Self-renewal Pathways Research Articles

85 NEUROMUSCULAR EXERCISE IMPROVES FUNCTIONAL PERFORMANCE IN PATIENTS WITH SEVERE HIP OSTEOARTHRHIS

detected in chondrogenic pellets and secreted by the differentiating MSCs. Finally, high levels of IL16 were detected in osteoarthritic cartilage. Conclusions: We hypothesise that differentiation of MSCs initially involves hypermethylation to facilitate the rapid down regulatation of genes involved in self-renewal or alternative differentiation pathways. Epigenetic mechanisms also represent an important aspect of control to ensure the sequential and temporal expression of critical genes throughout the differentiation process. IL16, previously associated with synovial fibroblasts from rheumatoid joints was identified as a novel factor in chondrogenesis.

Mechanisms of Hedgehog signalling in cancer

The Hedgehog (Hh) pathway is a conserved signalling system essential for embryonic development and for the maintenance of self-renewal pathways in progenitor cells. Mutations that deregulate Hh signalling are directly implicated in basal cell carcinoma and medulloblastoma. The mechanisms of Hh pathway activation in cancers in which no pathway mutations have been identified are less clear, but of great translational significance. Small molecule inhibitors of the pathway, many of which are in early phase clinical trials, may shed further light on this question. Canonical Hh signalling promotes the expression of target genes through the Glioma-associated oncogene (GLI) transcription factors. There is now increasing evidence suggesting that ‘non-canonical’ Hh signalling mechanisms, some of which are independent of GLI-mediated transcription, may be important in cancer and development. The focus of this review is to summarise some of the known mechanisms of Hh signalling as well as its emerging role in cancer.

Introduction of SV40ER and hTERT into mammospheres generates breast cancer cells with stem cell properties

Emerging evidence suggests that cancers arise in stem/progenitor cells. Yet, the requirements for transformation of these primitive cells remains poorly understood. In this study, we have exploited the 'mammosphere' system that selects for primitive mammary stem/progenitor cells to explore their potential and requirements for transformation. Introduction of Simian Virus 40 Early Region and hTERT into mammosphere-derived cells led to the generation of NBLE, an immortalized mammary epithelial cell line. The NBLEs largely comprised of bi-potent progenitors with long-term self-renewal and multi-lineage differentiation potential. Clonal and karyotype analyses revealed the existence of heterogeneous population within NBLEs with varied proliferation, differentiation and sphere-forming potential. Significantly, injection of NBLEs into immunocompromised mice resulted in the generation of invasive ductal adenocarcinomas. Further, these cells harbored a sub-population of CD44(+)/CD24(-) fraction that alone had sphere- and tumor-initiating potential and resembled the breast cancer stem cell gene signature. Interestingly, prolonged in vitro culturing led to their further enrichment. The NBLE cells also showed increased expression of stemness and epithelial to mesenchymal transition markers, deregulated self-renewal pathways, activated DNA-damage response and cancer-associated chromosomal aberrations-all of which are likely to have contributed to their tumorigenic transformation. Thus, unlike previous in vitro transformation studies that used adherent, more differentiated human mammary epithelial cells our study demonstrates that the mammosphere-derived, less-differentiated cells undergo tumorigenic conversion with only two genetic elements, without requiring oncogenic Ras. Moreover, the striking phenotypic and molecular resemblance of the NBLE-generated tumors with naturally arising breast adenocarcinomas supports the notion of a primitive breast cell as the origin for this subtype of breast cancer. Finally, the NBLEs represent a heterogeneous population of cells with striking plasticity, capable of differentiation, self-renewal and tumorigenicity, thus offering a unique model system to study the molecular mechanisms involved with these processes.

