Stem cell-like cancer cells in cancer cell lines

Both stem cells and cancer cells are thought to be capable of unlimited proliferation. Moreover, a small number of cancer cells express stem cell markers, including CD133 and ATP-binding cassette transporters, by which the cells can pump out specific fluorescence dyes, such as Hoechst33342, as well as anti-cancer drugs, suggesting that either cancer cells resemble stem cells or cancers contain stem cell-like cancer cells, called "cancer stem cells (CSCs)". Using the common characteristics of tissue-specific stem cells, it was demonstrated that many types of tumors and cancer cell lines contain CSCs, which self-renew, express stem cell markers, and are tumorigenic. It was also shown that CSCs are resistant to anti-cancer drugs and irradiation. Thus CSCs might be a crucial target for the therapy. Because tumors contain CSCs and recruited normal stem cells, both of which contribute to tumorigenesis, it is difficult to separate CSCs from tumors. By contrast, cancer cell lines do not have any contaminating normal stem cells that quickly loose mulitpotentiality and differentiate in normal culture condition, suggesting that cancer cell lines could be an attractive alternative source of cells for CSC research. In this review I summarize the recent progress in CSC research using cancer cell lines.     

Tumour stem cell-targeted treatment: elimination or differentiation.

A wide range of studies suggest that most cancers are clonal and may represent the progeny of a single cell, a cancer stem cell (CSC) endowed with the capacity to maintain tumour growth. The concept of a cancer stem cell emerged decades ago, and the haematopoietic system is where it has mostly gained ground. More recently, CSC have been described in breast cancer and brain tumours. Growing evidence suggests that pathways regulating normal stem cell self-renewal and differentiation are also present in cancer cells and CSC. Malignant tumours can be viewed as an abnormal organ in which a small population of tumourigenic cancer stem cells have escaped the normal limits of self-renewal giving rise to abnormally differentiated cancer cells that contribute to tumour progression and growth. This new model has important implications for the study and treatment of cancer. Understanding the molecular circuitry which contributes to the maintenance of stem cells may provide an insight into the molecular mechanisms of cancer and thus new approaches for elimination or differentiation therapy. Therapies targeting CSC should focus on pathways such as Wnt, Shh and Notch which are required for the maintenance of cancer stem cells, but also on the ABC transporter family and other specific properties of cancer stem cells.     

Cancer stem cells and brain tumors

Besides the role of normal stem cells in organogenesis, cancer stem cells are thought to be crucial for tumorigenesis. Most current research on human tumors is focused on molecular and cellular analysis of the bulk tumor mass. However, evidence in leukemia and, more recently, in solid tumors suggests that the tumor cell population is heterogeneous. In recent years, several groups have described the existence of a cancer stem cell population in different brain tumors. These neural cancer stem cells (NCSC) can be isolated by cell sorting of dissociated suspensions of tumor cells for the neural stem cell marker CD133. These CD133+ cells -which also express nestin, an intermediate filament that is another neural stem cell marker- represent a small fraction of the entire brain tumor population. The stem-like cancer cells appear to be solely responsible for propagating the disease in laboratory models. A promising new approach to treating glioblastoma proposes targeting cancer stem cells. Here, we summarize progress in delineating NCSC and the implications of the discovery of this cell population in human brain tumors.     

Stem cells in colon cancer

The concept that cancer might arise from a rare population of cells with stem cell-like properties was proposed 150 years ago. Increasing evidence during the past 2 decades suggests the existence of a small subgroup of cells in cancer that are responsible for tumor growth and proliferation. Stem cells have self-renewing properties; thus, they are appealing candidates for generating the malignant phenotype. Although the concept of stem cells in leukemia has received significant attention for more than the past decade, over the past several years, expression of several surface markers on cancer cells has led to identification of tumor-initiating cells in several solid tumors, including melanoma, brain, breast, prostate, liver, pancreatic, ovarian, and recently, colon cancer. This review will provide an update of the biologic basis of the stem cell model and possible targets for the treatment of colon cancer.     

