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PubMed2006

Neoplastic stem cells: a novel therapeutic target in clinical oncology.

Cancer is among the leading causes of morbidity and mortality in the Western world. Despite recent advances, most therapeutic approaches fail to eradicate the entire neoplastic clone. The remaining cells often develop metastasis and/or recurrences and therefore may represent attractive targets of therapy. A new exciting concept in this regard suggests that each neoplasm represents a heterogeneous population of cells that pertain to long-term tumor growth both in vivo in the natural host and in experimental animals. This concept postulates the existence of small fractions of 'tumor stem cells' that exhibit a capacity for self-renewal and unlimited growth and therefore are distinct from their progeny. Based on these hypotheses, the targeting of neoplastic stem cells is considered indispensable for eradication of the entire clone and for the development of curative treatment approaches. However, tumor stem cells often may be quiescent cells and may express a different profile of targets compared with 'more mature' tumor cells. Therefore, current efforts have attempted to characterize target expression profiles in cancer stem cells in various malignancies. In the this review, the authors have provided a brief summary of the current knowledge of neoplastic stem cells and the application of respective concepts in translational oncology with the ultimate objective of improving anticancer therapy.

Animals↗
PubMed2004

Blasts from the past: new lessons in stem cell biology from chronic myelogenous leukemia.

Cancer can be viewed as a hierarchical system that is dependent on a small population of "cancer stem cells" with unlimited self-renewal potential for continued growth and propagation of tumors. The identity and nature of these cells remains enigmatic, but an improved understanding of their biology may allow for selective therapeutic targeting. A recent report by sheds new light on leukemia stem cells by identifying the cells with in vitro self-renewing properties in various phases of chronic myelogenous leukemia, and linking the self-renewal properties of this population to activation of beta-catenin, a major effector of the canonical Wnt signaling pathway.

Cell Division↗
PubMed2025

Notch pathway defines an aggressive and immune-suppressive phenotype associated with checkpoint inhibitor resistance in pan-gastrointestinal adenocarcinomas.

The Notch pathway regulates the homeostasis and tumorigenesis of gastrointestinal epithelium. Given its roles in cancer stem cell capacity and cancer immunity, we hypothesized that Notch activation can predict poor prognosis and resistance to immune checkpoint inhibitors (ICIs) in gastrointestinal adenocarcinoma (GIAC). The mRNA expression and genomic alterations of Notch pathway were characterized in esophagus (ESAD), stomach (STAD), colon (COAD), or rectum (READ) adenocarcinomas from The Cancer Genome Atlas (TCGA) dataset. The prognostic model (mRNA-score) was constructed using the TCGA dataset (the training set) and was validated in 3 independent sets (GSE19417 [ESAD], GSE84437 [STAD], and GSE40967 [COAD]). The associations of the mRNA-score with drug sensitivity, immune cell infiltration, and immunotherapy efficacy were, respectively, analyzed using the Genomics of Drug Sensitivity in Cancer (GDSC) database, the TCGA dataset, and multiple clinical cohorts including GSE165252, PRJEB25780, IMvigor210, and CheckMate-009/010/025. Notch pathway genes exhibited conserved genomic/transcriptomic features across four GIAC subtypes. Three pan-GIAC clusters were determined by unsupervised clustering, and the cluster with higher expression of the Notch pathway genes had shorter overall survival (OS), immunosuppressive microenvironment, and higher scores of the signatures concerning angiogenesis, cell cycle, PI3K-AKT-mTOR, TGF-&#x3b2;, glycolysis, etc. A prognostic algorithm (mRNA-score) was constructed, which was correlated with poor OS in the training set (TCGA, P&#x2009;<&#x2009;0.001) and three validation sets (GSE19417, P&#x2009;=&#x2009;0.025; GSE84437, P&#x2009;=&#x2009;0.001, GSE40967, P&#x2009;=&#x2009;0.007). A high mRNA-score was linked with more "resting"/ "anti-inflammatory" rather than "activated"/ "pro-inflammatory" tumor-infiltrating immune cells and ICI resistance in GIACs (GSE165252, P&#x2009;=&#x2009;0.047; PRJEB25780, P&#x2009;=&#x2009;0.047) and other solid tumors such as urothelial carcinoma and clear cell renal cell carcinoma. Our findings demonstrate the utility of the Notch pathway in predicting prognosis and ICI resistance. Further studies are warranted to explore the efficacy of Notch inhibitors as immunotherapeutic adjuvants to overcome ICI resistance.

