia de Markov para simular a dinâmica de populações de um câncer in situ em fase avascular e o tratamento quimioterapico. As transições de estado das célu- las consideradas foram duplicação, migração, morte, geração de variação na população e quiescência. Assumimos que as taxas de duplicação, migração e morte, dependem do tamanho da população, onde a taxa de duplicação diminui conforme a população au- menta e as taxas de migração e morte aumentam conforme a população cresce. As taxas dependente do tamanho da população foram descritos em termos de funções sigmóidais onde a suavidade da transição entre os valores mínimos e máximos das taxas foi dado pelo parâmetro k, o tamanho da população na qual a taxa de duplicação cai na metade do valor máximo foi dado por N e a taxa de duplicação na qual as taxa de migração/morte atingem a metade do valor máximo por 0\'. A heterogeneidade do tumor foi representada como um conjunto de duas subpopulações (1) mais proliferativa e (2) mais migratória. Em seguida, foi aclopado um modelo de difusão de drogas e um modelo farmacodinâ- mico para avaliar a repopulação no tratamento com uma única droga. Resultados. As simulações acerca do crescimento tumoral mostram que a população atingiu a densidade de saturação de acordo com os valores do parâmetro k. A densidade das variantes prol iferativas e migratórias não foram diretamente relacionadas a taxa de geração de variação, mas sim pelos parâmetros N e a. Para determinado conjunto de valores atribuídos aos parâmetros k e N,espacialmente observou-se crescimento difuso da população. No que tange ao tratamento, houve emergência da resistência, todavia observou-se padrões diferente na repopulação de acordo com os valores da taxa de geração de variação, k e N. Espacialmente, observa-se que as células resistentes vão ao gradiente droga. O modelo no estágio atual consegue recuperar qualitativamente algumas evidências experimentais atreladas coexistência de duas subpopulações onde uma cresce mais do que a outra, crescimento difuso da população e migração da população resistente para o gradiente de droga / Introduction. The loss of response to the mechanism which regulates the growth of cell population in normal tissue, the changes at both genetic and epigenetic levei lead to carcinogenesis. During the growth of primary tumor or metastasis often there is an avascular phase which is featured by small tumor where the resource necessary to proli- feration nd survival come from surrounding tissues. Furthermore, a remarkable aspect of carcinogenesis is intratumoral heterogeneity which is fueled by both intrinsic and environ- mental facto r, playing a crucial role in the growth and treatment response. Methods Here we propose a stochastic spatial model in term of Markov Chain to simulate the population dynamic of in situ cancer in avascular phase and the chemotherapeutic treatment. The cells state transition considered was duplication, migration, death, generation of new variants in population and quiescence. We are assuming that duplication, migration and death rates depend on population size, where duplication rates decrease as long as population increase but both migration and death rates, in it turn increase. Theses population size dependent rates were described in terms of sigmoidal function where the smoothness of transition between maximal e minimum values was indicated by k, the size of population at which duplication rates falls on half of it maximal value was indicated by Nand the duplication rate where both migration and death rates goes to half of it maximal value was indicated by a. The heterogeneity was featured as a set of a (1) highly proliferative and (2) highly migratory cells. In doing so, we coupled a drug diffusion drug and a phar- macodynamical model in order to evaluate the repopulation in the single drug treatment. The simulations about tumor growth showed that population reached a saturation density accordingly with values of the parameter k.The density of both proliferative and migratory variants was not directed related to the generation of variants rates but by the parameter Nand a. To some specific set of assigned values to the parameters k and N,spatially was observed that diffuse growth of population. Concerning to the treatment, there was resistance emergence, h oweve r, we observed differents patterns in the repopulation ac- cordingly the generation of variants rates, k and N.Spatially, we observed the resistant cells goes to drug gradient. The model, currently, has recovered qualitatively some ex- perimental evidence linked to the co-existence of two subpopulations where one of them grow more than other, diffuse growth of population and migration of resistant population to drug gradient

Over 4,000 flavonoids have been identified, and among these, many of them are known to possess cardioprotective, anti-inflammatory, antimicrobial, and antitumor effects. However, most of these properties have yet to be fully understood. In this study, extracts from Gnaphalium gracile, thought to possess a mixture of flavonoids, have been tested for cytotoxic activity on pancreatic (MiaPaca, Panc28), colon (HCT-116, Caco-2), and prostate (PC3, LNCaP), cancer cell lines. Polar extracts from the leaves of G. gracile have the most cytotoxic effect on these cancer cell lines, particularly the prostate cancer cell lines PC3 and LNCaP. Evidence suggests the extracts have antineoplastic effects on these cancer cells lines possibly due to differentiation status on pancreatic and colon cancer, but not prostate cancer. Cytotoxic activity is not dependent on tumorigenic potential. Further research is needed to identify the bioactive compounds within these extracts.

Gene expression underlies all important biological processes in a cell and mis-regulated gene expression plays a causal or contributory role in several diseases including cancers. Towards identifying molecular determinants that confer susceptibility and resistance to tumor promoter induced neoplastic transformation, we analyzed the gene expression profile differences among tumor promoter TPA treated and untreated mouse epidermal JB6 cells by means of cDNA microarray analyses. The expression patterns for several genes were validated by real time PCR analyses. Seventy-four genes belonging to six functional categories were found to be differentially expressed. Data from this study implicate pathways which mediate cell adhesion, migration and interferon signalling, tumor suppressors, apoptotic proteins and transcription factors and includes twenty-six genes whose involvement has not been previously implicated in cancer. In a second study we used a DNA affinity chromatography based assay to purify two proteins that bound specifically to the AP-1 DNA binding site. Analyses of the purified proteins by mass spectrometric sequencing determined the identities of these proteins as nucleolin and Y-box binding protein 1 (YB-1). We tested the hypothesis that these proteins regulate transactivation at the AP-1 site. Overexpression of nucleolin and YB-1, both alone or in combination, repressed AP-1 dependent gene transactivation. To understand the mechanism of transrepression, we analyzed whether nucleolin and/or YB-1 affected the levels and/or disrupted the intracellular localization of the AP-1 protein subunits. Western blot analyses of all the AP-1 subunits revealed that the levels of AP-1 were unaffected. Cell fractionation confirmed that the AP-1 levels were not altered in the nuclear or cytoplasmic compartments. We further tested the hypothesis that nucleolin and YB-1 repressed AP-1 transactivation by competing with AP-1 proteins for the AP-1 site. The results from this experiment were inconclusive and the precise mechanism of repression is currently under investigation.