Breast Cancer Heterogeneity: Need to Review Current Treatment Strategies

Although the heterogeneity of breast cancer has long been recognized, the hierarchical organization and existence of tumor initiating subpopulation within breast tumors was not known until the last decade. These tumor initiating cells called cancer stem cells (CSCs) display features of stem cells such as unlimited ability to self-renew and lineage differentiation. Accumulating evidence now suggests that by virtue of their relative resistance to both radiation and chemotherapy, these cells contribute to resistance and relapse following therapy. Utilizing cell cultures and mouse xenograft models, we and others demonstrated that breast CSCs have far greater invasive and metastatic potential than differentiated tumor cells which comprise the tumor bulk. Altogether, these studies suggest that targeting and elimination of breast CSCs may be required to improve patient outcome. In this review, we will discuss recent developments in breast CSC research and advances in CSC specific targeted therapies that are in preclinical and clinical trials.     

Self-renewal and solid tumor stem cells

Solid tumors arise in organs that contain stem cell populations. The tumors in these tissues consist of heterogeneous populations of cancer cells that differ markedly in their ability to proliferate and form new tumors. In both breast cancers and central nervous system tumors, cancer cells differ in their ability to form tumors. While the majority of the cancer cells have a limited ability to divide, a population of cancer stem cells that has the exclusive ability to extensively proliferate and form new tumors can be identified based on marker expression. Growing evidence suggests that pathways that regulate the self-renewal of normal stem cells are deregulated in cancer stem cells resulting in the continuous expansion of self-renewing cancer cells and tumor formation. This suggests that agents that target the defective self-renewal pathways in cancer cells might lead to improved outcomes in the treatment of these diseases.     

Prostate cancer stem/progenitor cells: identification, characterization, and implications

Several solid tumors have now been shown to contain stem cell-like cells called cancer stem cells (CSC). These cells, although generally rare, appear to be highly tumorigenic and may be the cells that drive tumor formation, maintain tumor homeostasis, and mediate tumor metastasis. In this Perspective, we first provide our insight on how a CSC should be defined. We then summarize our current knowledge of stem/progenitor cells in the normal human prostate (NHP), an organ highly susceptible to hyperproliferative diseases such as benign prostate hyperplasia (BPH) and prostate cancer (PCa). We further review the evidence that cultured PCa cells, xenograft prostate tumors, and patient tumors may contain stem/progenitor cells. Along with our discussion, we present several methodologies that can be potentially used to identify putative tumor-reinitiating CSC. Finally, we present a hypothetical model for the hierarchical organization of human PCa cells and discuss the implications of this model in helping understand prostate carcinogenesis and design novel diagnostic, prognostic, and therapeutic approaches.     

恶性骨肿瘤之肿瘤干细胞理论

肿瘤干细胞近年来被发现具有自我更新、大量增殖以及可诱导的多向分化等干细胞性质.在血液病、乳腺癌、胶质细胞瘤、消化道癌等实体肿瘤中,肿瘤干细胞理论已被部分证实或认可.本文从肿瘤干细胞理论出发,阐述恶性骨肿瘤的干细胞起源及其转移、复发、耐药等生物学行为.     

Concepts of human leukemic development

Two fundamental problems in cancer research are identification of the normal cell within which cancer initiates and identification of the cell type capable of sustaining the growth of the neoplastic clone. There is overwhelming evidence that virtually all cancers are clonal and represent the progeny of a single cell. What is less clear for most cancers is which cells within the tumor clone possess tumorigenic or 'cancer stem cell' (CSC) properties and are capable of maintaining tumor growth. The concept that only a subpopulation of rare CSC is responsible for maintenance of the neoplasm emerged nearly 50 years ago. Testing of this hypothesis is most advanced for the hematopoietic system due to the establishment of functional in vitro and in vivo assays for stem and progenitor cells at all stages of development. This body of work led to conclusive proof for CSC with the identification and purification of leukemic stem cells capable of repopulating NOD/SCID mice. This review will focus on the historical development of the CSC hypothesis, the mechanisms necessary to subvert normal developmental programs, and the identification of the cell in which these leukemogenic events first occur.     

