Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells.

Accumulating lines of experimental evidence have revealed that hypoxia-inducible factors, HIF-1α and HIF-2α, are key regulators of the adaptation of cancer- and metastasis-initiating cells and their differentiated progenies to oxygen and nutrient deprivation during cancer progression under normoxic and hypoxic conditions. Particularly, the sustained stimulation of epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), stem cell factor (SCF) receptor KIT, transforming growth factor-ß receptors (TGF-ßRs) and Notch and their downstream signalling elements such as phosphatidylinositol 3'-kinase (PI3K)/Akt/molecular target of rapamycin (mTOR) may lead to an enhanced activity of HIFs. Moreover, the up-regulation of HIFs in cancer cells may also occur in the hypoxic intratumoral regions formed within primary and secondary neoplasms as well as in leukaemic cells and metastatic prostate and breast cancer cells homing in the hypoxic endosteal niche of bone marrow. The activated HIFs may induce the expression of numerous gene products such as induced pluripotency-associated transcription factors (Oct-3/4, Nanog and Sox-2), glycolysis- and epithelial-mesenchymal transition (EMT) programme-associated molecules, including CXC chemokine receptor 4 (CXCR4), snail and twist, microRNAs and angiogenic factors such as vascular endothelial growth factor (VEGF). These gene products in turn can play critical roles for high self-renewal ability, survival, altered energy metabolism, invasion and metastases of cancer cells, angiogenic switch and treatment resistance. Consequently, the targeting of HIF signalling network and altered metabolic pathways represents new promising strategies to eradicate the total mass of cancer cells and improve the efficacy of current therapies against aggressive and metastatic cancers and prevent disease relapse.

Frequent deregulations in the hedgehog signaling network and cross-talks with the epidermal growth factor receptor pathway involved in cancer progression and targeted therapies.

The hedgehog (Hh)/glioma-associated oncogene (GLI) signaling network is among the most important and fascinating signal transduction systems that provide critical functions in the regulation of many developmental and physiological processes. The coordinated spatiotemporal interplay of the Hh ligands and other growth factors is necessary for the stringent control of the behavior of diverse types of tissue-resident stem/progenitor cells and their progenies. The activation of the Hh cascade might promote the tissue regeneration and repair after severe injury in numerous organs, insulin production in pancreatic beta-cells, and neovascularization. Consequently, the stimulation of the Hh pathway constitutes a potential therapeutic strategy to treat diverse human disorders, including severe tissue injuries; diabetes mellitus; and brain, skin, and cardiovascular disorders. In counterbalance, a deregulation of the Hh signaling network might lead to major tissular disorders and the development of a wide variety of aggressive and metastatic cancers. The target gene products induced through the persistent Hh activation can contribute to the self-renewal, survival, migration, and metastasis of cancer stem/progenitor cells and their progenies. Moreover, the pivotal role mediated through the Hh/GLI cascade during cancer progression also implicates the cooperation with other oncogenic products, such as mutated K-RAS and complex cross-talk with different growth factor pathways, including tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), Wnt/beta-catenin, and transforming growth factor-beta (TGF-beta)/TGF-beta receptors. Therefore, the molecular targeting of distinct deregulated gene products, including Hh and EGFR signaling components and other signaling elements that are frequently deregulated in highly tumorigenic cancer-initiating cells and their progenies, might constitute a potential therapeutic strategy to eradicate the total cancer cell mass. Of clinical interest is that these multitargeted approaches offer great promise as adjuvant treatments for improving the current antihormonal therapies, radiotherapies, and/or chemotherapies against locally advanced and metastatic cancers, thereby preventing disease relapse and the death of patients with cancer.

Animal models relevant to human prostate carcinogenesis underlining the critical implication of prostatic stem/progenitor cells.

