Metformin Represses Self-Renewal of the Human Breast Carcinoma Stem Cells via Inhibition of Estrogen Receptor-Mediated OCT4 Expression

Metformin, a Type II diabetic treatment drug, which inhibits transcription of gluconeogenesis genes, has recently been shown to lower the risk of some diabetes-related tumors, including breast cancer. Recently, “cancer stem cells” have been demonstrated to sustain the growth of tumors and are resistant to therapy. To test the hypothesis that metformin might be reducing the risk to breast cancers, the human breast carcinoma cell line, MCF-7, grown in 3-dimensional mammospheres which represent human breast cancer stem cell population, were treated with various known and suspected breast cancer chemicals with and without non-cytotoxic concentrations of metformin. Using OCT4 expression as a marker for the cancer stem cells, the number and size were measured in these cells. Results demonstrated that TCDD (100 nM) and bisphenol A (10 µM) increased the number and size of the mammospheres, as did estrogen (10 nM E2). By monitoring a cancer stem cell marker, OCT4, the stimulation by these chemicals was correlated with the increased expression of OCT4. On the other hand, metformin at 1 and 10 mM concentration dramatically reduced the size and number of mammospheres. Results also demonstrated the metformin reduced the expression of OCT4 in E2 & TCDD mammospheres but not in the bisphenol A mammospheres, suggesting different mechanisms of action of the bisphenol A on human breast carcinoma cells. In addition, these results support the use of 3-dimensional human breast cancer stem cells as a means to screen for potential human breast tumor promoters and breast chemopreventive and chemotherapeutic agents

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Quantificação da função esfincteriana pela medida da capacidade de sustentação da pressão de contração voluntária do canal anal Sphincteric function quantification by measuring the capacity to sustain the squeeze pressure of the anal canal

RACIONAL: Tem sido demonstrado que a pressão máxima de contração voluntária e a pressão média de repouso não refletem a real situação clínica do paciente portador de incontinência fecal, não traduzem a realidade funcional do canal anal, além de poder estar comprometendo a conduta a ser tomada devido ao não-encaminhamento à terapêutica específica. OBJETIVO: Com a hipótese de que contrair e manter a contração é mais importante que simplesmente contrair, mesmo com pico momentaneamente elevado de pressão, analisou-se a capacidade de sustentação da pressão de contração voluntária do canal anal com o intuito de quantificar a função esfincteriana relativa à continência fecal. MATERIAL E MÉTODOS: Submeteram-se a exame manométrico anorretal 72 pacientes (56 mulheres) portadores de incontinência fecal de vários graus e 15 (9 mulheres) indivíduos continentes (normais), avaliando-se a pressão média de repouso, a pressão máxima de contração voluntária e a capacidade de sustentação da pressão de contração voluntária. RESULTADOS: Os indivíduos continentes apresentaram valores normais de pressão média de repouso e de pressão máxima de contração voluntária, além de adequada capacidade de sustentação da pressão de contração voluntária. Os pacientes incontinentes apresentaram pressão média de repouso e pressão máxima de contração voluntária com valores pressóricos normais ou abaixo do normal e perfil semelhante de capacidade de sustentação da pressão de contração voluntária, ou seja, moderada na fase inicial e ruim nas fases intermediária e final, com queda da mesma superior a 35% em 78% dos pacientes. A pressão máxima de contração voluntária apresenta excelente especificidade (100%) porém, sensibilidade baixa (46%) para incontinência fecal. Comparativamente, a capacidade de sustentação da pressão de contração voluntária apresenta elevadas especificidade (93%) e sensibilidade (78%) para incontinência fecal. Embora a pressão máxima de contração voluntária não indique falso-positivos, apresenta 72% de falso-negativos. A probabilidade deste fato acontecer com a medida de capacidade de sustentação da pressão de contração voluntária é, praticamente, 20% menor, valor estatisticamente significativo. CONCLUSÃO: O indicativo de função esfincteriana é melhor analisado pela capacidade de sustentação. A capacidade de sustentação traduz com mais exatidão, a capacidade funcional do canal anal em relação à continência voluntária, sendo isoladamente, melhor que a pressão máxima de contração voluntária.<br>BACKGROUND: It has been demonstrated that the maximum squeeze pressure and the mean resting pressure do not reflect the true clinical situation of patients having fecal incontinence, as well as the functional status of the anal canal. Furthermore, a wrong diagnosis could be obtained and therefore misleading to a not effective treatment. AIM: Under the hypothesis that squeezing and sustaining the anal canal contraction is more important than the maximum squeeze pressure, the capacity to sustain the squeeze pressure of the anal canal was analyzed aiming to quantify the sphincteric function. METHODS: Seventy-two patients having fecal incontinence in different degrees (56 female) and 15 normal individuals (9 female) were submitted to anorectal manometry to measure the mean resting pressure, the maximum voluntary squeeze pressure and the capacity to sustain the squeeze pressure. RESULTS: Normal individuals had normal values of mean resting pressure and maximum squeeze pressure, and adequate capacity to sustain the squeeze pressure of the canal anal. Incontinent patients had mean resting pressure and maximum squeeze pressure with normal or below normal pressoric values and similar profile of capacity to sustain which was moderate in the initial phase and worse in the intermediate and final phases, with decreasing of the capacity to sustain more than 35% in 78% of the patients. The maximum squeeze pressure presented excellent specificity (100%), but low sensitivity (46%) for fecal incontinence. Comparatively, the squeeze pressure presented high specificity (93%) and high sensitivity (78%) for fecal incontinence. Although the maximum squeeze pressure did not indicate false positive, it presented a 72% false negative. The probability of this event to happen with the capacity to sustain measure is 20% lower, and it was statistically significant. CONCLUSION: Sphincteric function can be better analyzed by using the capacity to sustain the squeeze pressure. capacity to sustain indicates more precisely the functional capacity of the anal canal in relation to voluntary continence, and it is better than maximum squeeze pressure as an isolated index