Stem cells & pancreatic cancer

It is now well established that human pancreatic ductal adenocarcinoma (PDAC) contains a subset of cells with self-renewal capabilities and subsequent exclusive in vivo tumorigenic capacity as assessed by limiting dilution tumorigenic transplantation assays into immunodeficient mice. These cells are considered pancreatic cancer stem cells (CSCs) and are able to form tumors indistinguishable from parental ones. Furthermore they display strong chemotherapy resistance and are implicated in tumor relapses and metastatic spread. Important next steps for advancing the field of pancreatic CSC research include the identification and characterization of CSCs in the unperturbed in vivo setting. This has been achieved just recently for other solid tumors such as glioblastoma using clonal analysis after lineage tracing in mice [1]. In vivo imaging of CSCs during tumor development should not only provide new insights into the in vivo features of CSCs, but also help to further unravel the influence of the stroma on CSC biology. Comprehensive studies of the tumor heterogeneity with respect to the coexistence of different clones potentially generated by distinct population of CSCs that are evolving by stochastic cell fate decisions may actually unite the CSC concept and the model of clonal evolution for pancreatic cancer. Eventually, the design of specific therapies against CSCs should open new alleys to improve survival of patients with PDAC. Combined therapies targeting CSCs and their progenies as well as the supportive stroma may represent the most promising approach for the future treatment of patients with PDAC.     

The biology of cancer stem cells and its clinical implication in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a highly malignant tumor with limited treatment options in its advanced state. The molecular mechanisms underlying HCC remain unclear because of the complexity of its multi-step development process. Cancer stem cells (CSCs) are defined as a small population of cells within a tumor that possess the capability for self-renewal and the generation of heterogeneous lineages of cancer cells. To date, there have been two theories concerning the mechanism of carcinogenesis, i.e., the stochastic (clonal evolution) model and the hierarchical (cancer stem cell-driven) model. The concept of the CSC has been established over the past decade, and the roles of CSCs in the carcinogenic processes of various cancers, including HCC, have been emphasized. Previous experimental and clinical evidence indicated the existence of liver CSCs; however, the potential mechanistic links between liver CSCs and the development of HCC in humans are not fully understood. Although definitive cell surface markers for liver CSCs have not yet been found, several putative markers have been identified, which allow the prospective isolation of CSCs from HCC. The identification and characterization of CSCs in HCC is essential for a better understanding of tumor initiation or progression in relation to signaling pathways. These markers could be used along with clinical parameters for the prediction of chemoresistance, radioresistance, metastasis and survival and may represent potential targets for the development of new molecular therapies against HCC. This review describes the current evidence for the existence and function of liver CSCs and discuss the clinical implications of CSCs in patients demonstrating resistance to conventional anti-cancer therapies, as well as clinical outcomes. Such data may provide a future perspective for targeted therapy in HCC.     

Molecular mediators of breast cancer metastasis

Breast cancer has the highest incidence rate of malignancy in women worldwide. A major clinical challenge faced by patients with breast cancer treated by conventional therapies is frequent relapse. This relapse has been attributed to the cancer stem cell (CSC) population that resides within the tumor and possess stemness properties. Breast CSCs are generated when breast cancer cells undergo epithelial-mesenchymal transition resulting in aggressive, highly metastatic, and invasive phenotypes that exhibit resistance towards chemotherapeutics. Metastasis, a phenomenon that aids in the migration of breast CSCs, occurs through any of three different routes: hematogenous, lymphatic, and transcoelomic. Hematogenous dissemination of breast CSCs leads to metastasis towards distant unrelated organs like lungs, liver, bone, and brain causing secondary tumor generation. Activation of metastasis genes or silencing of metastasis suppressor genes often leads to the advancement of metastasis. This review focuses on various genes and molecular factors that have been implicated to regulate organ-specific breast cancer metastasis by defying the available therapeutic interventions.     

Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling

Many tumors contain heterogeneous populations of cells, only some of which exhibit increased tumorigenicity and resistance to anticancer therapies. Evidence suggests that these aggressive cancer cells, often termed "cancer stem cells" or "cancer stem-like cells" (CSCs), rely upon developmental signaling pathways that are important for survival and expansion of normal stem cells. Here we report that, in analogy to embryonic mammary epithelial biology, estrogen signaling expands the pool of functional breast CSCs through a paracrine FGF/FGFR/Tbx3 signaling pathway. Estrogen or FGF9 pretreatment induced CSC properties of breast cancer cell lines and freshly isolated breast cancer cells, whereas cotreatment of cells with tamoxifen or a small molecule inhibitor of FGFR signaling was sufficient to prevent the estrogen-induced expansion of CSCs. Furthermore, reduction of FGFR or Tbx3 gene expression was able to abrogate tumorsphere formation, whereas ectopic Tbx3 expression increased tumor seeding potential by 100-fold. These findings demonstrate that breast CSCs are stimulated by estrogen through a signaling pathway that similarly controls normal mammary epithelial stem cell biology.     

Novel therapeutic target for cancer stem cells in hepatocellular carcinoma

Cancer is a disease of genetic and epigenetic alterations, which are emphasized as the central mechanisms of tumor progression in the multi-stepwise model. Discovery of rare subpopulations of cancer stem cells (CSCs) has created a new focus in cancer research. The heterogeneity of tumors can be explained with the help of CSCs supported by anti-apoptotic signaling. CSCs mimic normal adult stem cells by demonstrating unique characteristics of self-renewal and pluripotency, and the critical role for tumor growth and resistance to anti-cancer therapy. We found that CD13 was a surface marker for CSCs in human liver cancer cell lines and clinical samples, and that CD13+ CSCs were associated with a hypoxic marker in clinical hepatocellular carcinoma (HCC) sample, suggesting that CD13+ CSCs have the critical role in tumor growth and resistance to anti-cancer therapy in liver cancers. In this review article, we update recent findings regarding the involvement of CSCs, especially in HCC.     

Role of microRNA-regulated cancer stem cells in recurrent hepatocellular carcinoma

Among the most common cancers, hepatocellular carcinoma (HCC) has a high rate of tumor recurrence, tumor dormancy, and drug resistance after initial successful chemotherapy or radiotherapy. A small subset of cancer cells, cancer stem cells (CSCs), exhibit stem cell characteristics and are present in various cancers, including HCC. The dysregulation of microRNAs (miRNAs) often accompanies the occurrence and development of HCC. miRNAs can influence tumorigenesis, progression, recurrence, and drug resistance by regulating CSCs properties, which supports their clinical utility in managing and treating HCC. This review summarizes the regulatory effects of miRNAs on CSCs in HCC with a special focus on their impact on HCC recurrence.     

Pancreatic cancer stem cells: regulatory networks in the tumor microenvironment and targeted therapy

Recent evidence has demonstrated that the existence of a cancer stem cell (CSC) subset in a solid tumor is responsible for the progression and relapse of cancer as well as its resistance to current therapies. Over the past decade, CSC research on pancreatic cancer has progressed. A fundamental understanding of pancreatic CSCs may improve therapies and deepen insight into the role of cell–cell interactions within a tumor microenvironment in pancreatic cancer progression. This review focuses on the impact of pancreatic CSCs on the regulatory networks in the tumor microenvironment, and the implications of targeting CSCs to treat pancreatic cancer.     

Stem cell concepts in myelodysplastic syndromes: lessons and challenges

According to the cancer stem cell (CSC) hypothesis, CSCs are the only cancer cells that can give rise to and sustain all cells that constitute a cancer as they possess inherent or acquired self-renewal potential, and their elimination is required and potentially sufficient to achieve a cure. Whilst establishing CSC identity remains challenging in most cancers, studies of low-intermediate risk myelodysplastic syndromes (MDS), other chronic myeloid malignancies and clonal haematopoiesis of indeterminant potential (CHIP) strongly support that the primary target cell usually resides in the rare haematopoietic stem cell (HSC) compartment. This probably reflects the unique self-renewal potential of HSCs in normal human haematopoiesis, combined with the somatic initiating genomic driver lesion not conferring extensive self-renewal potential to downstream progenitor cells. Mutational ‘fate mapping’ further supports that HSCs are the only disease-propagating cells in low-intermediate risk MDS, but that MDS-propagating potential might be extended to progenitors upon disease progression. The clinical importance of MDS stem cells has been highlighted through the demonstration of selective persistence of MDS stem cells in patients at complete remission in response to therapy. This implies that MDS stem cells might possess unique resistance mechanisms responsible for relapses following otherwise efficient treatments. Specific surveillance of MDS stem cells should be considered to assess the efficiency of therapies and as an early indicator of emerging relapses in patients in clinical remission. Moreover, further molecular characterization of purified MDS stem cells should facilitate identification and validation of improved and more stem cell-specific therapies for MDS.     