Humans↗
PubMed2005

A quantitative matrigel assay for assessing repopulating capacity of prostate stem cells.

Homeostasis of prostate tissue is maintained by stem cells, although such cells have not been well characterized. Here, we report establishment of such a method using matrigel. Matrigel containing a single-cell suspension from adult prostatic cells was subcutaneously grafted into the flank of nude mice. Prostatic duct-like structures derived from donor tissue were observed in the gel 2 weeks after transplantation. Luminal and basal cells observed in the gel expressed several markers characteristic of prostatic and/or epithelial cells. When a mixture with both EGFP-positive and negative prostate cells was transplanted, prostatic ducts consisted of either EGFP-positive or negative cells and chimeric patterns were rarely observed, suggesting that ducts were reconstituted from a single cell. Stem cell number and function were also evaluated by competition with control cells. Overall this method revealed that cells localized in the proximal portion in prostate ducts had higher reconstitution capacity than those in the distal portion. We conclude that prostate stem/progenitor cells exist and that our method is applicable to analysis of prostate stem cells, epithelial mesenchyme interactions, and prostate cancer stem cells.

Animals↗
PubMed2005

A new role for p53 in maintaining genetic stability in embryonic stem cells.

Embryonic stem cells (ESCs) are capable of unlimited self-renewal and retain the pluripotency to differentiate into all cell lineages in the body. Since DNA damage occurs during normal cellular proliferation as well as after exposure to DNA damaging agents, it is critical for ESCs to possess stringent mechanisms to maintain genetic stability and prevent the passage of DNA damage to the progeny. Consistent with this notion, the rate of spontaneous mutation in ESCs is several magnitudes lower than that in somatic cells. Our recent findings indicate that tumor suppressor p53 plays an important role in maintaining genetic stability in ESCs by eliminating DNA-damaged ESCs from the replicative ESC pool. In this context, p53 induces the differentiation of DNA-damaged ESCs by directly suppressing the expression of Nanog, which is critical for the self-renewal of ESCs. This newly found role of p53 in cellular differentiation indicates an alternative mechanism for p53 to maintain genetic stability in ESCs and suggests the possibility that p53 might play a similar role in certain tissue stem cells and suppress the development of cancer stem cells.

Animals↗
PubMed2006

Molecular profiles of the mouse postnatal development of the esophageal epithelium showing delayed growth start.

Studies on molecular mechanisms of self-renewal in normal stem cells are required for understanding the cancer stem cell. Self-renewal in many kinds of normal stem cells might be accelerated in the growth of a young organism and in the repair of damaged tissue. This study examined whether the esophagus in growing neonates provides an experimental system for studies on epithelial stem cell renewal. The esophageal epithelium consists of 3 layers, from the luminal side to the bottom: the differentiated, epibasal and basal cell layers. The basal cell layer is known to contain the stem cells for the esophageal epithelium. This basic architecture is observed both in mice and humans. We investigated the basal cells in the mouse neonate by immunostaining with a basal cell marker, nerve growth factor receptor (Ngfr), and compared the basal cell content in the esophageal epithelium between mice and humans. A mouse esophageal epithelial cell primary culture system was developed for studies on the basal cell growth and keratinocyte differentiation, and microarray analysis was conducted for obtaining expression profiles of the basal cells. It was revealed that the growth of the esophageal epithelium begins from postnatal day 3, and that the timing is consistent with membrane localization of Ngfr in the basal cell. An increase in the basal cell number by Ngf treatment is observed in in vitro mouse esophageal epithelium cultures. Furthermore, mRNA overexpression of Pdgfrb encoding platelet derived growth factor receptor beta and Egfr encoding epidermal growth factor receptor is associated with the timing of the growth of the esophageal epithelium in the neonatal mice. This study provides a new experimental model for studies on the growth of the basal cells, which are considered to include the stem cells, and on the enlargement of the body size in young organisms.

Animals↗
PubMed1996

[High-dose therapy with autologous stem cell support in malignant lymphoma and breast cancer. Experiences with hematopoietic stem cells isolate from blood].

