Called Cancer Stem Cells Research Articles

Isolation and characterization of tumorigenic extrahepatic cholangiocarcinoma cells with stem cell‐like properties

Recent studies suggest that the ability to form and grow tumors specifically resides in a small cell population called cancer stem cells (CSCs). These studies were conducted mainly on various human cancers; however, isolation and characterization of stem cells from cholangiocarcinoma have not been attempted. The molecular markers CD24, CD44, CD34, and epithelial cell adhesion molecule (EpCAM) are widely used, individually or in combination, to characterize some types of CSCs. In this study, we used these markers to identify a subpopulation of cells in extrahepatic cholangiocarcinoma (ECC) with cancer stem/progenitor cell-like properties. We found that CD24(+) CD44(+) EpCAM(high) cells (0.39-2.27%) were present in human ECC tissues. The expression of a CD24(+) CD44(+) EpCAM(high) subpopulation was consistent with primary cancers and could be duplicated during serial in vivo passaging in NOD/SCID mice. CD24(+) CD44(+) EpCAM(high) cells isolated from 3 cholangiocarcinoma xenografts showed high tumorigenic potential compared with CD24(-) CD44(-) EpCAM(low/-) cells. These tumorigenic ECC cells exhibited the stem cell properties of self-renewal and ability to produce heterogeneous progeny. We report the identification of a CSC population in ECC characterized by CD24, CD44 and EpCAM phenotypes. Our findings could provide new insight into the tumorigenesis of cholangiocarcinoma and offer a potential target for anti-cancer therapy.

Hypoxia Increases the Expression of Stem-Cell Markers and Promotes Clonogenicity in Glioblastoma Neurospheres

Hypoxia promotes the expansion of non-neoplastic stem and precursor cell populations in the normal brain, and is common in malignant brain tumors. We examined the effects of hypoxia on stem-like cells in glioblastoma (GBM). When GBM-derived neurosphere cultures are grown in 1% oxygen, hypoxia-inducible factor 1alpha (HIF1alpha) protein levels increase dramatically, and mRNA encoding other hypoxic response genes, such as those encoding hypoxia-inducible gene-2, lysyl oxidase, and vascular endothelial growth factor, are induced over 10-fold. Hypoxia increases the stem-like side population over fivefold, and the percentage of cells expressing CD133 threefold or more. Notch pathway ligands and targets are also induced. The rise in the stem-like fraction in GBM following hypoxia is paralleled by a twofold increase in clonogenicity. We believe HIF1alpha plays a causal role in these changes, as when oxygen-stable HIF1alpha is expressed in normoxic glioma cells CD133 is induced. We used digoxin, which has been shown to lower HIF protein levels in vitro and in vivo, to inhibit the hypoxic response. Digoxin suppressed HIF1alpha protein expression, HIF1alpha downstream targets, and slowed tumor growth in vivo. In addition, pretreatment with digoxin reduced GBM flank xenograft engraftment of hypoxic GBM cells, and daily intraperitoneal injections of digoxin were able to significantly inhibit the growth of established subcutaneous glioblastoma xenografts, and suppressed expression of vascular endothelial growth factor.

Transgelin Promotes Migration and Invasion of Cancer Stem Cells

Recent studies have suggested the existence of a small subset of cancer cells called cancer stem cells (CSCs), which possess the ability to initiate malignancies, promote tumor formation, drive metastasis, and evade conventional chemotherapies. Elucidation of the specific signaling pathway and mechanism underlying the action of CSCs might improve the efficacy of cancer treatments. In this study, we analyzed differentially expressed proteins between tumerigenic and nontumorigenic cells isolated from the human hepatocellular carcinoma (HCC) cell line, Huh7, via proteomic analysis to identify proteins correlated with specific features of CSCs. The expression level of Transgelin was 25-fold higher in tumorigenic cells than nontumorigenic cells. Similar results were also observed in tumorigenic cells derived from colorectal adenocarcinoma and prostate carcinoma. More importantly, the elevated levels of Transgelin significantly increased the invasiveness of tumorigenic cells, whereas reduced levels decreased the invasive potential. Moreover, in tumors derived from Huh7-induced xenografts, Transgelin was also co-expressed with CXCR4, which is responsible for tumor invasion. Taken together, these results indicate that the metastatic potential of CSCs arises from highly expressed Transgelin.