A Cross-Species Analysis of a Mouse Model of Breast Cancer-Specific Osteolysis and Human Bone Metastases Using Gene Expression Profiling

BackgroundBreast cancer is the second leading cause of cancer-related death in women in the United States. During the advanced stages of disease, many breast cancer patients suffer from bone metastasis. These metastases are predominantly osteolytic and develop when tumor cells interact with bone. In vivo models that mimic the breast cancer-specific osteolytic bone microenvironment are limited. Previously, we developed a mouse model of tumor-bone interaction in which three mouse breast cancer cell lines were implanted onto the calvaria. Analysis of tumors from this model revealed that they exhibited strong bone resorption, induction of osteoclasts and intracranial penetration at the tumor bone (TB)-interface.MethodsIn this study, we identified and used a TB microenvironment-specific gene expression signature from this model to extend our understanding of the metastatic bone microenvironment in human disease and to predict potential therapeutic targets.ResultsWe identified a TB signature consisting of 934 genes that were commonly (among our 3 cell lines) and specifically (as compared to tumor-alone area within the bone microenvironment) up- and down-regulated >2-fold at the TB interface in our mouse osteolytic model. By comparing the TB signature with gene expression profiles from human breast metastases and an in vitro osteoclast model, we demonstrate that our model mimics both the human breast cancer bone microenvironment and osteoclastogenesis. Furthermore, we observed enrichment in various signaling pathways specific to the TB interface; that is, TGF-β and myeloid self-renewal pathways were activated and the Wnt pathway was inactivated. Lastly, we used the TB-signature to predict cyclopenthiazide as a potential inhibitor of the TB interface.ConclusionOur mouse breast cancer model morphologically and genetically resembles the osteoclastic bone microenvironment observed in human disease. Characterization of the gene expression signature specific to the TB interface in our model revealed signaling mechanisms operative in human breast cancer metastases and predicted a therapeutic inhibitor of cancer-mediated osteolysis.

The promotion of stemness and pluripotency following feeder-free culture of embryonic stem cells on collagen-grafted 3-dimensional nanofibrous scaffold

The components of extracellular matrix (ECM) may substitute for feeder layers that promote the self-renewal pathways in embryonic stem cells. Surface modification of electrospun nanofibrous scaffolds have been studied to closely resemble natural ECMs and support in vitro and in vivo proliferation, pluripotency and differentiation of stem cells. In this study, we analyzed the maintenance of stemness and pluripotency of the mouse embryonic stem cell (mESC) following feeder-free culture on collagen-grafted polyethersulfone (PES-COL) electrospun nanofibrous scaffold. Our results showed that, the mESCs cultured for seven passages on PES-COL scaffolds had a typical undifferentiated morphology, enhanced proliferation, stable diploid normal karyotype, and continued expression of stemness and pluripotency-associated markers, Oct-4, Nanog, SSEA-1, and Alkaline phosphatase (ALP) in comparison with PES scaffolds and gelatin-coated plate. Moreover, these cells retained their in vitro and in vivo pluripotency. Our results indicated the enhanced infiltration and teratoma formation of mESCs in PES-COL. Collagen-grafted polyethersulfone nanofibrous scaffold has potential for feeder-free culture of pluripotent stem cells because of its 3-dimensional structure and bioactivity which enhance pluripotency, proliferation, differentiation, and infiltration of embryonic stem cells.

L-Threonine Regulates G1/S Phase Transition of Mouse Embryonic Stem Cells via PI3K/Akt, MAPKs, and mTORC Pathways