Since 1994, 17 breast cancer patients and 16 lymphoma patients have been treated at the Norwegian Radium Hospital with high-dose therapy supported by autologous peripheral progenitor cells. All the patients were given granulocyte colony stimulating factor in the recovery phase after cytotoxic treatment in order to mobilize and harvest peripheral progenitor cells. Aphareses were successful in all patients and the mean number of CD34 cells reinfused per kilo body weight was 7.05 x 10(6) for the lymphoma patients and 11.1 x 10(6) for the breast cancer patients. The mean time to recover > or = 0.5 x 10(9)/l granulocytes and > or = 20 x 10(9)/l platelets after reinfusion of stem cells was 10 days and 11.7 days respectively for the lymphoma patients, while the breast cancer patients engrafted at day 8.6 and day 9.3. No severe treatment-related complications were observed.

Adult↗
PubMed1993

Hetero-duplication type of cancerous mitosis.

In normal mitosis, the two daughter cells are identical to each other. However, in the case of duplication mitosis of the non-matureable cancerous stem cell, the two daughter stem cells must be non-visually, but certainly different from each other in order to allow for the characteristic type of cancerous cell turnover development. One of these daughter stem cells is matureable and normally activated by the maturation factor, then undergoes maturation mitosis and finally passes through its lifespan. However, the other daughter stem cell is non-matureable and not activated by the maturation factor. It undergoes the original mitosis again, reproducing two daughter stem cells that differ from each other: te above matureable cell and the original non-matureable cell (Fig.). Such a hetero-duplication type of mitosis is peculiar to carcinoma and responsible for the oncogenesis. The origin of this mitosis is most probably an unequal division of a mitotic maturation promoting system (MMPS) at the mitotic phase, and may be dependent on some abnormal supplement of the MMPS. Thus, therapy aimed at the complete eradication of cancer should focus on removal of this supplement from the cancerous cell.

Animals↗
PubMed2005

Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study.

Previous studies of recipients of hematopoietic stem-cell transplants suggest that graft-versus-host disease (GVHD) and its therapy may increase the risk for solid cancers, particularly squamous-cell carcinomas (SCCs) of the buccal cavity and skin. However, the importance and magnitude of these associations are not well characterized. We conducted a case-control study of 183 patients with posttransplantation solid cancers (58 SCCs, 125 non-SCCs) and 501 matched control patients within a cohort of 24,011 patients who underwent hematopoietic stem-cell transplantation (HSCT) at 215 centers worldwide. Our results showed that chronic GVHD and its therapy were strongly related to the risk for SCC, whereas no increase in risk was found for non-SCCs. Major risk factors for the development of SCC were long duration of chronic GVHD therapy (P < .001); use of azathioprine, particularly when combined with cyclosporine and steroids (P < .001); and severe chronic GVHD (P = .004). Given that most patients who received prolonged immunosuppressive therapy and those with severe chronic GVHD were also treated with azathioprine, the independent effects of these factors could not be evaluated. Additional analyses determined that prolonged immunosuppressive therapy and azathioprine use were also significant risk factors for SCC of the skin and of the oral mucosa. These data provide further encouragement for strategies to prevent chronic GVHD and for the development of more effective and less carcinogenic treatment regimens for patients with moderate or severe chronic GVHD. Our results also suggest that clinical screening for SCC is appropriate among patients exposed to persistent chronic GVHD, prolonged immunosuppressive therapy, or both.

Adolescent↗
PubMed2005

The role of Wnt signaling in cancer and stem cells.

The Wingless-Int (Wnt) signaling pathway has been widely investigated in recent years. Initially, its role regulating cell proliferation and survival during embryogenesis aroused the interest of researchers. Later, the focus was placed on the link between aberrant Wnt pathway activation and human cancer. The improper function of Wnt signaling components can lead to aberrant cell proliferation and cancer. Mutations in the adenomatous polyposis coli and beta-catenin genes first implicated Wnt signaling in carcinogenesis. Over time, a wealth of evidence has indicated that amplification or inhibition of other components might also play a role in human cancers. In addition, Wnt signaling pathways also play a crucial role in normal tissue regeneration and stem cell self-renewal, raising the possibility of controlling immature tumor stem cells.

Animals↗
PubMed2006

Loss of the human polycomb group protein BMI1 promotes cancer-specific cell death.