175 Synergetic and alleviatory effects by combinational therapy of ascorbic acid and paclitaxel on sarcoma 180 implanted BALB/c mice

Recent evidence has suggested that breast cancer contains a rare population of cells called cancer stem cells (CSCs), which have an extensive self-renewal ability and contribute to metastasis and therapeutic resistance. This study evaluated the in vitro and in vivo effects of RAD001 (Everolimus) alone or in combination with docetaxel on stem cells from primary breast cancer cells and two breast cancer cell lines (MCF-7 and MDA-MB-231). In In vitro studies, we sorted ESA+CD44+CD24−/low cells as stem cells using flow cytometry from primary breast cancer cells, MCF-7 and MDA-MB-231 cell lines. MTT assays were used to quantify the inhibitory effect of the drugs on total cells and stem cells. Apoptosis and the cell cycle distributions of stem cells were examined by flow cytometry. The tumourigenicity of stem cells after treatment was investigated by soft agar colony formation assays. In In vivo studies, the BALB/c mice were injected with MDA-MB-231 stem cells and the different treatments were administered. After necropsy, the expression of Ki67, CD31, AKT1, and phospho-AKT (Thr308) was analysed by immunohistochemistry. In In vitro studies, all three populations of stem cells were resistant to the standard treatment doses of docetaxel compared with total cells treated with the same drug. Treatment with RAD001 resulted in growth inhibition of all stem cells in a dose-dependent manner. An additive growth inhibitory effect of the combination treatment on the three stem cells was observed in in vitro compared with treatment with RAD001 alone (P < 0.001). In addition, an increase in G2/M cell cycle arrest and an increased population of cells in early apoptosis were seen in the combination treatment group compared with either single-agent group (P < 0.01). In vivo, the volumes of the xenograft tumours significantly decreased in RAD001 alone group compared to control group (P = 0.008), and RAD001 plus docetaxel therapy was much more effective at reducing tumour volume in mice compared with either single-agent alone (P < 0.05). Compared with RAD001 alone, the combination of RAD001 and docetaxel reduced the expression of Ki67, CD31, AKT1 and phospho-AKT (Thr308) (P < 0.05). We conclude that the combination treatment of RAD001 and docetaxel can inhibit the growth of stem cells in vitro and in vivo by inhibiting cell proliferation, inducing apoptosis, cell cycle arrest and reducing the expression of Ki67, CD31, AKT1 and phospho-AKT (Thr308). These data indicate that combination treatment with RAD001 and docetaxel may represent an effective therapy for breast cancer. However, further studies are required to evaluate the drug interaction between RAD001 and docetaxel in the clinical setting.

In Situ Identification of Putative Cancer Stem Cells by Multiplexing ALDH1, CD44, and Cytokeratin Identifies Breast Cancer Patients with Poor Prognosis

A subset of cells, tentatively called cancer stem cells (CSCs), in breast cancer have been associated with tumor initiation, drug resistance, and tumor persistence or aggressiveness. They are characterized by CD44 positivity, CD24 negativity, and/or ALDH1 positivity in flow cytometric studies. We hypothesized that the frequency or density of these cells may be associated with more aggressive tumor behavior. We borrowed these multiplexed, flow-based methods to develop an in situ method to define CSCs in formalin-fixed paraffin-embedded breast cancer tissue, with the goal of assessing the prognostic value of the presence of CSCs in breast cancer. Using a retrospective collection of 321 node-negative and 318 node-positive patients with a mean follow-up time of 12.6 years, we assessed TMAs using the AQUA method for quantitative immunofluorescence. Using a multiplexed assay for ALDH1, CD44, and cytokeratin to measure the coexpression of these proteins, putative CSCs appear in variable sized clusters and in 27 cases (of 490), which showed significantly worse outcome (log rank P = 0.0003). Multivariate analysis showed that this marker combination is independent of tumor size, histological grade, nodal status, ER-, PR,- and HER2-status. In this cohort, ALDH1 expression alone does not significantly predict outcome. We conclude that the multiplexed method of in situ identification of putative CSCs identifies high risk patients in breast cancer.