Although amino acids can function as signaling molecules in the regulation of many cellular processes, mechanisms surrounding L-threonine involvement in embryonic stem cell (ESC) functions have not been explored. Thus, we investigated the effect of L-threonine on regulation of mouse (m)ESC self-renewal and related signaling pathways. In L-threonine-depleted mESC culture media mRNA of self-renewal marker genes, [(3)H]thymidine incorporation, expression of c-Myc, Oct4, and cyclins protein was attenuated. In addition, resupplying L-threonine (500 μM) after depletion restores/maintains the mESC proliferation. Disruption of the lipid raft/caveolae microdomain through treatment with methyl-β-cyclodextrin or transfection with caveolin-1 specific small interfering RNA blocked L-threonine-induced proliferation of mESCs. Addition of L-threonine induced phosphorylation of Akt, ERK, p38, JNK/SAPK, and mTOR in a time-dependent manner. This activity was blocked by LY 294002 (PI3K inhibitor), wortmannin (PI3K inhibitor), or an Akt inhibitor. L-threonine-induced activation of mTOR, p70S6K, and 4E-BP1 as well as cyclins and Oct4 were blocked by PD 98059 (ERK inhibitor), SB 203580 (p38 inhibitor) or SP 600125 (JNK inhibitor). Furthermore, L-threonine induced phosphorylation of raptor and rictor binding to mTOR was completely inhibited by 24 h treatment with rapamycin (mTOR inhibitor); however, a 10 min treatment with rapamycin only partially inhibited rictor phosphorylation. L-threonine induced translocation of rictor from the membrane to the cytosol/nuclear, which blocked by pretreatment with rapamycin. In addition, rapamycin blocked L-threonine-induced increases in mRNA expressions of trophoectoderm and mesoderm marker genes and mESC proliferation. In conclusion, L-threonine stimulated ESC G(1)/S transition through lipid raft/caveolae-dependent PI3K/Akt, MAPKs, mTOR, p70S6K, and 4E-BP1 signaling pathways.

Head neck squamous cell carcinoma c‐Met+ cells display cancer stem cell properties and are responsible for cisplatin‐resistance and metastasis

c-Met, the tyrosine kinase receptor for hepatocyte growth factor, is overexpressed in a variety of tumors in which it plays a central role in malignant transformation. Although c-Met has also been determined to be a critical signaling molecule in normal stem cell function, the potential role of c-Met as a single marker for cancer stem cells (CSCs) has not been previously examined. In our study, we reported that human head neck squamous cell carcinoma (HNSCC) cells expressing c-Met were capable of self-renewal and of generating tumors that recapitulate the heterogeneity of the parental tumors, and isolation of HNSCC cells using a second marker CD44 could further enhance upon the in-vivo tumorigenicity. We also reported that c-Met(+) HNSCC cells could readily make spherical colonies in nonadherent culture conditions, in contrast, c-Met(-) population did not; these spherical colonies could be passaged multiple times without loss of colony-forming capability. Furthermore, we showed that c-Met(+) HNSCC cells have increased expression of self-renewal pathways are spared by cisplatin treatment and are responsible for mediating metastasis. These results indicated that c-Met could serve as a novel marker for CSCs at least in HNSCC, and the highly chemoresistant and metastatic capabilities of c-Met(+) HNSCC population make them an important cell type to better define and understand their function.

Common and Overlapping Oncogenic Pathways Contribute to the Evolution of Acute Myeloid Leukemias

Fusion oncogenes in acute myeloid leukemia (AML) promote self-renewal from committed progenitors, thereby linking transformation and self-renewal pathways. Like most cancers, AML is a genetically and biologically heterogeneous disease, but it is unclear whether transformation results from common or overlapping genetic programs acting downstream of multiple mutations or by the engagement of unique genetic programs acting cooperatively downstream of individual mutations. This distinction is important, because the involvement of common programs would imply the existence of common molecular targets to treat AML, no matter which oncogenes are involved. Here we show that the ability to promote self-renewal is a generalized property of leukemia-associated oncogenes. Disparate oncogenes initiated overlapping transformation and self-renewal gene expression programs, the common elements of which were defined in established leukemic stem cells from an animal model as well as from a large cohort of patients with differing AML subtypes, where they strongly predicted pathobiological character. Notably, individual genes commonly activated in these programs could partially phenocopy the self-renewal function of leukemia-associated oncogenes in committed murine progenitors. Furthermore, they could generate AML following expression in murine bone marrow. In summary, our findings reveal the operation of common programs of self-renewal and transformation downstream of leukemia-associated oncogenes, suggesting that mechanistically common therapeutic approaches to AML are likely to be possible, regardless of the identity of the driver oncogene involved.

