Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase

Background In accord with the cancer stem cell (CSC) theory, only a small subset of cancer cells are capable of forming tumors. We previously reported that CD44 isolates tumorigenic cells from head and neck squamous cell cancer (HNSCC). Recent studies indicate that aldehyde dehydrogenase (ALDH) activity may represent a more specific marker of CSCs. Methods Six primary HNSCCs were collected. Cells with high and low ALDH activity (ALDH high /ALDH low ) were isolated. ALDH high and ALDH low populations were implanted into NOD/SCID mice and monitored for tumor development. Results ALDH high cells represented a small percentage of the tumor cells (1% to 7.8%). ALDH high cells formed tumors from as few as 500 cells in 24/45 implantations, whereas only 3/37 implantations of ALDH low cells formed tumors. Conclusions ALDH high cells comprise a subpopulation cells in HNSCCs that are tumorigenic and capable of producing tumors at very low numbers. This finding indicates that ALDH activity on its own is a highly selective marker for CSCs in HNSCC. © 2010 Wiley Periodicals, Inc. Head Neck, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77970/1/21315_ftp.pd

Cyclin A1 and P450 aromatase promote metastatic homing and growth of stem-like prostate cancer cells in the bone marrow

Bone metastasis is a leading cause of morbidity and mortality in prostate cancer (PCa). While cancer stem-like cells have been implicated as a cell of origin for PCa metastases, the pathways which enable metastatic development at distal sites remain largely unknown. In this study, we illuminate pathways relevant to bone metastasis in this disease. We observed that cyclin A1 (CCNA1) protein expression was relatively higher in PCa metastatic lesions in lymph node, lung, and bone/bone marrow. In both primary and metastatic tissues, cyclin A1 expression was also correlated with aromatase (CYP19A1), a key enzyme that directly regulates the local balance of androgens to estrogens. Cyclin A1 overexpression in the stem-like ALDHhigh subpopulation of PC3M cells, one model of PCa, enabled bone marrow integration and metastatic growth. Further, cells obtained from bone marrow metastatic lesions displayed self-renewal capability in colony forming assays. In the bone marrow, Cyclin A1 and aromatase enhanced local bone marrow-releasing factors, including androgen receptor, estrogen and matrix metalloproteinase MMP9 and promoted hte metastatic growth of PCa cells. Moreover, ALDHhigh tumor cells expressing elevated levels of aromatase stimulated tumor/host estrogen production and acquired a growth advantage in the presence of host bone marrow cells. Overall, these findings suggest that local production of steroids and MMPs in the bone marrow may provide a suitable microenvironment for ALDHhigh PCa cells to establish metastatic growths, offering new approaches to therapeutically target bone metastases

Multiobjective fractional variational calculus in terms of a combined Caputo derivative

The study of fractional variational problems in terms of a combined fractional Caputo derivative is introduced. Necessary optimality conditions of Euler-Lagrange type for the basic, isoperimetric, and Lagrange variational problems are proved, as well as transversality and sufficient optimality conditions. This allows to obtain necessary and sufficient Pareto optimality conditions for multiobjective fractional variational problems.Comment: Submitted 18-Nov-2010; accepted 28-Oct-2011; to Applied Mathematics and Computation (ISSN: 0096-3003). In press, DOI: 10.1016/j.amc.2011.10.07

Structural insights into the production of 3-hydroxypropionic acid by aldehyde dehydrogenase from Azospirillum brasilense

3-Hydroxypropionic acid (3-HP) is an important platform chemical to be converted to acrylic acid and acrylamide. Aldehyde dehydrogenase (ALDH), an enzyme that catalyzes the reaction of 3-hydroxypropionaldehyde (3-HPA) to 3-HP, determines 3-HP production rate during the conversion of glycerol to 3-HP. To elucidate molecular mechanism of 3-HP production, we determined the first crystal structure of a 3-HP producing ALDH, alpha-ketoglutarate-semialdehyde dehydrogenase from Azospirillum basilensis (AbKGSADH), in its apo-form and in complex with NAD(+). Although showing an overall structure similar to other ALDHs, the AbKGSADH enzyme had an optimal substrate binding site for accepting 3-HPA as a substrate. Molecular docking simulation of 3-HPA into the AbKGSADH structure revealed that the residues Asn159, Gln160 and Arg163 stabilize the aldehyde-and the hydroxyl-groups of 3-HPA through hydrogen bonds, and several hydrophobic residues, such as Phe156, Val286, Ile288, and Phe450, provide the optimal size and shape for 3-HPA binding. We also compared AbKGSADH with other reported 3-HP producing ALDHs for the crucial amino acid residues for enzyme catalysis and substrate binding, which provides structural implications on how these enzymes utilize 3-HPA as a substrate

Detecting semantic social engineering attacks with the weakest link: Implementation and empirical evaluation of a human-as-a-security-sensor framework