Recent development of animal models relevant to human prostate cancer (PC) etiopathogenesis has provided important information on the specific functions provided by key gene products altered during disease initiation and progression to locally invasive, metastatic and hormone-refractory stages. Especially, the characterization of transgenic mouse models has indicated that the inactivation of distinct tumor suppressor proteins such as phosphatase tensin homolog deleted on chromosome 10 (PTEN), Nkx3.1, p27(KIP1), p53 and retinoblastoma (pRb) may cooperate for the malignant transformation of prostatic stem/progenitor cells into PC stem/progenitor cells and tumor development and metastases. Moreover, the sustained activation of diverse oncogenic signaling elements, including epidermal growth factor receptor (EGFR), sonic hedgehog, Wnt/ß-catenin, c-Myc, Akt and nuclear factor-kappaB (NF-κB) also may contribute to the acquisition of more aggressive and hormone-refractory phenotypes by PC stem/progenitor cells and their progenies during disease progression. Importantly, it has also been shown that an enrichment of PC stem/progenitor cells expressing stem cell-like markers may occur after androgen deprivation therapy and docetaxel treatment in the transgenic mouse models of PC suggesting the critical implication of these immature PC cells in treatment resistance, tumor re-growth and disease recurrence. Of clinical interest, the molecular targeting of distinct gene products altered in PC cells by using different dietary compounds has also been shown to counteract PC initiation and progression in animal models supporting their potential use as chemopreventive or chemotherapeutic agents for eradicating the total tumor cell mass, improving current anti-hormonal and chemotherapies and preventing disease relapse.

Functions of normal and malignant prostatic stem/progenitor cells in tissue regeneration and cancer progression and novel targeting therapies.

This review summarizes the recent advancements that have improved our understanding of the functions of prostatic stem/progenitor cells in maintaining homeostasis of the prostate gland. We also describe the oncogenic events that may contribute to their malignant transformation into prostatic cancer stem/progenitor cells during cancer initiation and progression to metastatic disease stages. The molecular mechanisms that may contribute to the intrinsic or the acquisition of a resistant phenotype by the prostatic cancer stem/progenitor cells and their differentiated progenies with a luminal phenotype to the current therapies and disease relapse are also reviewed. The emphasis is on the critical functions of distinct tumorigenic signaling cascades induced through the epidermal growth factor system, hedgehog, Wnt/beta-catenin, and/or stromal cell-derived factor-1/CXC chemokine receptor-4 pathways as well as the deregulated apoptotic signaling elements and ATP-binding cassette multidrug transporter. Of particular therapeutic interest, we also discuss the potential beneficial effects associated with the targeting of these signaling elements to overcome the resistance to current treatments and prostate cancer recurrence. The combined targeted strategies toward distinct oncogenic signaling cascades in prostatic cancer stem/progenitor cells and their progenies as well as their local microenvironment, which could improve the efficacy of current clinical chemotherapeutic treatments against incurable, androgen-independent, and metastatic prostate cancers, are also described.

Great promise of tissue-resident adult stem/progenitor cells in transplantation and cancer therapies.

Recent progress in tissue-resident adult stem/progenitor cell research has inspired great interest because these immature cells from your own body can act as potential, easily accessible cell sources for cell transplantation in regenerative medicine and cancer therapies. The use of adult stem/progenitor cells endowed with a high self-renewal ability and multilineage differentiation potential, which are able to regenerate all the mature cells in the tissues from their origin, offers great promise in replacing non-functioning or lost cells and regenerating diseased and damaged tissues. The presence of a small subpopulation of adult stem/progenitor cells in most tissues and organs provides the possibility of stimulating their in vivo differentiation, or of using their ex vivo expanded progenies for cell-replacement and gene therapies with multiple applications in humans without a high-risk of graft rejection and major side effects. Among the diseases that could be treated by adult stem cell-based therapies are hematopoietic and immune disorders, multiple degenerative disorders such as Parkinson's and Alzheimer's diseases, Types 1 and 2 diabetes mellitus as well as skin, eye, liver, lung, tooth and cardiovascular disorders. In addition, a combination of the current cancer treatments with an adjuvant treatment consisting of an autologous or allogeneic adult stem/progenitor cell transplantation also represents a promising strategy for treating and even curing diverse aggressive, metastatic, recurrent and lethal cancers. In this chapter, we reviewed the most recent advancements on the characterization of phenotypic and functional properties of adult stem/progenitor cell types found in bone marrow, heart, brain and other tissues and discussed their therapeutic implications in the stem cell-based transplantation therapy.