Abstract LB-35: ETV6-NTRK3 basal-like breast cancers originating from Wap+ breast cells progress through a premalignant stage enriched in luminal progenitors

Abstract Breast cancer will affect one in nine women. ∼10% of breast cancer cases are hereditary, often caused by mutations in tumor suppressors (e.g., BRCA1 and 2). However, the majority of breast cancers are sporadic. Mechanisms of oncogenesis in sporadic breast cancers remain largely unknown, in part due to their cytogenetic complexity. Thus, model systems are needed to define key events leading to their formation. To address this, we previously generated a novel mouse model of human breast cancer based on a spontaneously acquired chromosomal translocation [t(12;15) ETV6-NTRK3 (EN) translocation] uniquely found in human secretory breast carcinoma, a type of basal-like breast cancer. The model is designed to initiate breast cancer from Wap+ (whey acidic protein promoter) cells in virgin mammary glands (MGs) by conditionally expressing the EN fusion oncoprotein from the endogenous Etv6 locus, using the Cre-lox approach. A unique feature of this model is that by including a conditional Cre-reporter (Rosa26-Stop-YFP), we can genetically mark affected cells by YFP when we turn on EN to initiate tumorigenesis. This allows us to track progression of the YFP-marked cells from their normal state to malignancy. We characterized these YFP+ cells at different stages by FACS analysis and by microarray expression profiling (of sorted YFP+ cells), followed by a cross-species comparison with published expression signatures of different subpopulations of cells sorted from normal human breast. We found that most normal Wap+ YFP+ cells in virgin MGs (i.e., normal target cells, <1% of total mammary cells) are CD24hi CD29med Sca-1- CD61+/− cells, whereas most YFP+ premalignant cells are CD24hi CD29med Sca-1low CD61+ cells. Furthermore, we found that at the molecular level, normal Wap+ YFP+ cells resemble human CD49f+ EpCAM− basal breast cells, whereas YFP+ premalignant cells resemble human CD49f+ EpCAM+ luminal progenitors. Thus, during cancer progression, there appears to be a phenotypic switch from basal-like Wap+ normal cells to luminal progenitors-like premalignant cells, and eventually to basal-like breast cancer cells. The YFP+ premalignant cells exhibit relaxed cell cycle control, upregulate genes related to DNA double-strand break repair (DSBR), and downregulate cell adhesion molecules. In sorted EN basal-like tumor cells, key DSBR genes are downregulated, suggesting this may represent a rate-limiting step in tumor progression. In addition, we found multiple stem cell-related pathways are initially active in normal Wap+ cells, while they are downregulated in YFP+ premalignant cells. Intriguingly, some of these pathways (e.g., hedgehog signaling) appear to be reactivated in (or acquired by) EN tumor cells. We hypothesize that such pathways may represent important self-renewal pathways required by cancer cells in order to progress from the premalignant stage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-35. doi:10.1158/1538-7445.AM2011-LB-35

