Antibodies targeting cancer stem cells: A new paradigm in immunotherapy?

Antibody targeting of cancer is showing clinical and commercial success after much intense research and development over the last 30 years. They still have the potential to delivery long-term cures but a shift in thinking towards a cancer stem cell (CSC) model for tumor development is certain to impact on how antibodies are selected and developed, the targets they bind to and the drugs used in combination with them. CSCs have been identified from many human tumors and share many of the characteristics of normal stem cells. The ability to renew, metabolically or physically protect themselves from xenobiotics and DNA damage and the range of locomotory-related receptors expressed could explain the observations of drug resistance and radiation insensitivity leading to metastasis and patient relapse.Targeting CSCs could be a strategy to improve the outcome of cancer therapy but this is not as simple as it seems. Targets such as CD133 and EpCAM/ESA could mark out CSCs from normal cells enabling specific intervention but indirect strategies such as interfering with the establishment of a supportive niche through anti-angiogenic or anti-stroma therapy could be more effective.This review will outline the recent discoveries for CSCs across the major tumor types highlighting the possible molecules for intervention. Examples of antibody-directed CSC therapies and the outlook for the future development of this emerging area will be given.Key words: antibody, targeting, cancer, stem cell, therapyMonoclonal antibodies are clinically and commercially-established therapeutics.^1,2 A great deal of progress has been made over the last 30 years in overcoming problems and translating the phenomenal amount of laboratory research into clinical products. However, antibodies or other molecular interventions against cancer do not necessarily cure. In many cases, they can increase survival and improve quality of life. So, have we been hitting the wrong targets? Certainly, receptors such as human epidermal growth factor-1 (HER1/EGFR), HER2, CD20 and growth factors such as vascular endothelial cell (VEGF) and Interleukin-6 (IL-6) are involved in the cancer process, but have we been overlooking the real culprits?This review aims to examine the biology of cancer stem cells considering the markers defining them and their survival and will describe the new antibody-focused strategies emerging to target them for more effective treatment of cancer.     

Antibodies targeting cancer stem cells: A new paradigm in immunotherapy?

Antibody targeting of cancer is showing clinical and commercial success after much intense research and development over the last 30 years. They still have the potential to delivery long-term cures but a shift in thinking towards a cancer stem cell (CSC) model for tumour development is certain to impact on how antibodies are selected and developed, the targets they bind to and the drugs used in combination with them. CSCs have been identified from many human tumours and share many of the characteristics of normal stem cells. The ability to renew, metabolically or physically protect themselves from xenobiotics and DNA damage and the range of locomotory-related receptors expressed could explain the observations of drug resistance and radiation insensitivity leading to metastasis and patient relapse.

Targeting CSCs could be a strategy to improve the outcome of cancer therapy but this is not as simple as it seems. Targets such as CD133 and EpCAM/ESA could mark out CSCs from normal cells enabling specific intervention but indirect strategies such as interfering with the establishment of a supportive niche through anti-angiogenic or anti-stroma therapy could be more effective.

This review will outline the recent discoveries for CSCs across the major tumour types highlighting the possible molecules for intervention. Examples of antibody-directed CSC therapies will be given and the outlook for the future development of this emerging area will be given.     

Role of p38γ MAPK in regulation of EMT and cancer stem cells

p38γ is a member of p38 MAPK family which contains four isoforms p38α, p38β, p38γ, and p38δ. p38γ MAPK has unique function and is less investigated. Recent studies revealed that p38γ MAPK may be involved in tumorigenesis and cancer aggressiveness. However, the underlying cellular/molecular mechanisms remain unclear. Epithelial-mesenchymal transition (EMT) is a process that epithelial cancer cells transform to facilitate the loss of epithelial features and gain of mesenchymal phenotype. EMT promotes cancer cell progression and metastasis, and is involved in the regulation of cancer stem cells (CSCs) which have self-renewal capacity and are resistant to chemotherapy and target therapy. We showed that p38γ MAPK significantly increased EMT in breast cancer cells; over-expression of p38γ MAPK enhanced EMT while its down-regulation inhibited EMT. Meanwhile, p38γ MAPK augmented CSC population while knock down of p38γ MAPK decreased CSC ratio in breast cancer cells. MicroRNA-200b (miR-200b) was down-stream of p38γ MAPK and inhibited by p38γ MAPK; miR-200b mimics blocked p38γ MAPK-induced EMT while miR-200b inhibitors promoted EMT. p38γ MAPK regulated miR-200b through inhibiting GATA3. p38γ MAPK induced GATA3 ubiquitination, leading to its proteasome-dependent degradation. Suz12, a Polycomb group protein, was down-stream of miR-200b and involved in miR-200b regulation of EMT. Thus, our study established an important role of p38γ MAPK in EMT and identified a novel signaling pathway for p38γ MAPK–mediated tumor promotion.     