Adsorption study of a commonly used antidepressant drug, fluoxetine hydrochloride, onto a crosslinked ß-cyclodextrin-carboxymethylcellulose polymer.

A study was carried out by ultraviolet-visible (UV-vis) and Fourier transform infrared (FTIR) spectroscopies to establish the efficiency of adsorption of fluoxetine hydrochloride (FLU), onto a crosslinked ß-cyclodextrin-carboxymethylcellulose (ß-CD-CMC) polymer. The adsorption was performed in mixtures containing aqueous FLU solution at 20 mg/L and 0.01-0.30 g of the ß-CD-CMC polymer, at 25 °C, and atmospheric pressure under stirring. The results have revealed that the adsorption is a rapid process and the polymer possesses a high affinity for FLU with an adsorption capacity of 5.076 mg of FLU/g of polymer. This adsorption may involve the formation of a stable inclusion compound ß-CD-CMC/FLU through the penetration of the FLU aromatic ring (A and/or B) into the ß-CD cavity, and a physical adsorption with the polymer network. The inclusion compound can be stabilized by the formation of H-bonds between the -CF(3) group of FLU and the 6'-OH group of ß-CD, and van der Waals interactions between the FLU aromatic ring and ß-CD cavity. The data from a kinetic study have also indicated that the adsorption process was well described by the pseudo-second-order kinetic model, in which the initial adsorption rate and constant were estimated at 1.938 mg/g min and 0.075 g/mg min, respectively. Moreover, the results of adsorption equilibrium fitted the Freundlich isotherm, indicating a multilayer coverage and heterogeneous surface. Together, these results suggest that the adsorption of FLU onto the crosslinked ß-CD-CMC polymer could constitute an advantageous technology for removing this commonly used antidepressant drug from wastewater due to the high adsorption capacity of the polymer and non-toxic character of ß-CD to humans and environment.

Frequent gene products and molecular pathways altered in prostate cancer- and metastasis-initiating cells and their progenies and novel promising multitargeted therapies.

Recent gene expression profiling analyses and gain- and loss-of-function studies performed with distinct prostate cancer (PC) cell models indicated that the alterations in specific gene products and molecular pathways often occur in PC stem/progenitor cells and their progenies during prostate carcinogenesis and metastases at distant sites, including bones. Particularly, the sustained activation of epidermal growth factor receptor (EGFR), hedgehog, Wnt/ß-catenin, Notch, hyaluronan (HA)/CD44 and stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) during the epithelial-mesenchymal transition (EMT) process may provide critical functions for PC progression to locally invasive, metastatic and androgen-independent disease states and treatment resistance. Moreover, an enhanced glycolytic metabolism in PC stem/progenitor cells and their progenies concomitant with the changes in their local microenvironment, including the induction of tumor hypoxia and release of diverse soluble factors by tumor myofibroblasts, also may promote the tumor growth, angiogenesis and metastases. More particularly, these molecular transforming events may cooperate to upregulate Akt, nuclear factor (NF)-κB, hypoxia-inducible factors (HIFs) and stemness gene products such as Oct3/4, Sox2, Nanog and Bmi-1 in PC cells that contribute to their acquisition of high self-renewal, tumorigenic and invasive capacities and survival advantages during PC progression. Consequently, the molecular targeting of these deregulated gene products in the PC- and metastasis-initiating cells and their progenies represent new promising therapeutic strategies of great clinical interest for eradicating the total PC cell mass and improving current antihormonal treatments and docetaxel-based chemotherapies, thereby preventing disease relapse and the death of PC patients.