Abstract 974: A selective Notch1 mAb targets leukemia progenitor cells in T-ALL

Abstract Introduction: Difficulties in maintaining primary cultures of leukemia cells hampered efforts to investigate the biology of human T cell acute lymphoblastic leukemia (T-ALL) underscoring the need for a direct transplantation model to characterize leukemia progenitor cells (LPC) in vivo and as a paradigm for screening candidate drugs that inhibit self-renewal pathways active in T-ALL. Approximately, 50% of patients with T-ALL harbor NOTCH1 activating mutations that promote therapeutic resistance providing the impetus for developing selective NOTCH1-inhibitory therapeutic strategies. To investigate 1) whether a select subclone of T-ALL cells harbor a greater capacity to propagate disease in vivo than other clones, 2) to establish a humanized T-ALL LPC mouse model and 3) to test whether a selective NOTCH1-NRR/Fc (hN1) mAb inhibits LPC survival and self-renewal. Experimental Procedures: To facilitate non-invasive in vivo monitoring of leukemic engraftment, lentiviral luciferase transduced LPC were intrahepatically transplanted into neonatal immune deficient mice to establish humanized T-ALL LPC mouse models. These models were treated with hN1 mAb or a control IgG1 mAb at the dose of 10 mg/kg every 4 days for 21 days, and another group was treated with mouse IgG1 isotype control at the same dosing plan. Mice were sacrificed one day after the last dose. Thymus, spleen, liver and bone marrow (BM) were collected and analyzed by FACS. Some BM were sectioned for CD45, NOTCH1 and active Caspase 3 examination by immunohistochemistry. Results: Human CD34+ enriched cells maintained leukemic engraftment while an equivalent number of Lin+ cells did not. T-ALL CD34+ progenitors from 32 T-ALL LPC models established with NOTCH1 mutated T-ALL have a significant higher engraftment in BM when compared with those from 14 T-ALL LPC models established with Non-NOTCH1 mutated T-ALL. Human CD45+CD34+CD2+ population in serial transplant recipients was more prominent in NOTCH1 mutated samples. Human CD34+ populations were significantly reduced in both BM (p < 0.01, Student t test) and spleen (p < 0.05, Student t test) when the T-ALL LPC treated with hN1 mAb, while CD45+ populations were also significantly reduced in both BM and spleen (p < 0.05, Student t test). NOTCH1 expression level in human CD34+ cells in NOTCH1 mutated T-ALL was markedly reduced after hN1 mAb treatment when compared with IgG1 mAb treatment. NOTCH1 and CD45 positive cells were significantly reduced, while apoptosis was remarkably increased in the BM treated with therapeutic hN1 mAb when compared with those treated with IgG1 mAb. Intracellular domain of Notch1 was significantly reduced in the BM treated with hN1 mAb when compared with those treated with IgG1 mAb. Conclusions: 1. Human T-ALL LPC have enhanced NOTCH1 expression. 2. Human self-renewing T-ALL LPC are enriched in the CD45+CD34+CD2+ population. 3. A selective hN1 mAb inhibits human T-ALL LPC survival and self-renewal in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 974. doi:10.1158/1538-7445.AM2011-974

Breast Cancer-Initiating Cells: Insights into Novel Treatment Strategies

There is accumulating evidence that breast cancer may arise from mutated mammary stem/progenitor cells which have been termed breast cancer-initiating cells (BCIC). BCIC identified in clinical specimens based on membrane phenotype (CD44+/CD24−/low and/or CD133+ expression) or enzymatic activity of aldehyde dehydrogenase 1 (ALDH1+), have been demonstrated to have stem/progenitor cell properties, and are tumorigenic when injected in immunocompromized mice at very low concentrations. BCIC have also been isolated and in vitro propagated as non-adherent spheres of undifferentiated cells, and stem cell patterns have been recognized even in cancer cell lines. Recent findings indicate that aberrant regulation of self renewal is central to cancer stem cell biology. Alterations in genes involved in self-renewal pathways, such as Wnt, Notch, sonic hedgehog, PTEN and BMI, proved to play a role in breast cancer progression. Hence, targeting key elements mediating the self renewal of BCIC represents an attractive option, with a solid rationale, clearly identifiable molecular targets, and adequate knowledge of the involved pathways. Possible concerns are related to the poor knowledge of tolerance and efficacy of inhibiting self-renewal mechanisms, because the latter are key pathways for a variety of biological functions and it is unknown whether their interference would kill BCIC or simply temporarily stop them. Thus, efforts to develop BCIC-targeted therapies should not only be focused on interfering on self-renewal, but could seek to identify additional molecular targets, like those involved in regulating EMT-related pathways, in reversing the MDR phenotype, in inducing differentiation and controlling cell survival pathways.