Safely targeting cancer stem cells via selective catenin coactivator antagonism

Throughout our life, long‐lived somatic stem cells (SSC) regenerate adult tissues both during homeostatic processes and repair after injury. The role of aberrant regulation of SSC has also recently gained prominence in the field of cancer research. Following malignant transformation, so termed cancer stem cells (CSC), endowed with the same properties as SSC (i.e. the ability to both self‐renew and generate differentiated progenitors), play a major part in tumor initiation, therapy resistance and ultimately relapse. The same signaling pathways involved in regulating SSC maintenance are involved in the regulation of CSC. CSC exist in a wide array of tumor types, including leukemias, and brain, breast, prostate and colon tumors. Consequently, one of the key goals in cancer research over the past decade has been to develop therapeutic strategies to safely eliminate the CSC population without damaging the endogenous SSC population. A major hurdle to this goal lies in the identification of the key mechanisms that distinguish CSC from the normal endogenous tissue stem cells. This review will discuss the discovery of the specific CBP/catenin antagonist ICG‐001 and the ongoing clinical development of the second generation CBP/catenin antagonist PRI‐724. Importantly, specific CBP/catenin antagonists appear to have the ability to safely eliminate CSC by taking advantage of an intrinsic differential preference in the way SSC and CSC divide.     

A case of an alpha-fetoprotein-producing intrahepatic cholangiocarcinoma suggests probable cancer stem cell origin

Recent evidence suggests that some cancers may originate from cancer stem cells, which may derive from carcinogenesis of normal stem cells. A hepatic progenitor cell population, which gives rise to hepatocytes and cholangiocytes, has been suggested in humans, though whether these cells can give rise to malignant tumors has not been confirmed. We report here a case of an alpha-fetoprotein (AFP)-producing intrahepatic cholangiocarcinoma (ICC) in an 81-year-old woman with chronic hepatitis C viral infection, suggesting malignant transformation of hepatic stem cells as a mechanism for hepatic neoplasia. Abdominal computed tomography revealed a low-density mass with surrounding enhancement measuring 5 cm x 5 cm in segments IV and VIII of the liver. The preoperative serum levels of tumor markers were 1.7 ng/ml of carcinoembryonic antigen, 22 mAU/ml of protein induced by vitamin K absence or antagonist II, 43.4 U/ml of carbohydrate antigen 19-9, and 1,560 ng/ml of AFP. Following central bisegmentectomy of the liver, serum AFP levels decreased dramatically. Histologically, the tumor cells showed indistinct glandular structures with abundant fibrous stroma. Immunohistochemical analysis demonstrated that the neoplastic cells reacted strongly to antibodies against AFP and cytokeratin (CK) 7. In addition, cancer cells showed partially positive reaction to anti-CK14, a liver stem cell marker, and to anticluster designation (CD) 133, a hematopoietic stem cell marker, and negative reaction to antihepatocyte paraffin (HepPar) 1. These data may indicate that the tumor was derived from a normal liver stem cell that underwent oncogenic transformation.     

Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic

Recently, several human cancers including leukemia and breast and brain tumors were found to contain stem-like cancer cells called cancer stem cells (CSC). Most of these CSCs were identified using markers that identify putative normal stem cells. In some cases, stem-like cancer cells were identified using the flow cytometry-based side population technique. In this study, we first show that approximately 30% of cultured human cancer cells and xenograft tumors examined ( approximately 30 in total) possess a detectable side population. Purified side population cells from two cell lines (U373 glioma and MCF7 breast cancer) and a xenograft prostate tumor (LAPC-9) are more tumorigenic than the corresponding non-side population cells. These side population cells also possess some intrinsic stem cell properties as they generate non-side population cells in vivo, can be further transplanted, and preferentially express some "stemness" genes, including Notch-1 and beta-catenin. Because the side population phenotype is mainly mediated by ABCG2, an ATP-binding cassette half-transporter associated with multidrug resistance, we subsequently studied ABCG2+ and ABCG2- cancer cells with respect to their tumorigenicity in vivo. Although side population cells show increased ABCG2 mRNA expression relative to the non-side population cells and all cancer cells and xenograft tumors examined express ABCG2 in a small fraction (0.5-3%) of the cells, highly purified ABCG2+ cancer cells, surprisingly, have very similar tumorigenicity to the ABCG2- cancer cells. Mechanistic studies indicate that ABCG2 expression is associated with proliferation and ABCG2+ cancer cells can generate ABCG2- cells. However, ABCG2- cancer cells can also generate ABCG2+ cells. Furthermore, the ABCG2- cancer cells form more and larger clones in the long-term clonal analyses and the ABCG2- population preferentially expresses several "stemness" genes. Taken together, our results suggest that (a) the side population is enriched with tumorigenic stem-like cancer cells, (b) ABCG2 expression identifies mainly fast-cycling tumor progenitors, and (c) the ABCG2- population contains primitive stem-like cancer cells.     