The polycomb group protein BMI1 has been shown to support normal stem cell proliferation via its putative stem cell factor function, but it is not known if BMI1 may also act as a cancer stem cell factor to promote cancer development. To determine the role of human BMI1 in cancer growth and survival, we performed a loss-of-function analysis of BMI1 by RNA interference (RNAi) in both normal and malignant human cells. Our results indicate that BMI1 is crucial for the short-term survival of cancer cells but not of normal cells. We also demonstrated that loss of BMI1 was more effective in suppressing cancer cell growth than retinoid-treatment, and surviving cancer cells showed significantly reduced tumorigenicity. The cancer-specific growth retardation was mediated by an increased level of apoptosis and a delayed cell cycle progression due to the loss of BMI1. By comparison, BMI1 deficiency caused only a moderate inhibition of the cell cycle progression in normal lung cells. In both normal and cancer cells, the loss of BMI1 led to an upregulation of INK4A-ARF, but with no significant effect on the level of telomerase gene expression, suggesting that other BMI1-cooperative factors in addition to INK4A-ARF activation may be involved in the BMI1-dependent cancer-specific growth retardation. Thus, human BMI1 is critical for the short-term survival of cancer cells, and inhibition of BMI1 has minimal effect on the survival of normal cells. These findings provide a foundation for developing a cancer-specific therapy targeting BMI1.

Apoptosis↗
PubMed2006

Neurospheres enriched in cancer stem-like cells are highly effective in eliciting a dendritic cell-mediated immune response against malignant gliomas.

Cancer stem-like cells (CSC) could be a novel target for cancer therapy, including dendritic cell (DC) immunotherapy. To address this, we developed experiments aimed at DC targeting of neurospheres (NS) from GL261 glioma cells because neurospheres can be enriched in CSC. We obtained murine neurospheres by growing GL261 cells in epidermal growth factor/basic fibroblast growth factor without serum. GL261-NS recapitulated important features of glioblastoma CSC and expressed higher levels of radial glia stem cell markers than GL261 cells growing under standard conditions (GL261 adherent cells, GL261-AC), as assessed by DNA microarray and real-time PCR. GL261-NS brain gliomas were highly infiltrating and more rapidly lethal than GL261-AC, as evidenced by survival analysis (P < 0.0001), magnetic resonance imaging and histology. DC from the bone marrow of syngeneic mice were then used for immunotherapy of GL261-NS and GL261-AC tumors. Strikingly, DC loaded with GL261-NS (DC-NS) cured 80% and 60% of GL261-AC and GL261-NS tumors, respectively (P < 0.0001), whereas DC-AC cured only 50% of GL261-AC tumors (P = 0.0022) and none of the GL261-NS tumors. GL261-NS expressed higher levels of MHC and costimulatory molecules (CD80 and CD86) than GL261-AC; the JAM assay indicated that DC-NS splenocytes had higher lytic activity than DC-AC splenocytes on both GL261-NS and GL261-AC, and immunohistochemistry showed that DC-NS vaccination was associated with robust tumor infiltration by CD8+ and CD4+ T lymphocytes. These findings suggest that DC targeting of CSC provides a higher level of protection against GL261 gliomas, a finding with potential implications for the design of clinical trials based on DC vaccination.

Animals↗
PubMed2006

Implications of a simple mathematical model to cancer cell population dynamics.

Recent research in cancer progression and treatment indicates that many forms of cancer arise from the development of a small subpopulation of abnormal cancer stem cells (CSCs) that promote cancer growth and spread. Many potential treatments preferentially interact with cells at certain stages of the cell cycle by either selective killing or halting the cell cycle, such as intense, nanosecond-duration pulsed electric fields (nsPEFs). Simple mathematical models of unfed cancer cell populations at the plateau of their growth characteristics may estimate the long-term consequences of these treatments on proliferating and quiescent cell populations. Applying such a model with no transition from the quiescent to proliferating state shows that it is possible for the proliferating cell population to fall below 1 if the quiescent cell population obtains a sufficient competitive advantage with respect to nutrient consumption and/or survival rate. Introducing small, realistic transition rates did not appreciably alter short-term or long-term population behaviour, indicating that the predicted small cell population behaviour (< 1 cell) is not an artefact of the simpler model. Experimental observations of nsPEF-induced effects on the cell cycle suggest that such a model may serve as a first step in assessing the viability of a given cancer treatment in vitro prior to clinical application.