Mouse sarcoma L1 cell line holoclones have a stemness signature

Accumulating data suggest that cancers contain a fraction of cells called cancer stem cells (CSCs), that may be responsible for upkeep and relapses of disease. In experimental settings, CSCs are regarded as most effective at tumour initiation in in vivo assays. Since the first isolation of cancer stem cells from acute myeloid leukaemia in 1994, cancer stem cells have been identified in human solid tumours and they have also been found in the established cell lines, based on ability of CSCs to form in vitro colonies of a specific morphology, called holoclones. Our study examined the ability of a mouse sarcoma cell line, derived from a lung metastasis of a BALB/c mouse and established as a stably growing line (L1), to produce holoclones in vitro. We aimed to verify a stemness signature of the holoclone cells. The L1 cell line was found to form holoclone colonies in vitro, which were shown to contain a percentage of CSC-like cells. A fraction of the L1 cells was able to repopulate the original cell line, and presented an increased clonogenic and metastatic potential (18th passage). In addition, MTT assay and flow cytometry of the side population fraction revealed that these cells were more resistant to chemotherapeutic drugs than the original cell line, and over-expressed the anti-apoptotic genes, GRP78 and GADD153. We conclude that mouse L1 sarcoma cell line contains CSC-like cells.

Abstract 3367: CD133- colorectal cancer cells have higher chemo-resistance ability than CD133+cells

Abstract (Background and purpose) Recently, many reports suggest that a limited population of tumor cells have the capability of tumorigenesis. These cells, called cancer stem cells (CSCs) or tumor initiating cells, are suggested to be involved in tumor recurrence after long interval as well as in chemo-resistance. There are several CSC markers, including CD44 and CD133. CD133, originally a hematopoietic stem cell marker, was identified also as a stem cell marker for various tumor types. In the present study, we aimed to compare the characteristics of CD133+ and CD133- colorectal cancer cells to test the hypothesis of CD133 being a potential specific marker for colorectal CSCs. (Methods) Using auto magnetic activated cell sorting (MACS), the human colon cancer cell line LoVo was separated into CD133+ and CD133- cell subpopulations, and their sensitivity to 5-FU, specially focusing on apoptosis and autophagy inductions were investigated. The sensitivity of CD133+ and - cells to 5-FU was tested by the MTS assay. And the induction of apoptosis was analyzed by flow-cytometry, after double-staining with annexin V-FITC/PI. The expression of β1-integrins was analyzed by flow-cytometry, and their ability to bind extracellular matrix (ECM) proteins was evaluated by the adhesion assay. Induction of autophagy was investigated by flow-cytometry after staining with acridine orange, and by Western blot for the expressions of the LC3 protein. (Results) After MACS isolation, CD133+ and CD133- cells were separately cultured. The purity of the obtained cell populations was more than 98%. After several days of culture, the proportion of CD133+ and CD133- cells was not changed in both cell populations during about a month. CD133- cells showed higher resistance to 5-FU than CD133+cells, in vitro. It was dependent on the higher induction of apoptosis in CD133+ cells. CD133+ cells had lower expression of β1-integrins compared with CD133- cells, and consequently, their ability to adhere ECM proteins was weaker. Additionally, AVOS formation was weaker in CD133+ cells, as well as the expression of LC3-II. (Discussion) CD133+ cells were more sensitive to 5-FU than CD133- cells, and it may be dependent on the higher ability of CD133- cells to induce autophagy in response to 5-FU. Additionally, CD133- cells had higher ability to adhere to ECM proteins through β1-integrins, and it may be another mechanism of chemo-resistance. Taking these results, higher ability to adhere to ECM proteins may confer resistance to 5-FU by improving the ability of cells to induce autophagy as a cell survival mechanism. Presently, there is controversy regarding CD133 as a specific marker of CSCs, but from our results, CD133- cells are more resistant to chemotherapy, one typical feature of CSCs. Therefore, we concluded that CD133 may not be used as a single CSC marker, but on the other hand, it may be a potential marker for the prediction of chemo-sensitivity in colorectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3367.