Identification of a stem-like cell population by exposing metastatic breast cancer cell lines to repetitive cycles of hypoxia and reoxygenation

Introduction  

The irregular vasculature of solid tumors creates hypoxic regions, which are characterized by cyclic periods of hypoxia and reoxygenation. Accumulated evidence suggests that chronic and repetitive exposure to hypoxia and reoxygenation seem to provide an advantage to tumor growth. Although the development of hypoxia tolerance in tumors predicts poor prognosis, mechanisms contributing to hypoxia tolerance remain to be elucidated. Recent studies have described a subpopulation of cancer stem cells (CSC) within tumors, which have stem-like properties such as self-renewal and the ability to differentiate into multiple cell types. The cancer stem cell theory suggests CSCs persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Since hypoxia is considered to be one of the critical niche factors to promote invasive growth of tumors, we hypothesize that repetitive cycles of hypoxia/reoxygenation also play a role in the enrichment of breast CSCs.     

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

Identification and characterization of cancer stem cells (CSCs) in gastric cancer are difficult owing to the lack of specific markers and consensus methods. In this study, we show that cells with the CD90 surface marker in gastric tumors could be enriched under non-adherent, serum-free and sphere-forming conditions. These CD90(+) cells possess a higher ability to initiate tumor in vivo and could re-establish the cellular hierarchy of tumors from single-cell implantation, demonstrating their self-renewal properties. Interestingly, higher proportion of CD90(+) cells correlates with higher in vivo tumorigenicity of gastric primary tumor models. In addition, it was found that ERBB2 was overexpressed in about 25% of the gastric primary tumor models, which correlates with the higher level of CD90 expression in these tumors. Trastuzumab (humanized anti-ERBB2 antibody) treatment of high-tumorigenic gastric primary tumor models could reduce the CD90(+) population in tumor mass and suppress tumor growth when combined with traditional chemotherapy. Moreover, tumorigenicity of tumor cells could also be suppressed when trastuzumab treatment starts at the same time as cell implantation. Therefore, we have identified a CSC population in gastric primary tumors characterized by their CD90 phenotype. The finding that trastuzumab targets the CSC population in gastric tumors suggests that ERBB2 signaling has a role in maintaining CSC populations, thus contributing to carcinogenesis and tumor invasion. In conclusion, the results from this study provide new insights into the gastric tumorigenic process and offer potential implications for the development of anticancer drugs as well as therapeutic treatment of gastric cancers.     

Cancer stem cells in hepatocellular carcinoma: Recent progress and perspective

Although the “cancer stem cell (CSC)” hypothesis was first proposed roughly 50 years ago, recent progress in stem cell biology and technologies has successfully achieved the identification of CSCs in a variety of cancers. CSCs are defined as a minor population which possesses a prominent ability to generate new tumors that faithfully reproduce the phenotype of original tumors in xenotransplant assays. Additionally, CSCs are able to self-renew and generate differentiated progenies to organize a hierarchical cell system in a similar fashion to normal stem cells. Although not all types of cancer follow the CSC theory, it provides an attractive cellular mechanism to account for the therapeutic resistance and recurrence of the disease. A minor population with CSC properties has been detected in a number of established hepatocellular carcinoma (HCC) cell lines and extensive analyses characterizing the CSC system in primary HCC samples are now ongoing. Considering that HCC has high rates of recurrence and mortality, novel therapeutic approaches are urgently required. Although the clinical relevance of CSCs remains elusive, deep understanding of the cellular organization of HCC may allow us to develop therapies targeting specific cell types such as CSCs.     

Is tumor growth sustained by rare cancer stem cells or dominant clones?

A key issue for cancer biology and therapy is whether the relentless growth of a tumor is driven by a substantial proportion of its cells or exclusively by a rare subpopulation, commonly termed "cancer stem cells." Support for the cancer stem cell model has been stimulated by experiments in which human tumor cells were transplanted into immunodeficient mice. Most notably, in human acute myeloid leukemia, only a minute proportion of the cells, displaying a defined phenotype, could seed leukemia in mice. Xenotransplantation, however, may fail to reveal many tumor growth-sustaining cells because the foreign microenvironment precludes essential interactions with support cells. In studies that instead have transplanted mouse leukemias and lymphomas into syngeneic animals, most of the tumors seem to be maintained by the dominant cell population, and only a few types of mouse leukemia seem to be sustained by a minor tumor growth-sustaining subpopulation. The collective evidence suggests that various tumors may span the spectrum between the extremes represented by the two models. If tumor growth can indeed be sustained either by rare cancer stem cells or dominant clones or both, as current evidence suggests, curative therapy for many types of tumors will most likely require targeting all the tumor cell populations.     