Cancer stem cells in colorectal cancer from pathogenesis to therapy: Controversies and perspectives

Colorectal cancer remains one of the most common and lethal malignancies worldwide despite the use of various therapeutic strategies.A better understanding of the mechanisms responsible for tumor initiation and progression is essential for the development of novel,more powerful therapies.The traditional,so-called"stochastic model"of tumor development,which assumes that each cancer cell is tumorigenic,has been deeply challenged during the past decade by the identification of cancer stem cells(CSCs),a biologically distinct subset of cells within the bulk of tumor mass.This discovery led to the development of the hierarchical model of tumorigenesis which assumes that only CSCs have the ability to initiate tumor growth,both at primary and metastatic sites.This model implies that the elimination of all CSCs is fundamental to eradicate tumors and that failure to do so might be responsible for the occurrence of relapses and/or metastases frequently observed in the clinical management of colorectal cancer patients.Identification and isolation of CSCs is essential for a better understanding of their role in the tumorigenetic process and for the development of CSC-specific therapies.Several methods have been used for this purpose and many efforts have been focused on the identification of specific CSC-surface markers.This review provides an overview of the proposed roles of CSC in human colorectal tumorigenesis focusing on the most important molecules identified as CSC-specific markers in colorectal cancer and on the potential strategies for the development of CSC-targeted therapy.     

消化系肿瘤干细胞研究进展

近年来,肿瘤干细胞（CSCs）已成为肿瘤研究的热点。CSCs是一类具有自我更新和分化潜能的细胞．参与肿瘤的发生、发展、转移和复发。迄今,已发现包括食管癌、胃癌、结肠癌、肝癌、胰腺癌等在内的多种消化系CSCs。本文就消化系CSCs的研究进展作一综述,以期为消化系肿瘤的治疗提供新的策略。     

Regulation of colon cancer recurrence and development of therapeutic strategies

Recurrence of colon cancer still remains a major issue which affects nearly 50% of patients treated by conventional therapeutics. Although the underlying causative factor(s) is not fully understood, development of drug-resistance has been associated with induction of cancer stem or stem-like cells (CSCs) which constitute a small sub-population of tumor cells known to be highly resistant to chemotherapy. In fact, the discovery of CSCs in a variety of tumors (including colon cancer) has changed the view of carcinogenesis and therapeutic strategies. Emerging reports have indicated that to improve patient outcomes, conventional anticancer therapies should be replaced with specifi c approaches targeting CSCs. Thus, therapeutic strategies that specifically target CSCs are being sought to reduce the risk of relapse and metastasis. In order to specifi cally target colon CSCs (while sparing somatic intestinal stem cells), it is critical to identify unique deregulated pathways responsible for self-renewal of CSCs and colon cancer recurrence. Colon CSCs present a unique opportunity to better understand the biology of solid tumors. Thus, a better understanding of the clinical signs and symptoms of colon cancer patients (under-going surgery or chemotherapy) during perioperative periods, along with the underlying regulatory events affecting the stem/progenitor cell self-renewal and differentiation of colon epithelial cells, is of immense importance. In this review we discuss the implication of clinical factors and the emerging role of CSCs during recurrence of colon cancer along with the development of new therapeutic strategies involving the use of natural agents.     

Breast cancer adaptive resistance: HER2 and cancer stem cell repopulation in a heterogeneous tumor society

Purpose

The lethal effects of cancer are associated with the enhanced tumor aggressiveness in recurrent and metastatic lesions that show resistant phenotype to anti-cancer therapy, a major barrier to improving overall survival of cancer patients. The presence of heterogeneous populations of cancer cells within a specific tumor including the tumor-initiating cells or so-called cancer stem cells (CSCs) has linked the acquired resistance (AR, or adaptive resistance). Herein, we discuss the CSC-mediated tumor repopulation in AR of breast cancer in this review.

Methods

We emphasize a dynamic feature of gene induction in tumor cells that undergo long-term treatment, and describe a specific HER2-NF-κB-HER2 pro-survival pathway that can be initiated in breast CSCs upon radiation therapy.

