Targeting pancreatic cancer stem cells for cancer therapy

Pancreatic cancer (PC) is the fourth most frequent cause of cancer death in the United States. Emerging evidence suggests that pancreatic cancer stem cells (CSCs) play a crucial role in the development and progression of PC. Recently, there is increasing evidence showing that chemopreventive agents commonly known as nutraceuticals could target and eliminate CSCs that have been proposed as the root of the tumor progression, which could be partly due to attenuating cell signaling pathways involved in CSCs. Therefore, targeting pancreatic CSCs by nutraceuticals for the prevention of tumor progression and treatment of PC may lead to the development of novel strategy for achieving better treatment outcome of PC patients. In this review article, we will summarize the most recent advances in the pancreatic CSC field, with particular emphasis on nutraceuticals that target CSCs, for fighting this deadly disease.     

Roles of cancer stem cells in gastrointestinal cancers

Cancer stem cells (CSCs) are the main cause of tumor growth, invasion, metastasis and recurrence. Recently, CSCs have been extensively studied to identify CSC-specific surface markers as well as signaling pathways that play key roles in CSCs self-renewal. The involvement of CSCs in the pathogenesis of gastrointestinal (GI) cancers also highlights these cells as a priority target for therapy. The diagnosis, prognosis and treatment of GI cancer have always been a focus of attention. Therefore, the potential application of CSCs in GI cancers is receiving increasing attention. This review summarizes the role of CSCs in GI cancers, focusing on esophageal cancer, gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer. In addition, we propose CSCs as potential targets and therapeutic strategies for the effective treatment of GI cancers, which may provide better guidance for clinical treatment of GI cancers.     

Cancer stem cell markers as potential targets for epithelial cancers

In recent years, the role of tumor-initiating cells (popularly known as cancer stem cells) in tumor development and availability of novel cancer stem cell/tumor initiating cell markers promises a new arena in understanding their role in developing novel targeted molecules. It is important to identify and understand the relevance of cancer stem cells (CSC)/tumor initiating cells (TIC) in tumor development and to design appropriate strategies for CSCs and TICs elimination, which is crucial to future cancer prevention and treatment. In this review, we attempt to define various potential markers of cancer stem cells and potential exploration as therapeutic targets for epithelial cancer prevention and treatment.     

Beyond tumorigenesis： cancer stem cells in metastasis

The importance of cancer stem cells （CSCs） in tumor-initiation has been firmly established in leukemia and recently reported for a variety of solid tumors. However, the role of CSCs in multistage cancer progression, particularly with respect to metastasis, has not been well-defined. Cancer metastasis requires the seeding and successful colonization of specialized CSCs at distant organs. The biology of normal stem cells and CSCs share remarkable similarities and may have important implications when applied to the study of cancer metastasis. Furthermore, overlapping sets of molecules and pathways have recently been identified to regulate both stem cell migration and cancer metastasis. These molecules constitute a complex network of cellular interactions that facilitate both the initiation of the pre-metastasis niche by the primary tumor and the formation of a nurturing organ microenvironment for migrating CSCs. In this review, we surveyed the recent advances in this dynamic field and propose a unified model of cancer progression in which CSCs assume a central role in both tumorigenesis and metastasis. Better understanding of CSCs as a fundamental component of the metastatic cascade will lead to novel therapeutic strategies against metastatic cancer.     

Epigenetic modulators for brain cancer stem cells: Implications for anticancer treatment

Primary malignant brain tumors are a major cause of morbidity and mortality in both adults and children, with a dismal prognosis despite multimodal therapeutic approaches. In the last years, a specific subpopulation of cells within the tumor bulk, named cancer stem cells(CSCs) or tumor-initiating cells, have been identified in brain tumors as responsible for cancer growth and disease progression. Stemness features of tumor cells strongly affect treatment response, leading to the escape from conventional therapeutic approaches and subsequently causing tumor relapse. Recent research efforts have focused at identifying new therapeutic strategies capable of specifically targeting CSCs in cancers by taking into consideration their complex nature. Aberrant epigenetic machinery plays a key role in the genesis and progression of brain tumors as well as inducing CSC reprogramming and preserving CSC characteristics. Thus, reverting the cancer epigenome can be considered a promising therapeutic strategy. Three main epigenetic mechanisms have been described: DNA methylation, histone modifications, and non-coding RNA, particularly micro RNAs. Each of these mechanisms has been proven to be targetable by chemical compounds, known as epigeneticbased drugs or epidrugs, that specifically target epigenetic marks. We review here recent advances in the study of epigenetic modulators promoting and sustaining brain tumor stem-like cells. We focus on their potential role in cancer therapy.     

