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 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genomic and proteomic profiling of human tumor samples and tumor-derived cell lines are essential for the realization of personalized therapy in oncology. Identification of the changes required for tumor initiation or maintenance will likely provide new targets for small-molecule and biological therapeutics. For example, inactivation of the p53 tumor suppressor pathway occurs in most human cancers. Although this can be due to frank p53 gene mutation, almost half of all cancers retain the wild-type p53 allele, indicating that the pathway is disabled by other means. Alternate mechanisms include deletion or epigenetic inactivation of the p53-positive regulator arf, methylation of the p53 promoter, or elevated expression of the p53 regulators Mdm2 and Mdmx. This review discusses current models of p53 regulation by Mdm2 and Mdmx and presents the rationale for design of future Mdmx-specific therapeutics based on our knowledge of its structure and biological functions.
Mol Cancer Res 2009 Jan
PMID:Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry? 1914 32

The tumor-suppressive role of p53 at the level of tumor initiation is well documented. It has also been shown previously that p53 acts against tumor progression/metastasis. However, its role in modulating cell migration and invasion leading to metastasis is poorly understood. In this study, using vascular smooth muscle cells and NIH 3T3 fibroblast cells, we have shown that p53 potently suppresses Src-induced podosome/rosette formation, extracellular matrix digestion, cell migration, and invasion. The overexpression of exogenous wild-type p53 or the activation of the endogenous p53 function suppresses, while the short hairpin RNA-mediated knockdown of p53 expression or the pageing of its function exacerbates, Src-induced migratory and invasive phenotypes. We have also found that p53 expression and function are downregulated in cells stably transformed with constitutively active Src that exhibit aggressive invasive properties. Lastly, p53 upregulates the expression of caldesmon, an actin-binding protein that has been shown to be an inhibitor of podosome/invadopodium formation. The ability of p53 to suppress Src phenotypes in transformed cells was largely abolished by knocking down caldesmon. This study reports a novel molecular mechanism (caldesmon), as well as a structural basis (podosomes/rosettes), to show how p53 can act as an anti-motility/invasion/metastasis agent.
Mol Cell Biol 2009 Jun
PMID:p53 suppresses Src-induced podosome and rosette formation and cellular invasiveness through the upregulation of caldesmon. 1934 2

Historically, it has been assumed that oxidative stress contributes to tumor initiation and progression solely by inducing genomic instability. Recent studies indicate that reactive oxygen species are upregulated in tumors and can lead to aberrant induction of signaling networks that cause tumorigenesis and metastasis. Here we review the role of redox-dependent signaling pathways and transcription factors that regulate tumorigenesis.
Cell Mol Life Sci 2009 Dec
PMID:Reactive oxygen species-dependent signaling regulates cancer. 1962 88

Cancer stem cells (CSC) represent a distinct subpopulation of cancer cells of integral importance. CSCs embody the refractory nature observed among many cancers: very competent initial tumor establishment and extremely aggressive metastatic nature. Recent discoveries indicate that CSCs embody chemo- and radioresistance and have been correlated with advanced disease and resistance to current therapies, and thus help explain the treatment resistance of many cancers. As CSCs are critical for tumor initiation, progression, persistence, and the development of metastasis, the success or failure of treatment approaches may be influenced greatly by the presence and treatment sensitivity of these cells. There also seems to be a direct link between epithelial-mesenchymal transition phenomena and CSCs. Cancer cure is predicated upon effectively targeting and eradicating the CSC population. Oncolytic viruses have undergone many developments and through multiple generations offer an effective way to specifically target and eradicate CSCs, while still maintaining the ability to affect the general tumor cell population. Conditionally replicative adenoviruses (CRAd) are one virotherapy that is especially promising. Multiple advanced targeting and infectivity enhancement schemes have been developed to allow the necessary specificity and transduction efficiency required for an effective therapy. Furthermore, these advanced generation CRAds can be armed with therapeutic transgenes to generate greater antitumor effects. Although ultimately, the rewards of targeting and eradicating CSCs will be evaluated in clinical trials, there are numerous methods for isolating primary CSCs based on surface marker expression and multiple established cell lines representative of CSCs for preliminary evaluation.
Mol Cancer Ther 2009 Aug
PMID:Oncolytic adenoviruses targeted to cancer stem cells. 1967 59

In this issue of Molecular Cell, Huang et al. (2009) demonstrate that hypoxia-inducible mir-210 acts as a rheostat for cellular adaptation and survival by inhibiting tumor initiation.
Mol Cell 2009 Sep 24
PMID:mir-210: a sensor for hypoxic stress during tumorigenesis. 1978 34

Cylindrospermopsin (CYN), a cyanotoxin produced by certain freshwater cyanobacteria, causes human intoxications and animal mortalities. CYN is a potent inhibitor of protein- and glutathione-synthesis. Preliminary evidence for in vivo tumor initiation has been found in mice but the mechanism remains unclear. Several in vitro and in vivo studies demonstrate that CYN is genotoxic and requires metabolic activation. In the present study, the genotoxicity of CYN was assessed in human hepatocyte and enterocyte cell lines, which are models for CYN target organs. The cytokinesis-block micronucleus assay was conducted on liver-derived HepaRG cells and colon-derived Caco-2 cells. Each cell-type was exposed to CYN in both the differentiated and the undifferentiated states, and both with and without the cytochrome P450 inhibitor, ketoconazole, to determine the involvement of metabolism in CYN genotoxicity. CYN increased the frequency of micronuclei in binucleated cells (MNBNC) in both Caco-2 and HepaRG cells. Moreover, ketoconazole reduced both the genotoxicity and cytotoxicity caused by CYN. Our results confirm the involvement of metabolic activation of CYN in mediating its toxicity and suggest that CYN is progenotoxic.
Environ Mol Mutagen 2010 Apr
PMID:Genotoxicity of a freshwater cyanotoxin, cylindrospermopsin, in two human cell lines: Caco-2 and HepaRG. 1990 17