Abstract 4304: Malignant melanoma cells with aggressive properties are common and not distinguishable by proposed markers for cancer stem cells

Abstract In malignant melanoma, conflicting results have been reported regarding the presence of exclusive cells with enhanced aggressive properties, so called cancer stem cells (CSC), raising a doubt whether melanoma follows a CSC model and is hierarchically organized. By characterizing melanoma cells from short-term cell cultures, xenografts and patient biopsies, we aim to collect further evidence either to: i) support the existence of distinct CSC-like subpopulations, or ii) strengthen a notion about the common presence of cells demonstrating aggressive behavior and lack of cellular hierarchy in melanoma. By using individual-cell assays, we have shown that a large fraction (up to 60 %) of random single melanoma cells display high clonogenicity and self-renewal i.e. properties associated with tumorigenic potential. In search for a marker for such clonogenic/tumorigenic cells, we found that melanomas often harbor a large distinct subpopulation with elevated activity of Aldehyde Dehydrogenase (ALDH), a proposed marker for CSC-like cells in some hierarchically organized cancers. Interestingly, ALDH activity in melanoma patient biopsies seemed to correlate to the expression of melanoma-associated-antigen, HMW-MAA, which is linked to tumor progression. Furthermore, in vivo ALDH+ melanoma cells could convert to ALDH−, while the opposite conversion was rare, indicating a certain “cellular hierarchy” with respect to the ALDH phenotype. However, comparison of ALDH+ and ALDH− cells revealed that both subpopulations are highly clonogenic, tumorigenic and resistant to drugs proposed for melanoma therapy, DTIC and HGS-ETR2. This suggests that in malignant melanoma, ALDH, likewise earlier investigated “surface markers” of CSCs, does not distinguish cells with enhanced biological aggressiveness. In conclusion, melanoma cells exhibiting properties linked to aggressive phenotype are common and not restricted to subpopulations expressing proposed “CSC markers”, which contradicts the traditional view of CSCs. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4304.

Abstract 3364: Evaluation of CD133/CD44 expression level in resected gastric cancer tissues after neoadjuvant chemotherapy

Abstract BACKGROUND: Increasing evidence suggests that there is a small subset of cells, called cancer stem cells (CSC), that are responsible for cancer initiation, development, metastasis and treatment resistance. Although CD133 and CD44 are thought to be the putative markers to characterize CSC of various solid tumors such as brain cancer, colorectal cancer, breast cancer and prostate cancer, the link between expression status of CD133/44 and the clnical future of resected gastric cancer tissues after neo-adjuvant chemotherapy has not yet studied. We evaluated CD133/44 expression status in resected gastric cancer issue after neoadjuvant chemotherapy. PATIENTS AND METHODS: 32 cases were selected from advanced gastric cancer specimens of patients who underwent neo-adjuvant chemotherapy (S-1 and cisplatin or irinotecan and cisplatin or S-1 monotherapy) and surgical resection between 2001 and 2007 at the National Cancer Center Hospital. Immunohistochemical staining with anti-CD133 and anti-CD44 antibody were performed with these specimens. Immunopositive cells were counted from 10 fields in the representative section and expressed as a percentage. The specimen with necrosis or disappearance of the tumor cells in more than 1/3 of the whole lesion was defined as positive histological response specimen. Correlation of immunoreactivity with clinicopathological variables was evaluated and survival curves were compared between CD133/CD44 positive and negative cases. RESULTS: Patient characteristics: median age 57 years (range 31-74); male/female 22/10; histological type diffuse-type/intestinal-type 25/7. CD133 and CD44 expression (positive cells: 0% &amp;lt;) were detected in 24 specimens (75%), and 29 specimens (91%), respectively. There was no significant difference of histological response rate between the CD133 positive and negative group (17% vs 50%, P=0.152). Median survival times were 30.4months in CD133+ group and 27.7months in CD133- group (P=0.65). Median relapse free survivals were 22.1months in CD133+ group and 17.6months in CD133- group (P=0.33). Histological type of gastric cancer (intestinal type vs diffuse type) was not correlated with CD133/CD44 expression. CONCLUSION: CD133 and CD44 were frequently expressed in gastric cancer tissues after neoadjuvant chemotherapy. This study had limited numbers of patient sample and we were unable to study the CD133/44 status before treatment. Further study to identify the usefulness of CD133 and CD44 to predict the prognosis in gastric cancer patients is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3364.