MDSCs might be “Achilles heel” for eradicating CSCs

During tumor initiation and progression, the complicated role of immune cells in the tumor immune microenvironment remains a concern. Myeloid-derived suppressor cells (MDSCs) are a group of immune cells that originate from the bone marrow and have immunosuppressive potency in various diseases, including cancer. In recent years, the key role of cancer stemness has received increasing attention in cancer development and therapy. Several studies have demonstrated the important regulatory relationship between MDSCs and cancer stem cells (CSCs). However, there is still no clear understanding regarding the complex interacting regulation of tumor malignancy, and current research progress is limited. In this review, we summarize the complicated role of MDSCs in the modulation of cancer stemness, evaluate the mechanism of the relationship between CSCs and MDSCs, and discuss potential strategies for eradicating CSCs with respect to MDSCs.     

Cancer stem cells switch on tumor neovascularization

Recent studies on cancer stem cells (CSCs), a special subpopulation of tumor cells, promote our understanding of tumorigenesis, neovascularization, invasion, drug resistance and tumor recurrence, which establishes new concepts for cancer diagnosis and treatment. Therefore, the biological features and behaviors of CSCs have become an exciting frontier of cancer research. CSCs initiate tumor neovascularization and promote invasion with yet to be defined mechanisms. In this review, we provide evidence for the role of CSCs in tumor vascularization and discuss the potential mechanisms and therapeutic significance based on the interaction between CSCs and their vascular niches.     

Beyond regulations at DNA levels: A review of epigenetic therapeutics targeting cancer stem cells

In the past few years, the paramount role of cancer stem cells (CSCs), in terms of cancer initiation, proliferation, metastasis, invasion and chemoresistance, has been revealed by accumulating studies. However, this level of cellular plasticity cannot be entirely explained by genetic mutations. Research on epigenetic modifications as a complementary explanation for the properties of CSCs has been increasing over the past several years. Notably, therapeutic strategies are currently being developed in an effort to reverse aberrant epigenetic alterations using specific chemical inhibitors. In this review, we summarize the current understanding of CSCs and their role in cancer progression, and provide an overview of epigenetic alterations seen in CSCs. Importantly, we focus on primary cancer therapies that target the epigenetic modification of CSCs by the use of specific chemical inhibitors, such as histone deacetylase (HDAC) inhibitors, DNA methyltransferase (DNMT) inhibitors and microRNA‐based (miRNA‐based) therapeutics.     

Berberis libanotica Ehrenb Extract Shows Anti-Neoplastic Effects on Prostate Cancer Stem/Progenitor Cells

Cancer stem cells (CSCs), including those of advanced prostate cancer, are a suggested reason for tumor resistance toward conventional tumor therapy. Therefore, new therapeutic agents are urgently needed for targeting CSCs. Despite the minimal understanding of their modes of action, natural products and herbal therapies have been commonly used in the prevention and treatment of many cancers. Berberis libanotica Ehrenb (BLE) is a plant rich in alkaloids which may possess anti-cancer activity and a high potential for eliminating CSCs. We tested the effect of BLE on prostate cancer cells and our data indicated that this extract induced significant reduction in cell viability and inhibited the proliferation of human prostate cancer cell lines (DU145, PC3 and 22Rv1) in a dose- and time-dependent manner. BLE extract induced a perturbation of the cell cycle, leading to a G0-G1 arrest. Furthermore, we noted 50% cell death, characterized by the production of high levels of reactive oxidative species (ROS). Inhibition of cellular migration and invasion was also achieved upon treatment with BLE extract, suggesting a role in inhibiting metastasis. Interestingly, BLE extract had a major effect on CSCs. Cells were grown in a 3D sphere-formation assay to enrich for a population of cancer stem/progenitor cells. Our results showed a significant reduction in sphere formation ability. Three rounds of treatment with BLE extract were sufficient to eradicate the self-renewal ability of highly resistant CSCs. In conclusion, our results suggest a high therapeutic potential of BLE extract in targeting prostate cancer and its CSCs.     

