Begell House Inc.
Onco Therapeutics
OT
2694-4642
7
1-2
2016
Preface: Probiotics and Immunity
v-vi
10.1615/ForumImmunDisTher.2016018171
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
Probiotics and Innate and Adaptive Immune Responses in Premature Infants
1-15
10.1615/ForumImmunDisTher.2016018178
Mark A.
Underwood
School of Medicine, University of California at Davis, Sacramento, CA
bifidobacteria
lactobacilli
necrotizing enterocolitis
probiotic
sepsis
Premature infants are at increased risk for morbidity and mortality due to necrotizing enterocolitis (NEC) and sepsis. Probiotics decrease the risk of NEC and death in premature infants; however, mechanisms of action are unclear. A wide variety of probiotic species have been evaluated for potential beneficial properties in vitro, in animal models, and in clinical trials of premature infants. Although there is variation by species and even strain, common mechanisms of protection include attenuation of intestinal inflammation, apoptosis, dysmotility, permeability, supplanting other gut microbes through production of bacteriocins, and more effective use of available nutrients. Here, we review the most promising probiotics and what is known about their impact on the innate and adaptive immune response.
Probiotics in Human Health
17-31
10.1615/ForumImmunDisTher.2016018570
Amit
Goyal
Department of Pharmacy, School of chemical sciences and pharmacy, Central University of Rajasthan, Rajasthan, India
Tarun
Garg
Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab, India
Goutam
Rath
Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab, India; Punjab Technical University, Kapurthala, Punjab, India
cancer
dietary supplements
infectious disease
probiotics
vaccine
According to the Food and Agriculture Organization/World Health Organization, probiotics are live microorganisms that when administered in adequate amounts confer a health benefit to the host. Probiotics show a number of beneficial effects on human health and well-being by influencing the composition of microflora. Probiotics have become an important dietary supplement and have been found to be useful in the formulation of vaccines, providing improved humoral and cellular immunity. They are well tolerated by both newborns and elders and have thus become increasingly popular. Probiotics have been used as an adjuvant in the treatment and prevention of many conditions and diseases including diarrhea, autoimmune disease, cancer, urogenital-related abnormalities, intestinal inflammation, diabetes, atherosclerosis, and allergies. This review provides an overview of the recent advances in various health benefits and biomedical applications of probiotics.
Gut Microbiota: Potential Impact on Chemotherapy-Related Adverse and Therapeutic Effects
33-40
10.1615/ForumImmunDisTher.2016018185
Yann
Touchefeu
Institut des Maladies de l'Appareil Digestif, Centre Hospitalier Universitaire de Nantes, France
M.
Salimon
Institut des Maladies de l'Appareil Digestif, Centre Hospitalier Universitaire de Nantes, France
E.
Montassier
Faculte de Medecine, Laboratoire EA 3826, Therapeutiques Cliniques et Experimentales des Infections, Universite de Nantes, France
chemotherapy
gut microbiota
mucositis
probiotics
Gut microbiota have a key role in the maintenance of intestinal integrity, but chemotherapy can induce major changes in the composition and gene function of gut microbiota. Such modifications may contribute to the development of gastrointestinal mucositis. The prevention of cancer therapy−induced mucositis has been investigated in clinical trials with promising results. The role of gut microbiota is important not only in the development of adverse events but also for immune-related therapeutic effects. Thus, gut microbiota may be an essential partner of chemotherapy in improving patient outcomes.
Activation of Natural Killer Cells by Probiotics
41-55
10.1615/ForumImmunDisTher.2016017095
Nabil
Aziz
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
GALT
immunity
infection
natural killer
probiotics
During the last decade, probiotics have been established to be important mediators of host immunity. Their effects on both innate and adaptive immunity have been documented in the literature. Although several reports have correlated different strains of bacteria as probiotics, their effects on immunity vary. Clearly, there is a complex interplay between various constituents of probiotics and the immune response in humans. The role of probiotics on natural killer (NK) cells in the gut has been the subject of a few reports. In this review, we summarize the reported findings on the role of probiotics in the activation of gut-associated NK cells and the response of NK cells to stimuli elicited by probiotics and their microenvironment. The effects of probiotics on the activation of NK cells and their secretion of immune factors (e.g., interferon−γ, tumor necrosis factor−α, interleukin-2, etc.) are discussed in regard to their clinical significance in various diseases. Current investigations are being pursued, in particular, on the role of probiotics-activated NK cells in promoting the adaptive immune response against pathogens.