Stem cells: The root of prostate cancer?

The cancer stem cell (CSC) model states that tumors contain a reservoir of self-renewing cells that maintain the heterogeneous cell population of the tumor. These cells appear to be resistant to therapy and can therefore survive to repopulate the tumor during progression to therapy resistant disease. The biology of CSCs is still not definitive since it is difficult to isolate them from solid tumors and analyze their characteristics in vitro. Another challenge is to correlate these characteristics with tumor development and progression in vivo. Using the prostate CSC as a model, this review presents the CSC hypothesis, reviews the origin, identification and functions of prostate CSCs, and discusses the clinical implications and therapeutic challenges CSCs have for cancer therapy.     

LOH-proficient embryonic stem cells: a model of cancer progenitor cells?

Cancers are thought to originate in stem cells through the accumulation of multiple mutations. Some of these mutations result in a loss of heterozygosity (LOH). A recent report demonstrates that exposure of mouse embryonic stem cells to nontoxic amounts of mutagens triggers a marked increase in the frequency of LOH. Thus, mutagen induction of LOH in embryonic stem cells suggests a new pathway to account for the multiple homozygous mutations in human tumors. This induction could mimic early mutagenic events that generate cancers in human tissue stem cells.     

Community genetics: what have we accomplished and where should we be going?

Research in community genetics seeks to understand how the dynamic interplay between ecology and evolution shapes simple and complex communities and ecosystems. A community genetics perspective, however, may not be necessary or informative for all studies and systems. To better understand when and how intraspecific genetic variation and microevolution are important in community and ecosystem ecology, we suggest future research should focus on three areas: (i) determining the relative importance of intraspecific genetic variation compared with other ecological factors in mediating community and ecosystem properties; (ii) understanding the importance of microevolution in shaping ecological dynamics in multi-trophic communities; and (iii) deciphering the phenotypic and associated genetic mechanisms that drive community and ecosystem processes. Here, we identify key areas of research that will increase our understanding of the ecology and evolution of complex communities but that are currently missing in community genetics. We then suggest experiments designed to meet these current gaps.     

Natural killer cell–based immunotherapy: From transplantation toward targeting cancer stem cells

Natural killer (NK) cells are key players of the innate immune system. NK cells provide protection against infectious pathogens and malignancies in cell. This characteristic may be attributable to their intrinsic diverse potentialities and also their cooperation with adaptive immune lymphocytes, known as B and T cells. The growth, recurrence, and metastasis of cancer cells, and the failure of cytoreductive therapies against cancer cells are due to the small population of intratumor stem-like cells, called cancer stem cells (CSCs). Furthermore, NK cells can efficiently eradicate heterogeneous tumor cells after a long-term treatment. Therefore, NK cell–based therapy is a promising strategy to target and break CSC-associated resistance to anticancer drugs treatment. In this review, we have presented an overview of the emerging knowledge of the characteristics, diversities, and mechanism-driven immune surveillance of human NK cells and advances in NK cell–based immunotherapies. Finally, we will discuss how these cells can be applied to introduce the next generation of vaccine- and immune-based approaches to prevent drug resistance.     

Fibrosis and cancer: Do myofibroblasts come also from epithelial cells via EMT?

Myofibroblasts produce and modify the extracellular matrix (ECM), secrete angiogenic and pro-inflammatory factors, and stimulate epithelial cell proliferation and invasion. Myofibroblasts are normally induced transiently during wound healing, but inappropriate induction of myofibroblasts causes organ fibrosis, which greatly enhances the risk of subsequent cancer development. As myofibroblasts are also found in the reactive tumor stroma, the processes involved in their development and activation are an area of active investigation. Emerging evidence suggests that a major source of fibrosis- and tumor-associated myofibroblasts is through transdifferentiation from non-malignant epithelial or epithelial-derived carcinoma cells through epithelial-mesenchymal transition (EMT). This review will focus on the role of EMT in fibrosis, considered in the context of recent studies showing that exposure of epithelial cells to matrix metalloproteinases (MMPs) can lead to increased levels of cellular reactive oxygen species (ROS) that stimulate transdifferentiation to myofibroblast-like cells. As deregulated MMP expression and increased cellular ROS are characteristic of both fibrosis and malignancy, these studies suggest that increased MMP expression may stimulate fibrosis, tumorigenesis, and tumor progression by inducing a specialized EMT in which epithelial cells transdifferentiate into activated myofibroblasts. This connection provides a new perspective on the development of the fibrosis and tumor microenvironments.     