Bioprocessing of Human Glioblastoma Brain Cancer Tissue

Solid cancer tumors are thought to arise from aberrant stem cell populations, called cancer stem cells (CSCs). Hence, the development of effective cancer therapies may rely on developing methods that specifically target these cells. However, the scarcity of CSCs in vivo represents a major impediment to such research, as there is an insufficient supply for basic biochemical and genetic analyses. It is therefore necessary to develop methods to expand reproducibly CSC tissue in vitro in a controlled environment. To date, we have developed bioreactor protocols for the suspension culture of an aggressive and deadly type of brain cancer called glioblastoma multiforme (GBM). Human GBM-derived cells achieved a maximum cell density of 2.4 x 10(6) cells/mL after 24 days under high shear conditions in batch culture conditions. In comparison, fed-batch cultures achieved 4.5 x 10(6) cells/mL after 32 days. Characterization of bioreactor-expanded cells using both flow cytometry and a differentiation assay indicated that bioreactor-generated human GBM-derived cells have similar characteristics to the initial cell population and achieve >90% CD133 expression. Additionally, genomic characterization indicated that a very small number of key genes were differentially expressed in the bioreactor-expanded GBM-derived cells, thereby conserving the basic nature of the brain cancer tissue in the cell expansion process.

New hope in the horizon: cancer stems cells

The major goal of researchers and oncologists is to develop promising ground for novel therapeutic strategies to prevent recurrence or relapse of cancer. Recent evidences suggest that a subset of cells called cancer stem cells (CSCs) are present within the tumor mass which possess tumorigenic capacity and may be responsible for propagation, relapse, and metastatic dissemination. These cells have certain stem cell-like properties, e.g. quiescence, selfrenewal, asymmetric division, and multidrug resistance which allow them to drive tumor growth and evade conventional therapies. A number of markers and assays have been designed to isolate and characterize the CSC population from the bulk tumor. The objective now is to selectively target the CSCs in order to eliminate the tumor from root, overcoming the emergence of clones capable of evading traditional therapy. This approach may help in increasing the overall disease-free survival in some cancers.

MicroRNAs in Human Embryonic and Cancer Stem Cells

MicroRNAs (miRNAs) are small non-coding RNAs that regulate messenger RNAs at the post-transcriptional level. They play an important role in the control of cell physiological functions, and their alterations have been related to cancer, where they can function as oncogenes or tumor suppressor genes. Recently, they have emerged as key regulators of "stemness", collaborating in the maintenance of pluripotency, control of self-renewal, and differen-tiation of stem cells. The miRNA pathway has been shown to be crucial in embryonic development and in embryonic stem (ES) cells, as shown by Dicer knockout analysis. Specific patterns of miRNAs have been reported to be expressed only in ES cells and in early phases of embryonic development. Moreover, many cancers present small populations of cells with stem cell characteristics, called cancer stem cells (CSCs). CSCs are responsible for relapse and treatment failure in many cancer patients, and the comparative analysis of expression patterns between ES cells and tumors can lead to the identification of a miRNA signature to define CSCs. Most of the key miRNAs identified to date in ES cells have been shown to play a role in tumor diagnosis or prognosis, and may well prove to be essential in cancer therapy in the foreseeable future.

Identification of Vitronectin as an Extrinsic Inducer of Cancer Stem Cell Differentiation and Tumor Formation

There is mounting evidence that tumors are initiated by a rare subset of cells called cancer stem cells (CSCs). CSCs are generally quiescent, self-renew, form tumors at low numbers, and give rise to the heterogeneous cell types found within a tumor. CSCs isolated from multiple tumor types differentiate both in vivo and in vitro when cultured in serum, yet the factors responsible for their differentiation have not yet been identified. Here we show that vitronectin is the component of human serum driving stem cell differentiation through an integrin alpha V beta 3-dependent mechanism. CSCs cultured on vitronectin result in downregulation of stem cell genes, modulation of differentiation markers, and loss of beta-catenin nuclear localization. Blocking integrin alpha V beta 3 inhibits differentiation and subsequently tumor formation. Thus, CSCs must be engaged by one or more extracellular signals to differentiate and initiate tumor formation, defining a new axis for future novel therapies aimed at both the extrinsic and intracellular pathways.

