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Combined Inactivation of pRB and Hippo Pathways Induces Dedifferentiation in the Drosophila Retina  [PDF]
Brandon N. Nicolay,Battuya Bayarmagnai,Nam Sung Moon,Elizaveta V. Benevolenskaya,Maxim V. Frolov
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000918
Abstract: Functional inactivation of the Retinoblastoma (pRB) pathway is an early and obligatory event in tumorigenesis. The importance of pRB is usually explained by its ability to promote cell cycle exit. Here, we demonstrate that, independently of cell cycle exit control, in cooperation with the Hippo tumor suppressor pathway, pRB functions to maintain the terminally differentiated state. We show that mutations in the Hippo signaling pathway, wts or hpo, trigger widespread dedifferentiation of rbf mutant cells in the Drosophila eye. Initially, rbf wts or rbf hpo double mutant cells are morphologically indistinguishable from their wild-type counterparts as they properly differentiate into photoreceptors, form axonal projections, and express late neuronal markers. However, the double mutant cells cannot maintain their neuronal identity, dedifferentiate, and thus become uncommitted eye specific cells. Surprisingly, this dedifferentiation is fully independent of cell cycle exit defects and occurs even when inappropriate proliferation is fully blocked by a de2f1 mutation. Thus, our results reveal the novel involvement of the pRB pathway during the maintenance of a differentiated state and suggest that terminally differentiated Rb mutant cells are intrinsically prone to dedifferentiation, can be converted to progenitor cells, and thus contribute to cancer advancement.
Alcohol Interacts with Genetic Alteration of the Hippo Tumor Suppressor Pathway to Modulate Tissue Growth in Drosophila  [PDF]
Anoj Ilanges, Maryam Jahanshahi, Denis M. Balobin, Cathie M. Pfleger
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078880
Abstract: Alcohol-mediated cancers represent more than 3.5% of cancer-related deaths, yet how alcohol promotes cancer is a major open question. Using Drosophila, we identified novel interactions between dietary ethanol and loss of tumor suppressor components of the Hippo Pathway. The Hippo Pathway suppresses tumors in flies and mammals by inactivating transcriptional co-activator Yorkie, and the spectrum of cancers associated with impaired Hippo signaling overlaps strikingly with those associated with alcohol. Therefore, our findings may implicate loss of Hippo Pathway tumor suppression in alcohol-mediated cancers. Ethanol enhanced overgrowth from loss of the expanded, hippo, or warts tumor suppressors but, surprisingly, not from over-expressing the yorkie oncogene. We propose that in parallel to Yorkie-dependent overgrowth, impairing Hippo signaling in the presence of alcohol may promote overgrowth via additional alcohol-relevant targets. We also identified interactions between alcohol and Hippo Pathway over-activation. We propose that exceeding certain thresholds of alcohol exposure activates Hippo signaling to maintain proper growth control and prevent alcohol-mediated mis-patterning and tissue overgrowth.
Genomic profiling of tumor initiating prostatospheres
Maria Duhagon, Elaine M Hurt, Jose R Sotelo-Silveira, Xiaohu Zhang, William L Farrar
BMC Genomics , 2010, DOI: 10.1186/1471-2164-11-324
Abstract: Traditional stem cell medium (SCM) supplemented with Knockout?SR (KO) allows the propagation of monoclonal PSs from cell lines and primary cells. PSs display gene expression and tumorigenicity hallmarks of TICs. Gene expression analysis defined a gene signature composed of 66 genes that characterize LNCaP and patient PSs. This set includes novel prostate TIC growth factors (NRP1, GDF1, JAG1), proteins implicated in cell adhesion and cytoskeletal maintenance, transcriptional regulators (MYCBP, MYBL1, ID1, ID3, FOS, ELF3, ELF4, KLF2, KLF5) and factors involved in protein biosynthesis and metabolism. Meta-analysis in Oncomine reveals that some of these genes correlate with prostate cancer status and/or progression. Reporter genes and inhibitors indicate that the Notch pathway contributes to prostatosphere growth.We have developed a model for the culture of PSs, and provide a genomic profile that support CSCs identity. This signature identifies novel markers and pathways that are predicted to correlate with prostate cancer evolution.There is overwhelming evidence supporting the concept that only a specific group of cells, among the cellular heterogeneity of a tumor, possesses self-renewal and multilineage differentiation potential and is, therefore, responsible for tumor development[1]. These cells, so called "tumor initiating cells" (TICs) or "cancer stem cells" (CSCs), have been documented in most circulating and solid tumors as well as in numerous established cancer cell lines[2]. The expression of adult stem cell surface markers (e.g. CD133, CD44, ESA) as well as the expression of specific embryonic stem cell genes (e.g. OCT3/4, NANOG, SOX2) is one of the hallmarks of the TIC [2]. TICs also display increased potential for anchorage-independent growth, capacity to form spheroids in vitro, and propensity to undergo epithelial-mesenchymal transition. Nevertheless, in the current paradigm, the gold standard property of a TIC is its ability to initiate and generate a tum