Neural stem cells, tumour stem cells and brain tumours: dangerous relationships?

Neural stem cells (NSC) have been implicated not only in brain development and neurogenesis but also in tumourigenesis. Brain tumour stem cells (BTSC) have been isolated from several paediatric or adult human brain tumours, however their origin is still disputed. This review discusses the normal role of NSC in the adult mammalian brain and their anatomical location. It compares the molecular characteristics and the biological behaviour of NSC/BTSC, and describes the molecular pathways involved in controlling self-renewal and maintenance of adult NSC/BTSC and brain tumour development. It also assesses the current hypotheses about the origin of BTSC and the clinical consequences.     

BM stem cells and cardiac repair: where do we stand in 2004?

Adult BM stem cells are being investigated for their potential to regenerate injured tissues by a process referred to as plasticity or transdifferentiation. Although data supporting stem cell plasticity is extensive, a controversy has emerged based on findings that propose cell-cell fusion as a more appropriate interpretation for this phenomenon. A major focus of this controversy is the claim that acutely infarcted myocardium in adult hearts can be regenerated by BM stem cells. Many researchers consider the adult heart to be a post-mitotic organ, whereas others believe that a low level of cardiomyocyte renewal occurs throughout life. If renewal occurs, it may be in response to cardiac stem cell activity or to stem cells that migrate from distant tissues. Post-mortem microscopic analysis of experimentally induced myocardial infarctions in several rodent models suggests that cardiomyocyte renewal is achieved by stem cells that infiltrate the damaged tissue. For a better understanding of the possible involvement of stem cells in myocardial regeneration, it is important to develop appropriate technologies to monitor myocardial repair over time with an emphasis on large animal models. Studies on non-human primate, swine and canine models of acute myocardial infarctions would enable investigators to utilize clinical quality cell-delivery devices, track labeled donor cells after precision transplantation and utilize non-invasive imaging for functional assays over time with clinical accuracy. In addition, if stem cell plasticity is to reach the next level of acceptance, it is important to identify the environmental cues needed for stem cell trafficking and to define the genetic and cellular mechanisms that initiate transdifferentiation. Only then will it be possible to determine if, and to what extent, BM stem cells are involved in myocardial regeneration and to begin to regulate precisely tissue repair.     

Steroid 5 α-reductase inhibitors targeting BPH and prostate cancer

Steroid 5 alpha-reductase inhibitors (5ARIs) have been approved for use clinically in treatment of benign prostate hyperplasia (BPH) and accompanying lower urinary tract symptoms (LUTS) and have also been evaluated in clinical trials for prevention and treatment of prostate cancer. There are currently two steroidal inhibitors in use, finasteride and dutasteride, both with distinct pharmacokinetic properties. This review will examine the evidence presented by various studies supporting the use of these steroidal inhibitors in the prevention and treatment of prostate disease. Article from the Special issue on Targeted Inhibitors.     

Epidermal stem cell fate: what can we learn from embryonic stem cells?

Because of its constant renewal and high propensity for repair, the epidermis is, together with the gut and the hematopoietic system, a tissue of choice to explore stem cell biology. Previous research over many years has revealed the complexity of the epidermis: the heterogeneity of the stem cell compartment, with its rare, slowly cycling, multipotent, hair-follicle, “bulge” stem cells and the more restricted interfollicular, follicle-matrix, and sebaceous-gland stem cells, which in turn generate the large pool of transit-amplifying progeny. Stem cell activity has been used for some considerable time to repair skin injuries, but ex-vivo keratinocyte amplification has its limitations, and grafted skin homeostasis is not totally satisfactory. Human embryonic stem cells raise the hope that the understanding of the developmental steps leading to the generation of epidermal stem cells and the characterization of the key signaling pathways involved in skin morphogenesis (such as p63) will be translated into therapeutic benefit. Our recent results suggest the feasibility not only of identifying but also of amplifying human ES cells, early ectodermal progenitors with an intact multipotent potential that might improve the quality and functionality of grafts, provided that preclinical in vivo studies confirm our expectations from in vitro analysis. The work described here was supported by funds from the Sixth EEC Framework Program under the EPISTEM project, l’Agence Nationale pour la Recherche (ANR projets blancs), INSERM, and the Institut National Contre le Cancer (INCa).