Epidermal stem cells are of major importance for tissue homeostasis, wound repair, tumor initiation, and gene therapy. Here we describe an in vivo regeneration assay to test for the ability of keratinocyte progenitors to maintain an epidermis over the long-term in vivo. Limiting dilution analysis of epidermal repopulating units in this in vivo regeneration assay at sequential time points allows the frequency of short-term (transit amplifying cell) and long-term (stem cell) repopulating cells to be quantified.
Methods Mol Biol 2010
PMID:Limiting dilution analysis of murine epidermal stem cells using an in vivo regeneration assay. 1990 20

14-3-3 proteins regulate many cellular functions, including proliferation. However, the detailed mechanisms by which they control the cell cycle remain to be fully elucidated. We report that one of the 14-3-3 isoforms, 14-3-3tau, is required for the G(1)/S transition through its role in ubiquitin-independent proteasomal degradation of p21. 14-3-3tau binds to p21, MDM2, and the C8 subunit of the 20S proteasome in G(1) phase and facilitates proteasomal targeting of p21. This function of 14-3-3tau may be deregulated in cancer. The overexpression of 14-3-3tau is frequently found in primary human breast cancer and correlates with lower levels of p21 and shorter patient survival. Tenascin-C, an extracellular matrix protein involved in tumor initiation and progression and a known 14-3-3tau inducer, decreases p21 and abrogates adriamycin-induced G(1)/S arrest. It has been known that p21 is required for a proper tamoxifen response in breast cancer. We show that the overexpression of 14-3-3tau inhibits tamoxifen-induced p21 induction and growth arrest in MCF7 cells. Together, the findings of our studies strongly suggest a novel oncogenic role of 14-3-3tau by downregulating p21 in breast cancer. Therefore, 14-3-3tau may be a potential therapeutic target in breast cancer.
Mol Cell Biol 2010 Mar
PMID:14-3-3Tau regulates ubiquitin-independent proteasomal degradation of p21, a novel mechanism of p21 downregulation in breast cancer. 2008 99

Anoikis is a mode of apoptotic cell death, consequential to insufficient cell-matrix interactions and a critical player in tumor angiogenesis and metastasis. The events involved in tumor cell progression toward metastasis potential are mediated by integrins, which upon engagement with components of the extracellular matrix (ECM), reorganize to form adhesion complexes. Targeting apoptotic players is of immense therapeutic significance since resistance to apoptosis is not only critical in conferring therapeutic failure to standard treatment strategies, but anoikis (apoptosis upon loss of anchorage and detachment from ECM) also plays an important role in angiogenesis and metastasis. The ability to survive in the absence of adhesion to the ECM, enables tumor cells to disseminate from the primary tumor site, invade a distant site and establish a metastatic lesion. Tumor cells can escape from detachment-induced apoptosis by controlling anoikis pathways, including the extrinsic death receptor pathway and the ECM-integrin mediated cell survival pathway. Considering the functional promiscuity of individual signaling effectors, it is critical to dissect the molecular networks mechanistically driving tumor cells to evade anoikis and embark on a metastatic spread. Resistance to die via anoikis dictates tumor cell survival and provides a molecular basis for therapeutic targeting of metastatic prostate cancer. Further dissection of critical anoikis signaling events will enable the therapeutic optimization of anoikis targeting to impair prostate cancer metastasis prior to its initiation. This review will discuss the molecular understanding of anoikis regulation in the tumor microenvironment and the in vivo pharmacological implementation of a novel class of antitumor-drugs to optimize apoptotic-based therapeutic targeting, bypassing anoikis-resistance to impair prostate cancer progression to metastasis. Potential combination strategies targeting tumor vascularity (via anoikis) and impairing tumor initiation (via "classic" apoptosis), provide strong therapeutic promise for metastatic prostate cancer by preventing the onset of metastasis.
Mol Aspects Med 2010 Apr
PMID:Targeting anoikis resistance in prostate cancer metastasis. 2015 62

Alterations in TGFbeta signaling are common in human cancers. TGFbeta has significant impact on tumor initiation and progression. Therapeutic strategies including neutralizing antibodies and small molecular inhibitors have been developed to target TGFbeta signaling. However, TGFbeta can work as both a tumor suppressor and a tumor promoter. A significant challenge to the development of successful TGFbeta antagonism treatment is understanding how and when TGFbeta switches its function from a tumor suppressor to a tumor promoter. Recent studies demonstrate that TGFbeta regulates the infiltration of inflammatory cells and cancer associated fibroblasts into the tumor microenvironment, resulting in changes in signaling cascade in tumor cells. Additionally, TGFbeta exerts systemic immune suppression and significantly inhibits host tumor immune surveillance. Neutralizing TGFbeta in preclinical mouse models enhances CD8+ T-cell and natural killer cell-mediated anti-tumor immune response. This new understanding of TGFbeta signaling in regulation of tumor microenvironment and immune response may provide useful information, particularly for patient selection and inflammation/immune biomarkers for TGFbeta antagonism therapy in clinical trials.
Curr Mol Med 2010 Jun
PMID:TGFbeta, a potent regulator of tumor microenvironment and host immune response, implication for therapy. 2045 54


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