The notion that the human user is the weakest link in information security has been strongly, and, we argue, rightly contested in recent years. Here, we take a step further showing that the human user can in fact be the strongest link for detecting attacks that involve deception, such as application masquerading, spearphishing, WiFi evil twin and other types of semantic social engineering. Towards this direction, we have developed a human-as-a-security-sensor framework and a practical implementation in the form of Cogni-Sense, a Microsoft Windows prototype application, designed to allow and encourage users to actively detect and report semantic social engineering attacks against them. Experimental evaluation with 26 users of different profiles running Cogni-Sense on their personal computers for a period of 45 days has shown that human sensors can consistently outperform technical security systems. Making use of a machine learning based approach, we also show that the reliability of each report, and consequently the performance of each human sensor, can be predicted in a meaningful and practical manner. In an organisation that employs a human-as-a-security-sensor implementation, such as Cogni-Sense, an attack is considered to have been detected if at least one user has reported it. In our evaluation, a small organisation consisting only of the 26 participants of the experiment would have exhibited a missed detection rate below 10%, down from 81% if only technical security systems had been used. The results strongly point towards the need to actively involve the user not only in prevention through cyber hygiene and user-centric security design, but also in active cyber threat detection and reporting

Curcumin: Updated Molecular Mechanisms and Intervention Targets in Human Lung Cancer

Curcumin, a yellow pigment derived from Curcuma longa Linn, has attracted great interest in the research of cancer during the past decades. Extensive studies documented that curcumin attenuates cancer cell proliferation and promotes apoptosis in vivo and in vitro. Curcumin has been demonstrated to interact with multiple molecules and signal pathways, which makes it a potential adjuvant anti-cancer agent to chemotherapy. Previous investigations focus on the mechanisms of action for curcumin, which is shown to manipulate transcription factors and induce apoptosis in various kinds of human cancer. Apart from transcription factors and apoptosis, emerging studies shed light on latent targets of curcumin against epidermal growth factor receptor (EGFR), microRNAs (miRNA), autophagy and cancer stem cell. The present review predominantly discusses significance of EGFR, miRNA, autophagy and cancer stem cell in lung cancer therapy. Curcumin as a natural phytochemicals could communicate with these novel targets and show synergism to chemotherapy. Additionally, curcumin is well tolerated in humans. Therefore, EGFR-, miRNA-, autophagy- and cancer stem cell-based therapy in the presence of curcumin might be promising mechanisms and targets in the therapeutic strategy of lung cancer

Isolation and Characterization of a Metastatic Hybrid Cell Line Generated by ER Negative and ER Positive Breast Cancer Cells in Mouse Bone Marrow

BACKGROUND: The origin and the contribution of breast tumor heterogeneity to its progression are not clear. We investigated the effect of a growing orthotopic tumor formed by an aggressive estrogen receptor (ER)-negative breast cancer cell line on the metastatic potential of a less aggressive ER-positive breast cancer cell line for the elucidation of how the presence of heterogeneous cancer cells might affect each other's metastatic behavior. METHODS: ER positive ZR-75-1/GFP/puro cells, resistant to puromycin and non-tumorigenic/non-metastatic without exogenous estrogen supplementation, were injected intracardiacally into mice bearing growing orthotopic tumors, formed by ER negative MDA-MB-231/GFP/Neo cells resistant to G418. A variant cell line B6, containing both estrogen-dependent and -independent cells, were isolated from GFP expressing cells in the bone marrow and re-inoculated in nude mice to generate an estrogen-independent cell line B6TC. RESULTS: The presence of ER negative orthotopic tumors resulted in bone metastasis of ZR-75-1 without estrogen supplementation. The newly established B6TC cell line was tumorigenic without estrogen supplementation and resistant to both puromycin and G418 suggesting its origin from the fusion of MDA-MB-231/GFP/Neo and ZR-75-1/GFP/puro in the mouse bone marrow. Compared to parental cells, B6TC cells were more metastatic to lung and bone after intracardiac inoculation. More significantly, B6TC mice also developed brain metastasis, which was not observed in the MDA-MB-231/GFP/Neo cell-inoculated mice. Low expression of ERα and CD24, and high expression of EMT-related markers such as Vimentin, CXCR4, and Integrin-β1 along with high CD44 and ALDH expression indicated stem cell-like characteristics of B6TC. Gene microarray analysis demonstrated a significantly different gene expression profile of B6TC in comparison to those of parental cell lines. CONCLUSIONS: Spontaneous generation of the novel hybrid cell line B6TC, in a metastatic site with stem cell-like properties and propensity to metastasize to brain, suggest that cell fusion can contribute to tumor heterogeneity

Breast cancer stem cells: tools and models to rely on

There is increasing evidence for the "cancer stem cell (CSC) hypothesis", which holds that cancers are driven by a cellular component that has stem cell properties, including self-renewal, tumorigenicity and multi-lineage differentiation capacity. Researchers and oncologists see in this model an explanation as to why cancer may be so difficult to cure, as well as a promising ground for novel therapeutic strategies. Given the specific stem cell features of self-renewal and differentiation, which drive tumorigenesis and contribute to cellular heterogeneity, each marker and assay designed to isolate and characterize CSCs has to be functionally validated. In this review, we survey tools and markers available or promising to identify breast CSCs. We review the main models used to study breast CSCs and how they challenge the CSC hypothesis