Synthesis and structure-activity study of quaternary ammonium functionalized beta-cyclodextrin-carboxymethylcellulose polymers.

Carboxymethylcellulose (CMC) and beta-cyclodextrin (beta-CD)-based polymers functionalized with two types of quaternary ammonium compounds (QACs), the alkaquat DMB-451 (N-alkyl (50% C14, 40% C12, 10% C10) dimethylbenzylammonium chloride) (DMD-451) named polymer DMB-451, and FMB 1210-8 (a blend of 32 w% N-alkyl (50% C14, 40% C12, 10% C10) dimethylbenzylammonium chloride and 48 w% of didecyldimethylammonium chloride) named polymer FMB 1210-8, were synthethized and characterized by Fourier transform infrared spectroscopy. The antimicrobial activities of these polymers against Eschericia coli were also evaluated at 25 degrees C in wastewater. The results have indicated that the polymer FMB 1210-8 possesses a high-affinity binding with bacterial cells that induces a rapid disinfection process. Moreover, in the same experimental conditions of disinfection (mixture of 1.0 g of polymer and 100 mL of wastewater), the polymer FMB 1210-8 has a higher antimicrobial efficiency (99.90%) than polymer DMB-451 (92.8%). This phenomenon might be associated to a stronger interaction with bacterial cells due to stronger binding affinity for E. coli cells and greater killing efficiency of the C10 alkyl chains QAC of polymer FMB 1210-8 to disrupt the bacterial cell membrane as compared to N-alkyl (50% C14, 40% C12, 10% C10) dimethylbenzylammonium chloride. Together, these results suggest that the polymer FMB 1210-8 could constitute a good disinfectant against Escherichia coli, which could be advantageously used in wastewater treatments due to the low toxicity of beta-CD and CMC, and moderated toxicity of FMB 1210-8 to human and environment.

Recent advances on skin-resident stem/progenitor cell functions in skin regeneration, aging and cancers and novel anti-aging and cancer therapies.

Recent advances in skin-resident adult stem/progenitor cell research have revealed that these immature and regenerative cells with a high longevity provide critical functions in maintaining skin homeostasis and repair after severe injuries along the lifespan of individuals. The establishment of the functional properties of distinct adult stem/progenitor cells found in skin epidermis and hair follicles and extrinsic signals from their niches, which are deregulated during their aging and malignant transformation, has significantly improved our understanding on the etiopathogenesis of diverse human skin disorders and cancers. Particularly, enhanced ultraviolet radiation exposure, inflammation and oxidative stress and telomere attrition during chronological aging may induce severe DNA damages and genomic instability in the skin-resident stem/progenitor cells and their progenies. These molecular events may result in the alterations in key signalling components controlling their self-renewal and/or regenerative capacities as well as the activation of tumour suppressor gene products that trigger their growth arrest and senescence or apoptotic death. The progressive decline in the regenerative functions and/or number of skin-resident adult stem/progenitor cells may cause diverse skin diseases with advancing age. Moreover, the photoaging, telomerase re-activation and occurrence of different oncogenic events in skin-resident adult stem/progenitor cells may also culminate in their malignant transformation into cancer stem/progenitor cells and skin cancer initiation and progression. Therefore, the anti-inflammatory and anti-oxidant treatments and stem cell-replacement and gene therapies as well as the molecular targeting of their malignant counterpart, skin cancer-initiating cells offer great promise to treat diverse skin disorders and cancers.

Divergent molecular mechanisms underlying the pleiotropic functions of macrophage inhibitory cytokine-1 in cancer.