The Function of E-Cadherin in Stem Cell Pluripotency and Self-Renewal

Embryonic stem (ES) and induced-pluripotent stem (iPS) cells can be grown indefinitely under appropriate conditions whilst retaining the ability to differentiate to cells representative of the three primary germ layers. Such cells have the potential to revolutionize medicine by offering treatment options for a wide range of diseases and disorders as well as providing a model system for elucidating mechanisms involved in development and disease. In recent years, evidence for the function of E-cadherin in regulating pluripotent and self-renewal signaling pathways in ES and iPS cells has emerged. In this review, we discuss the function of E-cadherin and its interacting partners in the context of development and disease. We then describe relevant literature highlighting the function of E-cadherin in establishing and maintaining pluripotent and self-renewal properties of ES and iPS cells. In addition, we present experimental data demonstrating that exposure of human ES cells to the E-cadherin neutralizing antibody SHE78.7 allows culture of these cells in the absence of FGF2-supplemented medium.

Cancer stem cells and cancer therapy

Cancer stem cells (CSCs) are a subpopulation of tumour cells that possess the stem cell properties of self-renewal and differentiation. Stem cells might be the target cells responsible for malignant transformation, and tumour formation may be a disorder of stem cell self-renewal pathway. Epigenetic alterations and mutations of genes involved in signal transmissions may promote the formation of CSCs. These cells have been identified in many solid tumours including breast, brain, lung, prostate, testis, ovary, colon, skin, liver, and also in acute myeloid leukaemia. The CSC theory clarifies not only the issue of tumour initiation, development, metastasis and relapse, but also the ineffectiveness of conventional cancer therapies. Treatments directed against the bulk of the cancer cells may produce striking responses but they are unlikely to result in long-term remissions if the rare CSCs are not targeted. In this review, we consider the properties of CSCs and possible strategies for controlling the viability and tumourigenecity of these cells, including therapeutic models for selective elimination of CSCs and induction of their proper differentiation.

Cancer stem cells: perspectives of new therapeutical approaches for breast cancer

Currently stem cells are hypothesized to play a central role in the origin, spread and resistance to treatment of breast cancer. Common anticancer therapy is effective but transient, with tumor relapse and metastatic disease often occurring. For therapy to be more effective, debulking of differentiated tumors must occur followed by targeting of the remaining surviving often quiescent tumor stem cells. New therapeutics aimed at cancer stem cells are achieved through non immunological and immunological methods. The former include elective ABC drug transporters or the heat shock protein 90 inhibition, targeting the self-renewal signalling pathways or the EMT program, differentiation therapy, or other interventions to eliminate BrCSCs. The latter include targeting specific antigens expressed on BrCSCs, dendritic cells (DCs) based vaccination and blockers of the extrinsic signals at CSC niche. Here all these novel approaches related to breast cancer stem cells are described.

Vaccine Potentiality and Stem Cells Enhancing Cure to Cancer

Vaccine potentiality and stem cell therapy is the new development in curing the Cancer. There are different types of cancer and different curing methods are being discussed by different scientist. The new diagnostic methods using DNA vaccine, adjuvants and target oriented cells methods are used in a descriptive method. The stem cell therapy also enhancing in identifying the site of tumour regenesis and curing the tumour by inducing different target oriented cells like chemokines and interleukin (IL). Beside these mesenchymal stem cells also regenerates the new cell lines for new target oriented cells. Hence no doubt at molecular level, the alteration of stem cell self-renewal pathways has been recognized as an essential step for cancer stem cells transformation. Influencive study and therapy will help to eradicate the disease and vaccines or stem cells will be new era in pharmaceuticals for Cancer.

Cancer Stem Cells - Therapeutic Boon!

Cancer stem cells (CSC) are recently proposed to be the cancer initiating cells responsible for tumorigenesis and contribute to cancer resistance. Like normal stem cells, cancer stem cells should be rare, quiescent and capable of self renewing & maintaining tumor growth and heterogeneity. Although the concept of cancer stem cells originates from that of normal stem cells, cancer stem cells are not necessarily aberrant counterparts of normal stem cells. In fact, they may arise from stem cells or committed progenitors of corresponding tissues & even cells from other tissues. At the molecular level, the alteration of stem cell self-renewal pathways has been recognized as an essential step for cancer stem cells transformation. Better understanding of cancer stem cell will no doubt lead to new era of both basic & clinical research, reclassification of human tumors & development of novel therapeutic strategies specifically targeting cancer stem cells.