Targeting head and neck tumoral stem cells: From biological aspects to therapeutic perspectives

Head and neck squamous cell cancer(HNSCC) is the sixth most common cancer in the world. Effective therapeutic modalities such as surgery, radiation, chemotherapy and combinations of each are used in the management of the disease. In most cases, treatment fails to obtain total cancer cure. In recent years, it appears that one of the key determinants of treatment failure may be the presence of cancer stem cells(CSCs) that escape currently available therapies. CSCs form a small portion of the total tumor burden but may play a disproportionately important role in determining outcomes. CSCs have stem features such as self-renewal, high migration capacity, drug resistance, high proliferation abilities. A large body of evidence points to the fact that CSCs are particularly resistant to radiotherapy and chemotherapy. In HNSCC, CSCs have been increasingly shown to have an integral role in tumor initiation, disease progression, metastasis and treatment resistance. In the light of such observations, the present review summarizes biological characteristics of CSCs in HNSCC, outlines targeted strategies for the successful eradication of CSCs in HNSCC including targeting the self-renewal controlling pathways, blocking epithelial mesenchymal transition, niche targeting, immunotherapy approaches and highlights the need to better understand CSCs biology for new treatments modalities.     

Presence and role of stem cells in ovarian cancer

Ovarian cancer is the deadliest gynecological malignancy. It is typically diagnosed at advanced stages of the disease, with metastatic sites disseminated widely within the abdominal cavity. Ovarian cancer treatment is challenging due to high disease recurrence and further complicated pursuant to acquired chemoresistance. Cancer stem cell(CSC) theory proposes that both tumor development and progression are driven by undifferentiated stem cells capable of self-renewal and tumor-initiation. The most recent evidence revealed that CSCs in terms of ovarian cancer are not only responsible for primary tumor growth, metastasis and relapse of disease, but also for the development of chemoresistance. As the elimination of this cell population is critical for increasing treatment success, a deeper understanding of ovarian CSCs pathobiology, including epithelial-mesenchymal transition, signaling pathways and tumor microenvironment, is needed. Finally, before introducing new therapeutic agents for ovarian cancer, targeting CSCs, accurate identification of different ovarian stem cell subpopulations, including the very small embryoniclike stem cells suggested as progenitors, is necessary. To these ends, reliable markers of ovarian CSCs should be identified. In this review, we present the current knowledge and a critical discussion concerning ovarian CSCs and their clinical role.     

Immunobiology and signaling pathways of cancer stem cells: implication for cancer therapy

Cancer stem cells (CSCs) need to survive cancer treatments with a specific end goal to provide new, more differentiated, metastatic-prone cancerous cells. This happens through diverse signals delivered within the tumor microenvironment where ample evidence indicates that altered developmental signaling pathways play an essential role in maintaining CSCs and accordingly the survival and the progression of the tumor itself. This review summarizes findings on the immunobiological properties of CSCs as compared with cancerous non-stem cells involving the expression of immunological molecules, cytokines and tumor antigens as well as the roles of the Notch, Wnt and Hedgehog pathways in the brain, breast and colon CSCs. We concluded that if CSCs are the main driving force behind tumor support and growth then understanding the molecular mechanisms and the immunological properties directing these cells for immune tolerance is of great clinical significance. Such knowledge will contribute to designing better targeted therapies that could prevent tumor recurrence and accordingly significantly improve cancer treatments and patient survival.     

Anti-tumor activity of a novel compound-CDF is mediated by regulating miR-21, miR-200, and PTEN in pancreatic cancer

Background

The existence of cancer stem cells (CSCs) or cancer stem-like cells in a tumor mass is believed to be responsible for tumor recurrence because of their intrinsic and extrinsic drug-resistance characteristics. Therefore, targeted killing of CSCs would be a newer strategy for the prevention of tumor recurrence and/or treatment by overcoming drug-resistance. We have developed a novel synthetic compound-CDF, which showed greater bioavailability in animal tissues such as pancreas, and also induced cell growth inhibition and apoptosis, which was mediated by inactivation of NF-κB, COX-2, and VEGF in pancreatic cancer (PC) cells.

Methodology/Principal Findings

In the current study we showed, for the first time, that CDF could significantly inhibit the sphere-forming ability (pancreatospheres) of PC cells consistent with increased disintegration of pancreatospheres, which was associated with attenuation of CSC markers (CD44 and EpCAM), especially in gemcitabine-resistant (MIAPaCa-2) PC cells containing high proportion of CSCs consistent with increased miR-21 and decreased miR-200. In a xenograft mouse model of human PC, CDF treatment significantly inhibited tumor growth, which was associated with decreased NF-κB DNA binding activity, COX-2, and miR-21 expression, and increased PTEN and miR-200 expression in tumor remnants.

Conclusions/Significance

These results strongly suggest that the anti-tumor activity of CDF is associated with inhibition of CSC function via down-regulation of CSC-associated signaling pathways. Therefore, CDF could be useful for the prevention of tumor recurrence and/or treatment of PC with better treatment outcome in the future.     