Multifunctional macrophage inhibitory cytokine-1, MIC-1, is a member of the transforming growth factor-beta (TGF-beta) superfamily that plays key roles in the prenatal development and regulation of the cellular responses to stress signals and inflammation and tissue repair after acute injuries in adult life. The stringent control of the MIC-1 expression, secretion, and functions involves complex regulatory mechanisms and the interplay of other growth factor signaling networks that control the cell behavior. The deregulation of MIC-1 expression and signaling pathways has been associated with diverse human diseases and cancer progression. The MIC-1 expression levels substantially increase in cancer cells, serum, and/or cerebrospinal fluid during the progression of diverse human aggressive cancers, such as intracranial brain tumors, melanoma, and lung, gastrointestinal, pancreatic, colorectal, prostate, and breast epithelial cancers. Of clinical interest, an enhanced MIC-1 expression has been positively correlated with poor prognosis and patient survival. Secreted MIC-1 cytokine, like the TGF-beta prototypic member of the superfamily, may provide pleiotropic roles in the early and late stages of carcinogenesis. In particular, MIC-1 may contribute to the proliferation, migration, invasion, metastases, and treatment resistance of cancer cells as well as tumor-induced anorexia and weight loss in the late stages of cancer. Thus, secreted MIC-1 cytokine constitutes a new potential biomarker and therapeutic target of great clinical interest for the development of novel diagnostic and prognostic methods and/or cancer treatment against numerous metastatic, recurrent, and lethal cancers.

Adsorption and recovery of nonylphenol ethoxylate on a crosslinked beta-cyclodextrin-carboxymethylcellulose polymer.

A study of adsorption/recovery of nonylphenol 9 mole ethoxylate (NP9EO) on a crosslinked beta-cyclodextrin-carboxymethylcellulose (beta-CD-CMC) polymer was carried out by ultraviolet-visible (UV-vis) and Fourier transform infrared (FTIR) spectroscopies. The adsorption was performed in mixtures containing 500 mg of the beta-CD-CMC polymer and aqueous NP9EO solutions at concentrations 12-82 mg/L, whereas the recovery of NP9EO was effectuated by shaking the beta-CD-CMC polymer loaded with methanol. The assays were made at 25 degrees C and atmospheric pressure under agitation. The results have shown that the adsorption is a rapid process and the beta-CD-CMC polymer exhibits a high NP9EO adsorption capacity of 83-92 w% (1.1-6.8 mg NP9EO/g beta-CD-CMC polymer) dependent of the initial NP9EO concentration in liquid phase. This adsorption may involve the formation of an inclusion complex beta-CD-NP9EO and a physical adsorption in the polymer network. The adsorption equilibrium measurements, which were analyzed using the Langmuir isotherm, have indicated a monolayer coverage and the homogeneous distribution of active sites at the surface of the beta-CD-CMC polymer. Moreover, the negative value obtained for the free energy change (-13.2 kJ/mol) has indicated that the adsorption process is spontaneous. In parallel, the beta-CD-CMC polymer exhibited a high NP9EO recovery efficiency of 97 w% that may occur through a decrease of binding strength between beta-CD-CMC polymer and NP9EO. Together, these results suggest that the beta-CD-CMC polymer could constitute a good adsorbent for removing nonylphenol ethoxylates from wastewater due to its high adsorption capacity and non-toxic character of beta-CD and CMC to environment.

Characterization of nonmalignant and malignant prostatic stem/progenitor cells by Hoechst side population method.