Quantitative Phosphoproteomic Analysis of the STAT3/IL-6/HIF1α Signaling Network: An Initial Study in GSC11 Glioblastoma Stem Cells

Initiation and maintenance of several cancers including glioblastoma (GBM) may be driven by a small subset of cells called cancer stem cells (CSCs). CSCs may provide a repository of cells in tumor cell populations that are refractory to chemotherapeutic agents developed for the treatment of tumors. STAT3 is a key transcription factor associated with regulation of multiple stem cell types. Recently, a novel autocrine loop (IL-6/STAT3/HIF1alpha) has been observed in multiple tumor types (pancreatic, prostate, lung, and colon). The objective of this study was to probe perturbations of this loop in a glioblastoma cancer stem cell line (GSC11) derived from a human tumor by use of a JAK2/STAT3 phosphorylation inhibitor (WP1193), IL-6 stimulation, and hypoxia. A quantitative phosphoproteomic approach that employed phosphoprotein enrichment, chemical tagging with isobaric tags, phosphopeptide enrichment, and tandem mass spectrometry in a high-resolution instrument was applied. A total of 3414 proteins were identified in this study. A rapid Western blotting technique (<1 h) was used to confirm alterations in key protein expression and phosphorylation levels observed in the mass spectrometric experiments. About 10% of the phosphoproteins were linked to the IL-6 pathway, and the majority of remaining proteins could be assigned to other interlinked networks. By multiple comparisons between the sample conditions, we observed expected changes and gained novel insights into the contribution of each factor to the IL6/STAT3/HIF1alpha autocrine loop and the CSC response to perturbations by hypoxia, inhibition of STAT3 phosphorylation, and IL-6 stimulation.

Mammary epithelial and breast cancer stem cells

The perpetual renewal of tissues and organs is driven by resident stem cells and progenitors. These cells guarantee tissue maintenance and regeneration after injury or involution and most tissues and organs contain small populations of primitive stem cells and progenitors. These cells play a major role in the developing foetus and contribute to the generation of tissues and organs. Stem cells are positioned on top of the cellular hierarchy and give rise to progenitors with more restricted lineage potential. The stem cells can divide and self-renew to generate daughter stem cells or they can differentiate into a variety of mature cell types [1]. The stem cell hypothesis has been extrapolated to tumour tissues and the postulation of stem cells has many attractive conceptual and practical implications. Cancer cells are distinguished by multiple mutations which alter their cell cycle regulation, their sensitivity to apoptotic signals and their lifespan. Since stem cells persist within the organism for long periods of time, they have the potential to accumulate genetic damage and propagate them to their daughter stem cells and their downstream progenitors. Many tumours comprise minor populations of tumour-initiating cells, cells able to reconstitute a tumour upon transplantation; these cells have been called cancer stem cells (CSCs) [2]. CSCs share characteristics of normal stem cells, i.e. they can self-renew and they can give rise to heterogeneous cell populations within a tumour and maintain the tumour mass [3]. They are also more resistant to chemotherapeutic drugs and radiotherapy than their progenitors and thus represent a cellular reservoir for tumour recurrence. CSCs can be derived directly from mutational events in stem cells which confer proliferative properties or they can result from mutations in progenitor cells which provide them with self renewal capacity. Both pathways might be used and result in tumours with different pathological properties [4,5]. The characterisation of the signalling pathways which provide self renewal properties to CSCs and the targeted interference with limiting signal transduction components offer a promising new therapeutic approach for the treatment of cancer.

Therapeutic implications of cancer initiating cells

Background: Until few years ago, all neoplastic cells within a tumour were suggested to have tumorigenic capacity, but recent evidences hint to the possibility that such feature is confined to a subset of Cancer Initiating Cells (CICs), also called Cancer Stem Cells (CSCs). These cells are the reservoir of the heterogeneous populations of differentiated cancer cells constituting the tumour bulk. Mechanisms shared with somatic stem cells, such as quiescence, self-renewal ability, asymmetric division and multidrug resistance, allow to these cells to drive tumour growth and to evade conventional therapy. Objective: Here, we give a brief overview on the origin of CICs, the mechanisms involved in chemoresistance and therapeutic implications. Conclusion: Current cancer treatments, based on the assumption that tumour cell population responds homogeneously, have been developed to eradicate proliferating cells. The new model of tumorigenesis entails significant therapeutic implications, in fact if a small fraction of CICs survives conventional therapy it may lead to recurrence after month or years of apparent remission. Selective targeting of CICs could eliminate the tumour from the root, overcoming the emergence of clones capable of evading traditional therapy and increasing overall disease free survival.