EZH2 Promotes Expansion of Breast Tumor Initiating Cells through Activation of RAF1-β-Catenin Signaling

It has been proposed that an aggressive secondary cancer stem cell population arises from a primary cancer stem cell population through acquisition of additional genetic mutations and drives cancer progression. Overexpression of Polycomb protein EZH2, essential in stem cell self-renewal, has been linked to breast cancer progression. However, critical mechanism linking increased EZH2 expression to BTIC (breast tumor initiating cell) regulation and cancer progression remains unclear. Here, we identify a mechanism in which EZH2 expression-mediated downregulation of DNA damage repair leads to accumulation of recurrent RAF1 gene amplification in BTICs, which activates p-ERK-β-catenin signaling to promote BTIC expansion. We further reveal that AZD6244, a clinical trial drug that inhibits RAF1-ERK signaling, could prevent breast cancer progression by eliminating BTICs.

An Old Player on a New Playground: Bmi-1 as a Regulator of Prostate Stem Cells

The polycomb group transcriptional repressor Bmi-1 regulates both normal and cancer stem cells in multiple tissues. In this issue of Cell Stem Cell , Lukacs et al. (2010) report that Bmi-1 also regulates the self-renewal of at least one prostate stem cell population and is involved in prostate cancer initiation and progression.

The Molecular Basis of Lmo2-Induced T-Cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is commonly caused by the overexpression of oncogenic transcription factors in developing T cells. In a mouse model of one such oncogene, LMO2, the cellular effect is to induce self-renewal of committed T cells in the thymus, which persist long-term while acquiring additional mutations and eventually giving rise to leukemia. These precancerous stem cells (pre-CSC) are intrinsically resistant to radiotherapy, implying that they may be refractory to conventional cancer therapies. However, they depend on an aberrantly expressed stem cell-like self-renewal program for their maintenance, in addition to a specialized thymic microenvironmental niche. Here, we discuss potential approaches for targeting pre-CSCs in T-ALL by using therapies directed at oncogenic transcription factors themselves, downstream self-renewal pathways, and the supportive cell niche.

Abstract CN08-02: Implications of the cancer stem cell hypothesis for breast cancer prevention

Abstract The cancer stem cell hypothesis proposes that cancers arise in cell populations that either dysregulate or acquire the stem cell property of self-renewal. Resulting cancers are hierarchically organized and driven by a subpopulation that retains stem cell properties. This suggests that dysregulation of self-renewal plays an important role in early stages of carcinogenesis and that an understanding of the pathways which regulate self-renewal may lead to new strategies for cancer prevention. Our laboratory has identified markers including CD44+/CD24- and Aldehyde dehydrogenase which have proven useful in identifying populations of normal and transformed breast epithelial cells. Furthermore, we have developed in vitro and animal models to elucidate pathways which regulate self-renewal in these cells. These studies, and others, suggest that stem cell self-renewal is regulated by an interaction of intrinsic and extrinsic pathways. Intrinsic regulation occurs through interacting developmental pathways including Notch, hedgehog, Wnt and Akt. Cytokine networks in the stem cell niche including IL-8 and IL6 also play important roles in stem cell regulation. These pathways may also contribute to the well-known links between inflammation and cancer. Inflammatory cytokines may contribute to clonal expansion of stem cell populations which can then acquire secondary genetic changes resulting in expression of the fully malignant phenotype. We have demonstrated that dietary components including curcumin and sulforaphane which have been shown to have chemopreventive properties are able to target Wnt signaling in stem cell populations. These and other studies support the approach of targeting stem cell self-renewal pathways for cancer prevention.