Recent technical progress in the field of cancer stem/progenitor cell research revealed that these malignant cells may provide critical roles for primary tumor growth, metastases at distant tissues and organs, treatment resistance, and disease relapse. The precise molecular oncogenic events that frequently occur in cancer stem/progenitor cells and their early progenies during the early and late stages of cancer progression as well as their contribution to the treatment resistance and disease recurrence remain poorly defined. This lack of information on the deregulated gene products that may be involved in the malignant transformation of tissue-resident adult stem/progenitor cells into highly tumorigenic and/or migrating cancer stem/progenitor cells emphasizes the urgent need to perform future investigations. Toward this direction, we describe in this book chapter the characterization of nonmalignant and malignant prostatic stem/progenitor cells from well-established cell lines by Hoechst side population method. This novel approach should help to establish novel in vitro and in vivo models of human cancer stem/progenitor cell mimicking more closely the genetic and phenotypic changes occurring during the different stages of prostate carcinogenesis and disease progression in clinical settings. Of therapeutic interest, the identification of new biomarkers and molecular targets specific to these prostatic cancer-initiating cells should also help to develop more effective diagnostic and prognostic tests and chemopreventive and therapeutic treatments for the patients diagnosed at early and late stages of disease progression.

Recent progress on tissue-resident adult stem cell biology and their therapeutic implications.

Recent progress in the field of the stem cell research has given new hopes to treat and even cure diverse degenerative disorders and incurable diseases in human. Particularly, the identification of a rare population of adult stem cells in the most tissues/organs in human has emerged as an attractive source of multipotent stem/progenitor cells for cell replacement-based therapies and tissue engineering in regenerative medicine. The tissue-resident adult stem/progenitor cells offer the possibility to stimulate their in vivo differentiation or to use their ex vivo expanded progenies for cell replacement-based therapies with multiple applications in human. Among the human diseases that could be treated by the stem cell-based therapies, there are hematopoietic and immune disorders, multiple degenerative disorders, such as Parkinson's and Alzheimer's diseases, type 1 or 2 diabetes mellitus as well as eye, liver, lung, skin and cardiovascular disorders and aggressive and metastatic cancers. In addition, the genetically-modified adult stem/progenitor cells could also be used as delivery system for expressing the therapeutic molecules in specific damaged areas of different tissues. Recent advances in cancer stem/progenitor cell research also offer the possibility to targeting these undifferentiated and malignant cells that provide critical functions in cancer initiation and progression and disease relapse for treating the patients diagnosed with the advanced and metastatic cancers which remain incurable in the clinics with the current therapies.

Advances in principal factors influencing carbon dioxide adsorption on zeolites.

We report the advances in the principal structural and experimental factors that might influence the carbon dioxide (CO2) adsorption on natural and synthetic zeolites. The CO2 adsorption is principally govern by the inclusion of exchangeable cations (countercations) within the cavities of zeolites, which induce basicity and an electric field, two key parameters for CO2 adsorption. More specifically, these two parameters vary with diverse factors including the nature, distribution and number of exchangeable cations. The structure of framework also determines CO2 adsorption on zeolites by influencing the basicity and electric field in their cavities. In fact, the basicity and electric field usually vary inversely with the Si/Al ratio. Furthermore, the CO2 adsorption might be limited by the size of pores within zeolites and by the carbonates formation during the CO2 chemisorption. The polarity of molecules adsorbed on zeolites represents a very important factor that influences their interaction with the electric field. The adsorbates that have the most great quadrupole moment such as the CO2, might interact strongly with the electric field of zeolites and this favors their adsorption. The pressure, temperature and presence of water seem to be the most important experimental conditions that influence the adsorption of CO2. The CO2 adsorption increases with the gas phase pressure and decreases with the rise of temperature. The presence of water significantly decreases adsorption capacity of cationic zeolites by decreasing strength and heterogeneity of the electric field and by favoring the formation of bicarbonates. The optimization of the zeolites structural characteristics and the experimental conditions might enhance substantially their CO2 adsorption capacity and thereby might give rise to the excellent adsorbents that may be used to capturing the industrial emissions of CO2.

Combined targeting of epidermal growth factor receptor and hedgehog signaling by gefitinib and cyclopamine cooperatively improves the cytotoxic effects of docetaxel on metastatic prostate cancer cells.