吉西他滨联合顺铂与吉西他滨单药化疗治疗晚期胰腺癌比较的Meta分析

目的：通过Meta分析.探讨吉西他滨联合顺铂和吉西他滨单药化疗在治疗晚期胰腺癌的意义.方法：通过MEDLLNE,EMBASE,ASCO论文集等数据为检索国内外已发表和未发展的相关文献,选择治疗组为吉西他滨联合铂化疗,对照组为吉西他滨单药化疗的晚期县级腺癌对照试验（randomized controlled trial RCT）.由两位评委者分别按上述检索策略收集资料,按铵入标准入选,主要对生存率进行Meat分析,其次是客观缓解率和毒副反应.结果：共纳入6个RCT,吉西他滨联合顺铂化疗与吉西他滨单药化疗比较,装卸生存率无差别（P=0.25）,临床获益反应率无差别（P=0.58）,客观缓解率提高6%（P=0.08）,血小板减少症增加8%（P=0.17）,恶心/呕吐增加11%（P=0.07）,但均无统计学意义.结论：现有证据不推荐吉西他滨联合铂治疗晚期胰腺癌,吉西他滨单药化疗仍是目前的标准治疗.     

肝癌干细胞研究进展

近几年,肿瘤起源于干细胞的假说正在人类各种肿瘤中得到证实,包括肝癌。目前认为肿瘤干细胞对肿瘤发生、转移和预后起了关键作用,因此如何分离和鉴定肝癌干细胞对于改善预防方法、促进早期检测以及研发新的治疗方法都是一个非常紧迫的课题。本文就有关肝癌干细胞存在的依据、来源、表面标志物分选等研究进展作一综述。     

肝癌干细胞研究进展

近几年,肿瘤起源于干细胞的假说正在人类各种肿瘤中得到证实,包括肝癌。目前认为肿瘤干细胞对肿瘤发生、转移和预后起了关键作用,因此如何分离和鉴定肝癌干细胞对于改善预防方法、促进早期检测以及研发新的治疗方法都是一个非常紧迫的课题。本文就有关肝癌干细胞存在的依据、来源、表面标志物分选等研究进展作一综述。     

Cancer stem cell markers are associated with adverse biomarker profiles and molecular subtypes of breast cancer

Cumulative evidence has demonstrated the presence of cancer stem cells (CSC) in breast cancer and its putative role in cancer progression. Nonetheless, the clinical significance of CSC in breast cancer remains elusive. The underlying reasons could be due to the heterogeneity of breast cancer subtypes as well as different markers used to define breast CSC. In this study, three widely used markers (aldehyde dehydrogenase (ALDH)1+ and CD24?CD44+) were used to define two populations of CSC in a large cohort of breast cancers. The expressions of these markers were correlated with different clinicopathological features and the molecular subtypes. ALDH1+ breast cancers were associated with basal-like and HER2-overexpressing subtypes and the characteristics histologic features were related to these two subtypes. On the other hand, CD24?CD44+ breast cancers were associated positively with the presence of extensive in situ component, the absence of lymph node involvement, and basal markers, but negatively with HER2. CD24?CD44+ breast cancers were also positively associated with luminal B cancers. As the expression of CSC markers varied among different molecular subtypes and different clinicopathological features, it appeared that each CSC population could have distinct clinical values in different subgroups of breast cancers. For improved prognostication with CSC, combining the analysis of CSC markers would be required. Within the luminal cancers, CSC appeared to identify cancers with poor outcome. The presence of CSC populations was associated with ER?PR+ cancers and tumors expressing basal markers. Basal marker expression can complement with CSC for improved indicator for poor prognosis in luminal breast cancers. For the first time, the possible contribution of CSC to these aggressive luminal cancers was demonstrated. The association of basal features and CSC in luminal cancers also raised the possibility that luminal cancer cells may acquire basal phenotype and CSC properties together during their progression.