Turning Cancer Stem Cells Inside Out: An Exploration of Glioma Stem Cell Signaling Pathways

Tumors are complex collections of heterogeneous cells with recruited vasculature, inflammatory cells, and stromal elements. Neoplastic cells frequently display a hierarchy in differentiation status. Recent studies suggest that brain tumors have a limited population of neoplastic cells called cancer stem cells with the capacity for sustained self-renewal and tumor propagation. Brain tumor stem cells contribute to therapeutic resistance and tumor angiogenesis. In this minireview, we summarize recent data regarding critical signaling pathways involved in brain tumor stem cell biology and discuss how targeting these molecules may contribute to the development of novel anti-glioma therapies.

Mechanisms of bone metastases of breast cancer

Cancer development is a multi-step process driven by genetic alterations that elicit the progressive transformation of normal human cells into highly malignant derivatives. The altered cell proliferation phenotype of cancer involves a poorly characterized sequence of molecular events, which often result in the development of distant metastasis. In the case of breast cancer, the skeleton is among the most common of metastatic sites. In spite of its clinical importance, the underlying cellular and molecular mechanisms driving bone metastasis remain elusive. Despite advances in our understanding of the phenotype of cancer cells, the increased focus on the contribution of the tumor microenvironment and the recent revival of interest in the role of tumor-propagating cells (so called cancer stem cells) that may originate or be related to normal stem cells produced in the bone marrow, many important questions remain unanswered. As such, a more complete understanding of the influences of both the microenvironment and the tumor phenotype, which impact the entire multi-step metastatic cascade, is required. In this review, the importance of tumor heterogeneity, tumor-propagating cells, the microenvironment of breast cancer metastasis to bone as well as many current endocrine therapies for the prevention and treatment of metastatic breast cancer is discussed.

Effects of the sesquiterpene lactone parthenolide on prostate tumor‐initiating cells: An integrated molecular profiling approach

Recent evidence suggests tumor-initating cells (TICs), also called cancer stem cells, are responsible for tumor initiation and progression; therefore, they represent an important cell population for development of future anti-cancer therapies. In this study, we show that the sesquiterpene lactone parthenolide (PTL) is cytotoxic to prostate TICs isolated from prostate cancer cell lines: DU145, PC3, VCAP, and LAPC4, as well as primary prostate TICs. Furthermore, PTL inhibited TIC-driven tumor formation in mouse xenografts. Using an integrated molecular profiling approach encompassing proteomics, profiles of activated transcription factors and genomics we ascertained the effects of PTL on prostate cancer cells. In addition to the previously described effects of PTL, we determined that the non-receptor tyrosine kinase src, and many src signaling components, including: Csk, FAK, beta1-arrestin, FGFR2, PKC, MEK/MAPK, CaMK, ELK-1, and ELK-1-dependent genes are novel targets of PTL action. Furthermore, PTL altered the binding of transcription factors important in prostate cancer including: C/EBP-alpha, fos related antigen-1 (FRA-1), HOXA-4, c-MYB, SNAIL, SP1, serum response factor (SRF), STAT3, X-box binding protein-1 (XBP1), and p53. In summary, we show PTL is cytotoxic to prostate TICs and describe the molecular events of PTL-mediated cytotoxicity. Therefore, PTL represents a promising therapeutic for prostate cancer treatment.

Identification of CD15 as a Marker for Tumor-Propagating Cells in a Mouse Model of Medulloblastoma

The growth of many cancers depends on self-renewing cells called cancer stem cells or tumor-propagating cells (TPCs). In human brain tumors, cells expressing the stem cell marker CD133 have been implicated as TPCs. Here we show that tumors from a model of medulloblastoma, the Patched mutant mouse, are propagated not by CD133(+) cells but by cells expressing the progenitor markers Math1 and CD15/SSEA-1. These cells have a distinct expression profile that suggests increased proliferative capacity and decreased tendency to undergo apoptosis and differentiation. CD15 is also found in a subset of human medulloblastomas, and tumors expressing genes similar to those found in murine CD15(+) cells have a poorer prognosis. Thus, CD15 may represent an important marker for TPCs in medulloblastoma.