The epidermal growth factor receptor (EGFR) and hedgehog cascades provide a critical role in prostate cancer progression and contribute to the resistance to clinical therapies and disease relapse. Therefore, we evaluated, for the first time, the antiproliferative and cytotoxic effects induced by a combination of selective inhibitors of EGFR tyrosine kinase and smoothened hedgehog signaling element, gefitinib and cyclopamine, with a current chemotherapeutic drug used in the clinics, docetaxel, on some metastatic prostate cancer cell lines. Immunohistochemical analyses revealed that sonic hedgehog (SHH) expression was enhanced in 39% of primary prostatic adenocarcinomas (Gleason scores 4-10) compared with the corresponding normal tissues of the same prostate gland from 32 prostate cancer patients. The confocal microscopy and Western blot analyses have also indicated the high expression levels of SHH and EGFR in metastatic LNCaP, DU145, and PC3 cells. Moreover, the results revealed that the drugs, alone or in combination, at lower concentrations inhibited the growth of EGF plus SHH-stimulated and serum-stimulated androgen-responsive LNCaP-C33 and androgen-independent LNCaP-C81, DU145, and PC3 cells. Importantly, the combined docetaxel, gefitinib, and cyclopamine also caused a higher rate of apoptotic death of prostate cancer cells compared with individual agents. The cytotoxic effects induced by these drugs in PC3 cells seem to be mediated in part through the cellular ceramide production and activation of caspase cascades via a mitochondrial pathway and the release of cytochrome c into the cytosol. Additionally, the combined agents were more effective at suppressing the invasiveness of PC3 cells through Matrigel in vitro than the single drugs. These findings indicate that the combined use of inhibitors of EGF-EGFR and hedgehog signaling with docetaxel could represent a more promising strategy for treatment in patients with metastatic and androgen-independent prostate cancer.

Inhibition of hedgehog signaling improves the anti-carcinogenic effects of docetaxel in prostate cancer.

The establishment of docetaxel-based chemotherapeutic treatments has improved the survival of castration-resistant prostate cancer (CRPC) patients. However, most patients develop resistance supporting the development of therapy. The current study was undertaken to establish the therapeutic benefit to target hedgehog signaling cascade using GDC-0449 to improve the efficacy of chemotherapeutic drug, docetaxel. Here, we show that the combination of GDC-0449 plus docetaxel inhibited the proliferation of WPE1-NB26 cells and PC3 cells via a blockade of G1 and G2M phases. The combined treatment significantly inhibited PC cell migration in vitro. Moreover, the apoptotic effect induced by GDC-0449 plus docetaxel on PC3 cells was mediated, at least partly, via the mitochondrial membrane depolarization, H2O2 production and caspase cascade activation. Interestingly, GDC-0449 was effective at inhibiting the prostasphere formation, inducing the prostasphere disintegration and apoptotic death of side population (SP) from PC3 cells and reversing the resistance of SP cells to docetaxel. In addition, GDC-0449 plus docetaxel also have shown a greater anti-tumoral growth inhibitory effect on PC3 cell xenografts. These findings support the use of the hedgehog inhibitor GDC-0449, which is currently in clinical trials, for improving the anticarcinogenic efficacy of docetaxel-based chemotherapeutic treatments against locally advanced, AI and metastatic PC.

New advances on structural and biological functions of ceramide in apoptotic/necrotic cell death and cancer.

Recent data on the cellular ceramide functions and its involvement in the apoptotic/necrotic cell death as well as its anticarcinogenic properties are presented. The emphasis is on the connections between the ceramide and caspase signaling pathways during the apoptotic cell death process. Notably, the experimental strategies and pharmacological tools used for establishment of the role of ceramide in triggering cell death are described. Moreover, the importance of a compartmentation of endogenous ceramide within the plasma membrane microdomains, lysosomes and mitochondria is discussed. Information on the deregulated functions of ceramide and caspase signaling pathways in several metastatic cancer types is also presented.

Molecular biomarkers of cancer stem/progenitor cells associated with progression, metastases, and treatment resistance of aggressive cancers.