Results

Elucidation of HER2-induced pro-survival networks, specifically the force driving tumor repopulation due to radioresistant CSCs during anticancer therapies, will have a significant impact on the generation of new diagnostic and therapeutic targets to control of recurrent and metastatic breast tumors.     

CD13: Waving the flag for a novel cancer stem cell target

Cancer stem cells (CSCs) are generally dormant or slowly cycling tumor cells that have the ability to reconstitute tumors. They are thought to be involved in tumor resistance to chemo/radiation therapy and tumor relapse and progression. However, neither their existence nor their identity within many cancers has been well defined. Here, we have demonstrated that CD13 is a marker for semiquiescent CSCs in human liver cancer cell lines and clinical samples and that targeting these cells might provide a way to treat this disease. CD13+ cells predominated in the G0 phase of the cell cycle and typically formed cellular clusters in cancer foci. Following treatment, these cells survived and were enriched along the fibrous capsule where liver cancers usually relapse. Mechanistically, CD13 reduced ROS-induced DNA damage after genotoxic chemo/radiation stress and protected cells from apoptosis. In mouse xenograft models, combination of a CD13 inhibitor and the genotoxic chemotherapeutic fluorouracil (5-FU) drastically reduced tumor volume compared with either agent alone. 5-FU inhibited CD90+ proliferating CSCs, some of which produce CD13+ semiquiescent CSCs, while CD13 inhibition suppressed the self-renewing and tumor-initiating ability of dormant CSCs. Therefore, combining a CD13 inhibitor with a ROS-inducing chemo/radiation therapy may improve the treatment of liver cancer.     

Characterization of side population in thyroid cancer cell lines: cancer stem-like cells are enriched partly but not exclusively

There is increasing evidence that cancers contain their own stem-like cells called cancer stem cells (CSCs). A small subset of cells, termed side population (SP), has been identified using flow cytometric analysis. The SP cells have the ability to exclude the DNA binding dye, Hoechst33342, and are highly enriched for stem cells in many kinds of normal tissues. Because CSCs are thought to be drug resistant, SP cells in cancers might contain CSCs. We initially examined the presence of SP cells in several human thyroid cancer cell lines. A small percentage of SP cells were found in ARO (0.25%), FRO (0.1%), NPA (0.06%), and WRO (0.02%) cells but not TPC1 cells. After sorting, the SP cells generated both SP and non-SP cells in culture. The clonogenic ability of SP cells was significantly higher than that of non-SP cells. Moreover, the SP prevalence was dependent on cell density in culture, suggesting that SP cells preferentially survived at lower cell density. Microarray experiment revealed differential gene expression profile between SP and non-SP cells, and several genes related to stemness were up-regulated. However, non-SP population also contained cells that were tumorigenic in nude mice, and non-SP cells generated a small number of SP cells. These results suggest that cancer stem-like cells are partly, but not exclusively, enriched in SP population. Clarifying the key tumorigenic population might contribute to the establishment of a novel therapy for thyroid cancer.     

Stem cells in gastric cancer

Gastric cancer(GC) is one of the leading causes of cancerrelated mortality worldwide.Cancer stem cells(CSCs),which were first identified in acute myeloid leukemia and subsequently in a large array of solid tumors,play important roles in cancer initiation,dissemination and recurrence.CSCs are often transformed tissue-specific stem cells or de-differentiated transit amplifying progenitor cells.Several populations of multipotent gastric stem cells(GSCs) that reside in the stomach have been determined to regulate physiological tissue renewal and injury repair.These populations include the Villin+ and Lgr5+ GSCs in the antrum,the Troy+ chief cells in the corpus,and the Sox2+ GSCs that are found in both the antrum and the corpus.The disruption of tumor suppressors in Villin+ or Lgr5+ GSCs leads to GC in mouse models.In addition to residing GSCs,bone marrow-derived cells can initiate GC in a mouse model of chronic Helicobacter infection.Furthermore,expression of the cell surface markers CD133 or CD44 defines gastric CSCs in mouse models and in human primary GC tissues and cell lines.Targeted elimination of CSCs effectively reduces tumor size and grade in mouse models.In summary,the recent identification of normal GSCs and gastric CSCs has greatly improved our understanding of the molecular and cellular etiology of GC and will aid in the development of effective therapies to treat patients.     

