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.

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.

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/β-catenin, Notch, transforming growth factor-β (TGF-β)/TGF-βR 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.

Development of animal models underlining mechanistic connections between prostate inflammation and cancer.

The characterization of animal models has indicated that the genetic, dietary and environmental factors and hormonal imbalance may influence the risk to develop prostate inflammatory lesions and prostate cancer (PC) confirming human epidemiologic data. It is now established that the prostate inflammatory response typically results in major changes in the local microenvironment of epithelial cells of the prostate gland, including an intense stromal remodeling, activation of fibroblasts, infiltration of immune cells such as mast cells, macrophages and B and T lymphocytes and collagen deposition. The immune cells recruited at prostate inflammatory lesions and myofibroblasts may contribute to the release of numerous pro-inflammatory cytokines and chemokines that in turn can promote the oxidative stress, genomic instability and proliferation of epithelial cells.

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-β receptors (TGF-βRs) 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.

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.

Adsorption study of a commonly used antidepressant drug, fluoxetine hydrochloride, onto a crosslinked β-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 β-cyclodextrin-carboxymethylcellulose (β-CD-CMC) polymer. The adsorption was performed in mixtures containing aqueous FLU solution at 20 mg/L and 0.01-0.

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.

Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas.

Cutaneous malignant melanoma is the most aggressive form of skin cancer with an extremely poor survival rate for the patients diagnosed with locally invasive and metastatic disease states. Intensive research has led in last few years to an improvement of the early detection and curative treatment of primary cutaneous melanomas that are confined to the skin by tumor surgical resection. However, locally advanced and disseminated melanomas are generally resistant to conventional treatments, including ionizing radiation, systemic chemotherapy, immunotherapy and/or adjuvant stem cell-based therapies, and result in the death of patients.

Pathobiological implications of the expression of EGFR, pAkt, NF-κB and MIC-1 in prostate cancer stem cells and their progenies.

The progression of prostate cancers (PCs) to locally invasive, androgen-independent and metastatic disease states is generally associated with treatment resistance and disease relapse. The present study was undertaken to establish the possibility of using a combination of specific oncogenic products, including epidermal growth factor receptor (EGFR), pAkt, nuclear factor-kappaB (NF-κB) and macrophage inhibitory cytokine-1 (MIC-1) as biomarkers and therapeutic targets for optimizing the management of patients with localized PC at earlier disease stages. The immunohistochemical and immunofluorescence data have revealed that the expression levels of EGFR, Ser(473)-pAkt, NF-κB p65 and MIC-1 proteins were significantly enhanced in the same subset of 76 cases of prostatic adenocarcinoma specimens during the disease progression and these biomarkers were expressed in a small subpopulation of CD133(+) PC cells and the bulk tumor mass of CD133(-) PC cells.

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.

Potential applications of curcumin and its novel synthetic analogs and nanotechnology-based formulations in cancer prevention and therapy.

Curcumin has attracted great attention in the therapeutic arsenal in clinical oncology due to its chemopreventive, antitumoral, radiosensibilizing and chemosensibilizing activities against various types of aggressive and recurrent cancers. These malignancies include leukemias, lymphomas, multiple myeloma, brain cancer, melanoma and skin, lung, prostate, breast, ovarian, liver, gastrointestinal, pancreatic and colorectal epithelial cancers. Curcumin mediates its anti-proliferative, anti-invasive and apoptotic effects on cancer cells, including cancer stem/progenitor cells and their progenies, through multiple molecular mechanisms.

Complex oncogenic signaling networks regulate brain tumor-initiating cells and their progenies: pivotal roles of wild-type EGFR, EGFRvIII mutant and hedgehog cascades and novel multitargeted therapies.

Complex signaling cross-talks between different growth factor cascades orchestrate the primary brain cancer development. Among the frequent deregulated oncogenic pathways, the ligand-activated wild-type epidermal growth factor receptor (EGFR), constitutively activated EGFRvIII mutant and sonic hedgehog pathways have attracted much attention because of their pivotal roles in pediatric medulloblastomas and adult glioblastoma multiformes (GBM) brain tumors. The enhanced expression levels and activation of EGFR, EGFRvIII mutant and hedgehog signaling elements can provide key roles for the sustained growth, migration and local invasion of brain tumor-initiating cells (BTICs) and their progenies, resistance to current therapies and disease relapse.

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/β-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.

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.

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.

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.

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.

New promising drug targets in cancer- and metastasis-initiating cells.

The unique properties of cancer- and metastasis-initiating cells endowed with a high self-renewal and aberrant differentiation potential (including their elevated expression levels of anti-apoptotic factors, multidrug transporters, and DNA repair and detoxifying enzymes) might be associated with their resistance to current clinical cancer therapies and disease recurrence. The eradication of cancer- and metastasis-initiating cells by molecular targeting of distinct deregulated signaling elements that might contribute to their sustained growth, survival, and treatment resistance, therefore, is of immense therapeutic interest. These novel targeted approaches should improve the efficacy of current therapeutic treatments against highly aggressive, metastatic, recurrent, and lethal cancers.

MUC4 down-regulation reverses chemoresistance of pancreatic cancer stem/progenitor cells and their progenies.

The present study was undertaken to estimate the therapeutic benefit to down-regulate the MUC4 mucin for reversing chemoresistance of pancreatic cancer (PC) stem/progenitor cells and their progenies. The results have revealed that MUC4 mucin is overexpressed in CD133(+) and CD133(-) pancreatic cells (PCs) detected in patient's adenocarcinoma tissues while no significant expression was seen in normal pancreatic tissues. The gain- and loss-of-function analyses have indicated that the overexpression of MUC4 in PC lines is associated with a higher resistance to the anti-proliferative, anti-invasive and apoptotic effects induced by gemcitabine.

Novel therapies against aggressive and recurrent epithelial cancers by molecular targeting tumor- and metastasis-initiating cells and their progenies.

A growing body of experimental evidence has revealed that the highly tumorigenic cancer stem/progenitor cells endowed with stem cell-like properties might be responsible for initiation and progression of numerous aggressive epithelial cancers into locally invasive, metastatic and incurable disease states. The malignant transformation of tissue-resident adult stem/progenitor cells or their progenies into tumorigenic and migrating cancer stem/progenitor cells and their resistance to current cancer therapies have been associated with their high expression levels of specific oncogenic products and drug resistance-associated molecules. In this regard, we describe the tumorigenic cascades that are frequently activated in cancer stem/progenitor cells versus their differentiated progenies during the early and late stages of the epithelial cancer progression.

Cytotoxic effects induced by docetaxel, gefitinib, and cyclopamine on side population and nonside population cell fractions from human invasive prostate cancer cells.

The present study has been undertaken to establish the therapeutic benefit of cotargeting epidermal growth factor receptor (EGFR) and sonic hedgehog pathways by using gefitinib and cyclopamine, respectively, for improving the efficacy of the current chemotherapeutic drug docetaxel to counteract the prostate cancer progression from locally invasive to metastatic and recurrent disease stages. The data from immuofluorescence analyses revealed that EGFR/Tyr(1173)-pEGFR, sonic hedgehog ligand, smoothened coreceptor, and GLI-1 were colocalized with the CD133(+) stem cell-like marker in a small subpopulation of prostate cancer cells. These signaling molecules were also present in the bulk tumor mass of CD133(-) prostate cancer cells with a luminal phenotype detected in patient's adenocarcinoma tissues.

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.

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.