Animals↗
PubMed2005

miRNAs, cancer, and stem cell division.

MicroRNAs (miRNAs) are known to regulate the expression of genes involved in the control of development, proliferation, apoptosis, and the stress response. As a cluster of recent Nature papers now show, altered expression of specific miRNA genes contributes to the initiation and progression of cancer.

Animals↗
PubMed2005

A tumorigenic subpopulation with stem cell properties in melanomas.

Recent studies suggest that cancer can arise from a cancer stem cell (CSC), a tumor-initiating cell that has properties similar to those of stem cells. CSCs have been identified in several malignancies, including those of blood, brain, and breast. Here, we test whether stem cell-like populations exist in human melanomas. In approximately 20% of the metastatic melanomas cultured in growth medium suitable for human embryonic stem cells, we found a subpopulation of cells propagating as nonadherent spheres, whereas in standard medium, adherent monolayer cultures were established. Individual cells from melanoma spheres (melanoma spheroid cells) could differentiate under appropriate conditions into multiple cell lineages, such as melanocytic, adipocytic, osteocytic, and chondrocytic lineages, which recapitulates the plasticity of neural crest stem cells. Multipotent melanoma spheroid cells persisted after serial cloning in vitro and transplantation in vivo, indicating their ability to self-renew. Furthermore, they were more tumorigenic than adherent cells when grafted to mice. We identified similar multipotent spheroid cells in melanoma cell lines and found that the stem cell population was enriched in a CD20+ fraction of melanoma cells. Based on these findings, we propose that melanomas can contain a subpopulation of stem cells that contribute to heterogeneity and tumorigenesis. Targeting this population may lead to effective treatments for melanomas.

Animals↗
PubMed2007

STAT3-induced WNT5A signaling loop in embryonic stem cells, adult normal tissues, chronic persistent inflammation, rheumatoid arthritis and cancer (Review).

Leukemia inhibitory factor (LIF), oncostatin M, leptin, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine factor 1, interleukin 6 (IL6), interleukin 11 and interleukin 27 activate the gp130-JAK-STAT3 signaling cascade. Here, WNT5A was characterized as the evolutionarily conserved target of the STAT3 signaling cascade based on 11-bp-spaced tandem STAT3-binding sites within intron 4 of human, chimpanzee, cow, mouse and rat WNT5A orthologs. Canonical WNT5A signaling through Frizzled and LRP5/LRP6 receptors activates FGF20, WISP1, MYC and CCND1 transcription for the maintenance of stem/progenitor cells, while non-canonical WNT5A signaling through Frizzled and ROR2/PTK7/RYK receptors activates the RHOA, JNK, NLK and NFAT signaling cascades for the control of tissue polarity, cell adhesion or movement. LIF-induced Wnt5a activates canonical Wnt signaling in mouse embryonic stem cells for self-renewal. STAT3-induced Wnt5a activates non-canonical Wnt signaling in rat cardiac myocytes for N-cadherin-dependent aggregation. IL6, secreted from epithelial cells or macrophages, induces WNT5A upregulation in mesenchymal cells. WNT5A then activates canonical WNT signaling in epithelial cells. IL6-induced WNT5A activates canonical WNT signaling for autocrine proliferation of human synovial fibroblasts in rheumatoid arthritis. IL-6 signaling is activated during human chronic atrophic gastritis with Helicobacter pylori infection, and aberrant Stat3 signaling activation gives rise to mouse gastric tumors. WNT5A is frequently upregulated in human primary gastric cancer due to tumor-stromal interaction. WNT5A might be downregulated in advanced cancer with poorer prognosis due to genetic alterations compensating WNT5A signaling. Oncogenic WNT5A activates canonical WNT signaling in cancer stem cells for self-renewal, and non-canonical WNT signaling at the tumor-stromal interface for invasion and metastasis. SNP of genes encoding components of the cytokine-induced WNT5A signaling loop is a predicted risk factor for RA and cancer, especially diffuse-type gastric and pancreatic cancer. Humanized anti-IL6 receptor antibody and WNT5A mimetic small-molecule antagonist could be applied to personalized medicine for RA and cancer driven by the IL6-induced WNT5A signaling loop.

Animals↗