Kinetics of MDR Transport in Tumor-Initiating Cells  [PDF]
Vasilij Koshkin, Burton B. Yang, Sergey N. Krylov
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079222
Abstract: Multidrug resistance (MDR) driven by ABC (ATP binding cassette) membrane transporters is one of the major causes of treatment failure in human malignancy. MDR capacity is thought to be unevenly distributed among tumor cells, with higher capacity residing in tumor-initiating cells (TIC) (though opposite finding are occasionally reported). Functional evidence for enhanced MDR of TICs was previously provided using a “side population” assay. This assay estimates MDR capacity by a single parameter - cell’s ability to retain fluorescent MDR substrate, so that cells with high MDR capacity (“side population”) demonstrate low substrate retention. In the present work MDR in TICs was investigated in greater detail using a kinetic approach, which monitors MDR efflux from single cells. Analysis of kinetic traces obtained allowed for the estimation of both the velocity (Vmax) and affinity (KM) of MDR transport in single cells. In this way it was shown that activation of MDR in TICs occurs in two ways: through the increase of Vmax in one fraction of cells, and through decrease of KM in another fraction. In addition, kinetic data showed that heterogeneity of MDR parameters in TICs significantly exceeds that of bulk cells. Potential consequences of these findings for chemotherapy are discussed.
Markers of Tumor-Initiating Cells Predict Chemoresistance in Breast Cancer  [PDF]
Chang Gong,Herui Yao,Qiang Liu,Jingqi Chen,Junwei Shi,Fengxi Su,Erwei Song
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015630
Abstract: Evidence is lacking whether the number of breast tumor-initiating cells (BT-ICs) directly correlates with the sensitivity of breast tumors to chemotherapy. Here, we evaluated the association between proportion of BT-ICs and chemoresistance of the tumors.
Immunotherapies Towards Tumor Initiating Cells and Cancer Stem Cells
Prithi RajanRoopa Srinivasan
The Open Cancer Immunology Journal , 2008, DOI: 10.2174/1876401000801010001]
Abstract: Active immunotherapy of cancer is a promising treatment modality by inducing long lived tumor reactive immune effector cells. Several vaccine trials have indicated that its effectiveness is probably best when the tumor burden is low. An attractive population of cells to target by this approach may be tumor initiating cells (TICs). Recent research suggests that such types of cells may be precursors to cancer possibly giving rise to metastatic disease. Although more work is being done to characterize appropriate phenotypic and functional markers, this population of cells would make an ideal target for active immunotherapy in high risk patients, so as to achieve remission over much longer periods of time. This review gives an overview of the potential of immunotherapy and how it may target TICs as a potential treatment option for cancer patients.
Regulation of Ovarian Cancer Stem Cells or Tumor-Initiating Cells  [PDF]
Mi Jeong Kwon,Young Kee Shin
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms14046624
Abstract: Cancer stem cells or tumor-initiating cells (CSC/TICs), which can undergo self-renewal and differentiation, are thought to play critical roles in tumorigenesis, therapy resistance, tumor recurrence and metastasis. Tumor recurrence and chemoresistance are major causes of poor survival rates of ovarian cancer patients, which may be due in part to the existence of CSC/TICs. Therefore, elucidating the molecular mechanisms responsible for the ovarian CSC/TICs is required to develop a cure for this malignancy. Recent studies have indicated that the properties of CSC/TICs can be regulated by microRNAs, genes and signaling pathways which also function in normal stem cells. Moreover, emerging evidence suggests that the tumor microenvironments surrounding CSC/TICs are crucial for the maintenance of these cells. Similarly, efforts are now being made to unravel the mechanism involved in the regulation of ovarian CSC/TICs, although much work is still needed. This review considers recent advances in identifying the genes and pathways involved in the regulation of ovarian CSC/TICs. Furthermore, current approaches targeting ovarian CSC/TICs are described. Targeting both CSC/TICs and bulk tumor cells is suggested as a more effective approach to eliminating ovarian tumors. Better understanding of the regulation of ovarian CSC/TICs might facilitate the development of improved therapeutic strategies for recurrent ovarian cancer.