The validation of novel diagnostic, prognostic, and predictive biomarkers and therapeutic targets in tumor cells is of critical importance for optimizing the choice and efficacy of personalized therapies. Importantly, recent advances have led to the identification of gene-expression signatures in cancer cells, including cancer stem/progenitor cells, in the primary tumors, exosomes, circulating tumor cells (CTC), and disseminated cancer cells at distant metastatic sites. The gene-expression signatures may help to improve the accuracy of diagnosis and predict the therapeutic responses and overall survival of patients with cancer. Potential biomarkers in cancer cells include stem cell-like markers [CD133, aldehyde dehydrogenase (ALDH), CD44, and CD24], growth factors, and their cognate receptors [epidermal growth factor receptor (EGFR), EGFRvIII, and HER2], molecules associated with epithelial-mesenchymal transition (EMT; vimentin, N-cadherin, snail, twist, and Zeb1), regulators of altered metabolism (phosphatidylinositol-3' kinase/Akt/mTOR), and drug resistance (multidrug transporters and macrophage inhibitory cytokine-1). Moreover, different pluripotency-associated transcription factors (Oct3/4, Nanog, Sox2, and Myc) and microRNAs that are involved in the epigenetic reprogramming and acquisition of stem cell-like properties by cancer cells during cancer progression may also be exploited as molecular biomarkers to predict the risk of metastases, systemic treatment resistance, and disease relapse of patients with cancer.

Altered gene products involved in the malignant reprogramming of cancer stem/progenitor cells and multitargeted therapies.

Recent studies in the field of cancer stem cells have revealed that the alterations in key gene products involved in the epithelial-mesenchymal transition (EMT) program, altered metabolic pathways such as enhanced glycolysis, lipogenesis and/or autophagy and treatment resistance may occur in cancer stem/progenitor cells and their progenies during cancer progression. Particularly, the sustained activation of diverse developmental cascades such as hedgehog, epidermal growth factor receptor (EGFR), Wnt/ß-catenin, Notch, transforming growth factor-ß (TGF-ß)/TGF-ßR receptors and/or stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) can play critical functions for high self-renewal potential, survival, invasion and metastases of cancer stem/progenitor cells and their progenies. It has also been observed that cancer cells may be reprogrammed to re-express different pluripotency-associated stem cell-like markers such as Myc, Oct-3/4, Nanog and Sox-2 along the EMT process and under stressful and hypoxic conditions. Moreover, the enhanced expression and/or activities of some drug resistance-associated molecules such as Bcl-2, Akt/molecular target of rapamycin (mTOR), nuclear factor-kappaB (NF-κB), hypoxia-inducible factors (HIFs), macrophage inhibitory cytokine-1 (MIC-1) and ATP-binding cassette (ABC) multidrug transporters frequently occur in cancer cells during cancer progression and metastases. These molecular events may cooperate for the survival and acquisition of a more aggressive and migratory behavior by cancer stem/progenitor cells and their progenies during cancer transition to metastatic and recurrent disease states. Of therapeutic interest, these altered gene products may also be exploited as molecular biomarkers and therapeutic targets to develop novel multitargeted strategies for improving current cancer therapies and preventing disease relapse.

Emergence of zebrafish models in oncology for validating novel anticancer drug targets and nanomaterials.

The in vivo zebrafish models have recently attracted great attention in molecular oncology to investigate multiple genetic alterations associated with the development of human cancers and validate novel anticancer drug targets. Particularly, the transparent zebrafish models can be used as a xenotransplantation system to rapidly assess the tumorigenicity and metastatic behavior of cancer stem and/or progenitor cells and their progenies. Moreover, the zebrafish models have emerged as powerful tools for an in vivo testing of novel anticancer agents and nanomaterials for counteracting tumor formation and metastases and improving the efficacy of current radiation and chemotherapeutic treatments against aggressive, metastatic and lethal cancers.