Advance in metabolism and target therapy in breast cancer stem cells

Breast cancer, like many other cancers, is believed to be driven by a population of cells that display stem cell properties. Recent studies suggest that cancer stem cells (CSCs) are essential for tumor progression, and tumor relapse is thought to be caused by the presence of these cells. CSC-targeted therapies have also been proposed to overcome therapeutic resistance in breast cancer after the traditional therapies. Additionally, the metabolic properties of cancer cells differ markedly from those of normal cells. The efficacy of metabolic targeted therapy has been shown to enhance anti-cancer treatment or overcome therapeutic resistance of breast cancer cells. Metabolic targeting of breast CSCs (BCSCs) may be a very effective strategy for anti-cancer treatment of breast cancer cells. Thus, in this review, we focus on discussing the studies involving metabolism and targeted therapy in BCSCs.     

Cancerous ovarian stem cells: Obscure targets for therapy but relevant to chemoresistance

Chemotherapy with platinum and taxanes is the first line of treatment for all epithelial ovarian cancer (EOC) patients after debulking surgery. Even though the treatment is initially effective in 80% of patients, recurrent cancer is inevitable in the vast majority of cases. Emerging evidence suggests that some tumor cells can survive chemotherapy by activating the self‐renewal pathways resulting in tumor progression and clinical recurrence. These defined population of cells commonly termed as “cancer stem cells” (CSC) may generate the bulk of the tumor by using differentiating pathways. These cells have been shown to be resistant to chemotherapy and, to have enhanced tumor initiating abilities, suggesting CSCs as potential targets for treatment. Recent studies have introduced a new paradigm in ovarian carcinogenesis which proposes in situ carcinoma at the fimbrial end of the fallopian tube to generate high‐grade serous ovarian carcinomas, in contrast to ovarian cortical inclusion cysts (CIC) which produce borderline and low grade serous, mucinous, endometrioid, and clear cell carcinomas. This review summarizes recent advances in our understanding of the cellular origin of EOC and the molecular mechanisms defining the basis of CSC in EOC progression and chemoresistance. Using a model ovarian cancer cell line, we highlight the role of CSC in response to chemotherapy, and relate how CSCs may impact on chemoresistance and ultimately recurrence. We also propose the molecular targeting of CSCs and suggest ways that may improve the efficacy of current chemotherapeutic regimens needed for the management of this disease. J. Cell. Biochem. 114: 21–34, 2012. © 2012 Wiley Periodicals, Inc.     

The dynamic interactions between the stroma,pancreatic stellate cells and pancreatic tumor development: Novel therapeutic targets

The stroma is a main driver of metastasis and aggressiveness in pancreatic cancer (PC), one of the deadliest malignancies worldwide. Pancreatic stellate cells (PSCs) form approximately 50% of the pancreatic tumor stroma, causing desmoplasia, extracellular matrix (ECM) deposition, epithelial-to-mesenchymal transition (EMT) and metastatic spread. Furthermore, activated PSCs can remodel the pancreatic tumor microenvironment (TME) via dynamic and complex interactions and feedback loops with PC cells, thus facilitating tumor growth through various signalling and immune pathways. Hence, increased understanding of these cellular cross-talks and how they shape the TME in PC might guide the development of novel treatment approaches against this stubborn and deadly malignancy that has so far resisted therapeutic advances. In this review, we will explore the role of the stroma and PSCs in PC development, invasion and metastasis, examine their interaction with PC cells and discuss potential treatment approaches aimed at targeting PSCs in order to reprogram the pancreatic tumor environment.     

Microorganisms in chemotherapy for pancreatic cancer: An overview of current research and future directions

Pancreatic cancer is a malignant tumor of the digestive system with a very high mortality rate. While gemcitabine-based chemotherapy is the predominant treatment for terminal pancreatic cancer, its therapeutic effect is not satisfactory. Recently, many studies have found that microorganisms not only play a consequential role in the occurrence and progression of pancreatic cancer but also modulate the effect of chemotherapy to some extent. Moreover, microorganisms may become an important biomarker for predicting pancreatic carcinogenesis and detecting the prognosis of pancreatic cancer. However, the existing experimental literature is not sufficient or convincing. Therefore, further exploration and experiments are imperative to understanding the mechanism underlying the interaction between microorganisms and pancreatic cancer. In this review, we primarily summarize and discuss the influences of oncolytic viruses and bacteria on pancreatic cancer chemotherapy because these are the two types of microorganisms that are most often studied. We focus on some potential methods specific to these two types of microorganisms that can be used to improve the efficacy of chemotherapy in pancreatic cancer therapy.