An inhibitor of K+ channels modulates human endometrial tumor-initiating cells
Brandon M Schickling, Nukhet Aykin-Burns, Kimberly K Leslie, Douglas R Spitz, Victoria P Korovkina
Cancer Cell International , 2011, DOI: 10.1186/1475-2867-11-25
Abstract: A non-selective antagonist of multiple types of K+ channels, tetraethylammonium (TEA), was found to suppress colony formation in endometrial cancer cells via inhibition of putative TIC. The data also indicated that withdrawal of TEA results in a significant enhancement of tumorigenesis. When the TIC-enriched subpopulation was isolated from the endometrial cancer cells, TEA was also found to inhibit growth in vitro.These studies suggest that the activity of potassium channels significantly contributes to the progression of endometrial tumors, and the antagonists of potassium channels are candidate anti-cancer drugs to specifically target tumor initiating cells in endometrial cancer therapy.Potassium (K+) ion channels are important contributors to the malignant phenotype in cancer cells and as such have been shown to drive progression of cancers of the breast, prostate, endometrium and brain [1-8]. Multiple mechanisms exist by which K+ channels exert their oncogenic functions. For example, K+ channels have been shown to modulate cell cycle progression to increase cell proliferation as well as promote cytoskeletal remodeling to enhance invasion and migration [9-21]. Inhibitors of K+ channels thus constitute putative anti-cancer drugs [1,2,22-26], though to date none of these antagonists have been explored in a clinical trial setting for any type of cancer.Novel developments in cancer research demonstrate that tumor initiating cells (TIC, also referred to as cancer stem cells) cause the onset and recurrence of cancers [27-29]. Several biological agents that aim to eradicate TIC are currently in phase I/II clinical trials, but a clinical need remains to identify other pharmacologic approaches to prevent TIC-mediated tumorigenesis.Interestingly, K+ channels genes have been shown to be amplified in cancers, but the roles of K+ channels in TIC and by extension in cancer progression have not been rigorously addressed. In this manuscript, we present novel observations that an
Residual Tumor Cells That Drive Disease Relapse after Chemotherapy Do Not Have Enhanced Tumor Initiating Capacity  [PDF]
Ganapati V. Hegde, Cecile de la Cruz, Jeffrey Eastham-Anderson, Yanyan Zheng, E. Alejandro Sweet-Cordero, Erica L. Jackson
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0045647
Abstract: Although chemotherapy is used to treat most advanced solid tumors, recurrent disease is still the major cause of cancer-related mortality. Cancer stem cells (CSCs) have been the focus of intense research in recent years because they provide a possible explanation for disease relapse. However, the precise role of CSCs in recurrent disease remains poorly understood and surprisingly little attention has been focused on studying the cells responsible for re-initiating tumor growth within the original host after chemotherapy treatment. We utilized both xenograft and genetically engineered mouse models of non-small cell lung cancer (NSCLC) to characterize the residual tumor cells that survive chemotherapy treatment and go on to cause tumor regrowth, which we refer to as tumor re-initiating cells (TRICs). We set out to determine whether TRICs display characteristics of CSCs, and whether assays used to define CSCs also provide an accurate readout of a cell’s ability to cause tumor recurrence. We did not find consistent enrichment of CSC marker positive cells or enhanced tumor initiating potential in TRICs. However, TRICs from all models do appear to be in EMT, a state that has been linked to chemoresistance in numerous types of cancer. Thus, the standard CSC assays may not accurately reflect a cell’s ability to drive disease recurrence.
Okadaic Acid: A Tool to Study the Hippo Pathway  [PDF]
Yutaka Hata,Shikshya Timalsina,Sainawaer Maimaiti
Marine Drugs , 2013, DOI: 10.3390/md11030896
Abstract: Mammalian Ste20-like kinases 1 and 2 (MST1 and MST2) are activated in NIH3T3 cells exposed to okadaic acid. The Hippo pathway is a newly emerging signaling that functions as a tumor suppressor. MST1 and MST2 work as core kinases of the Hippo pathway and their activities depend on the autophosphorylation, which is negatively regulated by protein phosphatase 2A (PP2A). Okadaic acid has been frequently used to enhance the phosphorylation of MST1 and MST2 and to trigger the activation of the Hippo pathway. However other components of the Hippo pathway could also be targets of okadaic acid. In this review we first briefly summarize the molecular architecture of the Hippo pathway for the reference of researchers outside the field. We explain how MST kinases are regulated by PP2A and how okadaic acid activates MST2. Thereafter we discuss which components of the Hippo pathway are candidate substrates of protein phosphatases and which points we need to consider in the usage of okadaic acid to study the Hippo pathway.
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