Cancer relapse occurs with substantial frequency even after treatment with curative intent. Here we studied drug-tolerant colonies (DTCs), which are subpopulations of cancer cells that survive in the presence of drugs. Proteomic characterization of DTCs identified stemness- and epithelial-dominant subpopulations, but functional screening suggested that DTC formation was regulated at the transcriptional level independent from protein expression patterns. We consistently found that α-amanitin, an RNA polymerase II (RNAPII) inhibitor, effectively inhibited DTCs by suppressing TAF15 expression, which binds to RNA to modulate transcription and RNA processing. Sequential administration of α-amanitin and cisplatin extended overall survival in a cancer-relapse mouse model, namely peritonitis carcinomatosa. Therefore, post-treatment cancer relapse may occur through non-distinct subpopulations and may be effectively prevented by α-amanitin to disrupt transcriptional machinery, including TAF15.
SUMMARYSeveral reports have demonstrated a close correlation between plasma atrial natriuretic peptide (ANP) concentration and atrial pressure in stable heart diseases. However, few studies have investigated whether plasma ANP concentration is a noninvasive indicator of hemodynamic parameters during the treatment of heart failure. Thus, we have studied the relationship between peripheral plasma ANP concentration and concurrent hemodynamic variables during the treatment of heart failure, and, in order to determine whether secretion of ANP is stimulated in this disease condition, we compared the plasma ANP concentration in the pulmonary artery with that in the peripheral veins.Studies were performed in each of 9 patients with acute heart failure due to myocardial infarction (Group A) or chronic heart failure (Group B), who were matched as closely as possible for treatment, age, sex and cardiac output. In group A, no significant correlation was found between plasma ANP levels and any measured hemodynamic variables. In group B, peripheral plasma ANP concentrations were significantly correlated with left atrial pressure (r=0.82, p<0.01), but not with right atrial pressure (r=0.56, p>0.05). Furthermore, in group B ANP levels in pulmonary arterial plasma were consistently higher than those in peripheral venous plasma, whereas in group A the opposite was observed in expired cases.These results suggest that measurement of peripheral plasma ANP is a useful noninvasive method for estimating left atrial pressure during the treatment of chronic heart failure. However, plasma ANP concentration may not be a valid means of estimating hemodynamic parameters in acute heart failure due to myocardial infarction. In such cases, the increased secretion of ANP was not obvious, and there may be other factors , in addition to atrial pressure, that regulate cardiac secretion of ANP.
[Background] Functional heterogeneity within cancer cell populations plays an important role in responses to genotoxic stresses caused by anticancer agents. We have characterized 2,400 colonies derived in the presence of anticancer drugs using human cancer cell lines by newly introduced colony lysate array technique (CoLA). In the present study, we attempted to identify molecular components that could induce anticancer drug-tolerance phenotypes. [Materials and Methods] Using five cancer cell lines and four anticancer agents, CoLA was produced using 2,400 drug-tolerant colonies, followed by protein expression analysis employing specific immunodetection and using a panel of primary antibodies. Transcriptional products that may be important to the formation of colonies in the presence of anticancer drugs were identified by DNA microarray. Candidate genes were examined to determine whether they were associated with the suppression of colony formation, using gene knockdown by siRNA. [Results] This study revealed that CoLA is capable of analyzing lysates from individual colonies in a quantitative manner, by a panel of protein markers. Colonies that expressed pluripotent and CSC markers tended to express low levels of epithelial proteins. However, individual protein expression levels were not well-associated with drug concentrations, suggesting that the phenotypes of drug-tolerant colonies were not necessarily induced by drugs, and emerged spontaneously. Subsequent analysis identifying molecular fractions important to drug-tolerant phenotypes revealed that transcriptional products play an important role in developing these phenotypes. DNA microarray analysis allowed for the narrowing down of 12 genes that are potentially associated with these phenotypes. A gene knockdown by siRNA identified two out of 12 candidate genes as involved in the suppressed colony formation of MCF7 human breast cancer cell line in the presence of cisplatin. [Discussion] CoLA assay revealed that a number of CSC marker-negative colonies exist in the presence of anticancer drugs, suggesting that drug-tolerant cells may not always be associated with CSCs. In the context of drug-tolerant phenotype acquisition, protein expression may merely be a handy marker, whereas transcriptional control may be more critical. Further functional analysis of candidate genes for colony suppression in the presence of anticancer drugs is necessary. Together, de novo drug-tolerance inducing factors are possibly involved in the heterogeneity of cancer cell populations. Citation Format: Kohei Kume, Satoshi Nishizuka, Miyuki Ikeda, Sawako Miura, Yuriko Wada, Shuji Fujikawa, Chihaya Maesawa, Go Wakabayashi. Analysis of cancer cell populations by isolated single colonies for the identification of drug-tolerance inducing factors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4060. doi:10.1158/1538-7445.AM2013-4060
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