The ever-changing landscape of pancreatic cancer stem cells

Over the past decade, the cancer stem cell (CSC) concept in solid tumors has gained enormous momentum as an attractive model to explain tumor heterogeneity. The model proposes that tumors contain a subpopulation of rare cancer cells with stem-like properties that maintain the hierarchy of the tumor and drive tumor initiation, progression, metastasis, and chemoresistance. The identification and subsequent isolation of CSCs in pancreatic ductal adenocarcinoma (PDAC) in 2007 provided enormous insight into this extremely metastatic and chemoresistant tumor and renewed hope for developing more specific therapies against this disease. Unfortunately, we have made only marginal advances in applying the knowledge learned to the development of new and more effective treatments for pancreatic cancer. The latter has been partly due to the lack of adequate in vitro and in vivo systems compounded by the use of markers that do not reproducibly nor exclusively select for an enriched CSC population. Thus, attempts to define a pancreatic CSC-specific genetic, epigenetic or proteomic signature has been challenging. Fortunately recent advances in the CSC field have overcome many of these challenges and have opened up new opportunities for developing therapies that target the CSC population. In this review, we discuss these current advances, specifically new methods for the identification and isolation of pancreatic CSCs, new insights into the metabolic profile of CSCs at the level of mitochondrial respiration, and the utility of genetically engineered mouse models as surrogate systems to both study CSC biology and evaluate CSC-specific targeted therapies in vivo.     

A subpopulation of CD24⁺ cells in colon cancer cell lines possess stem cell characteristics

Cancer stem cells (CSCs) have been shown to contribute to the resistance and relapse in a range of cancer types such as breast cancer and glioma. However, colon cancer stem cells remain poorly characterized. Here we reported that CD24+ subpopulation in colon cancer cell lines HCT116 and SW480 exhibited cancer stem cell-like characteristics. Using flow cytometry candidate CSCs markers were selected after initial screening of known CSCs markers from other types of cancer on colon cancer cell lines HCT116, SW480 and HT29. CD24 was expressed in the minority of bulk cell population of HCT116 and SW480 cell lines. Moreover, functional tests demonstrated that CD24+ cells exhibited enhanced chemotherapy-resistance, self-renewal and tumorigenic capacity both in vitro and in vivo, compared to CD24- subpopulations. These results suggest that CD24+ subpopulation in colon cancer cell lines HCT116 and SW480 exhibits CSCs like characteristics, and represents a nice model to study and develop effective strategies to overcome chemo-resistance and relapse of colon cancer.     

Recent progress on normal and malignant pancreatic stem/progenitor cell research: therapeutic implications for the treatment of type 1 or 2 diabetes mellitus and aggressive pancreatic cancer

Recent progress on pancreatic stem/progenitor cell research has revealed that the putative multipotent pancreatic stem/progenitor cells and/or more committed beta cell precursors may persist in the pancreatic gland in adult life. The presence of immature pancreatic cells with stem cell-like properties offers the possibility of stimulating their in vivo expansion and differentiation or to use their ex vivo expanded progenies for beta cell replacement-based therapies for type 1 or 2 diabetes mellitus in humans. In addition, the transplantation of either insulin-producing beta cells derived from embryonic, fetal and other tissue-resident adult stem/progenitor cells or genetically modified adult stem/progenitor cells may also constitute alternative promising therapies for treating diabetic patients. The genetic and/or epigenetic alterations in putative pancreatic adult stem/progenitor cells and/or their early progenies may, however, contribute to their acquisition of a dysfunctional behaviour as well as their malignant transformation into pancreatic cancer stem/progenitor cells. More particularly, the activation of distinct tumorigenic signalling cascades, including the hedgehog, epidermal growth factor-epidermal growth factor receptor (EGF-EGFR) system, wingless ligand (Wnt)/beta-catenin and/or stromal cell-derived factor-1 (SDF-1)-CXC chemokine receptor 4 (CXCR4) pathways may play a major role in the sustained growth, survival, metastasis and/or drug resistance of pancreatic cancer stem/progenitor cells and their further differentiated progenies. The combination of drugs that target the oncogenic elements in pancreatic cancer stem/progenitor cells and their microenvironment, with the conventional chemotherapeutic regimens, could represent promising therapeutic strategies. These novel targeted therapies should lead to the development of more effective treatments of locally advanced and metastatic pancreatic cancers, which remain incurable with current therapies.