PREFACE: Contrasting Roles of KLF4 as an Oncogene or Tumor Suppressor
57-59
10.1615/ForumImmunDisTher.2016018172
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
Mario I.
Vega
Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center IMSS, Mexico City, Mexico; Department of Medicine, Hematology-Oncology Division, Greater Los Angeles VA Healthcare Center, David Geffen School of
Medicine, University of California, Los Angeles
Role of Immune-Cell−Expressing Kruppel-Like Factor 4 in Cancer Development
61-75
10.1615/ForumImmunDisTher.2016018247
Walden
Ai
Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208
KLF4
cancer stem cells
immunosurveillance
MDSCs
fibrocytes
FSP1
Kruppel-like factor 4 (KLF4), a transcription factor that is expressed in a wide range of tissues in mammals, has been reported to function as either a tumor suppressor or an oncoprotein, depending on different cellular contexts. The underlying mechanisms remain largely unknown. KLF4 was originally cloned in epithelial cells and is now also expressed in stem cells. Expression of KLF4 in both stem and epithelial cells may be one of the reasons for its controversial roles in cancer development. In addition, emerging evidence suggests that cancer development is largely controlled by the host immune system or immunosurveillance, but it is unclear how immune-cell−expressing KLF4 contributes to tumor development. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with phenotypic plasticity that have a broad role in tumor development due to their immunosuppressive activities. This review discusses functions of stem-cell−expressing KLF4 and MDSC-expressing KLF4 in cancer development, based on studies in our laboratory.
Identification of the Alternating Oncogenic and Tumor-Suppressor Activities of Kruppel-Like Factor 4 in Various Human Cancers
77-93
10.1615/ForumImmunDisTher.2016017233
Elad
Moyal
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095
Samantha
Kaufhold
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, California; Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
cancer
KLF4
oncogene
tumor suppressor
The Kruppel-like transcription factor 4 (KLF4) is a member of a large family of Kruppel-like transcription factors. KLF4 exerts many functions in both normal and cancerous tissues. In cancer, KLF4 has been reported to act either as an oncogene or tumor suppressor. It is also involved in the regulation of cancer stem cells and resistance to cytotoxic therapeutics. The expression of KLF4 messenger RNA (mRNA) in a variety of hematologic and solid malignancies has been analyzed by bioinformatics. In the majority of the studied cancers, the findings reveal that the high expression levels of KLF4 were associated with tumor progression and that KLF4 was thus acting as an oncogene. In a small number of cancers, the expression level of KLF4 was associated with tumor regression and KLF4 was therefore acting as a tumor suppressor. The data analyzed herein by bioinformatics extended the findings reported in the literature for a few cancers and assigned KLF4 as either an oncogene or tumor suppressor for all cancers studied. The findings derived from bioinformatics require experimental validation. Hence, the expression level of KLF4 may be of prognostic significance for certain cancers, and furthermore, targeting KLF4 may be a potential therapeutic when it acts as an oncogene. We suggest the application of inhibitors specific for KLF4, alone or in combination with conventional therapies, in clinical trials for the reversal of resistance and for tumor suppression.
Dual Roles of Kruppel-Like Factor 4 as a Tumor Suppressor or Oncogene
95-106
10.1615/ForumImmunDisTher.2016017463
Wen-Ting
Yang
Department of Reproductive Medicine, First Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an 710061, People's Republic of China
Peng-Sheng
Zheng
Department of Reproductive Medicine, First Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an 710061, People's Republic of China; Section of Cancer Stem Cell Research, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of the People's Republic of China, Xi'an, The People's Republic of China
KLF4
oncogene
tumor suppressor
Kruppel-like factors (KLFs) have been reported to have important roles in several cellular functions, including carcinogenesis. Recently, KLF4, a member of the KLF family, has been shown to be involved in cell proliferation, differentiation, apoptosis, and migration. By regulating target genes and mediating the cell-signaling pathway, KLF4 acts as an oncogene or a tumor suppressor in a tissue-dependent manner. In this review, we summarize the dual roles of KLF4 as an opposing tumor regulator and focus on the mechanism of KLF4 in carcinogenesis. We discuss that some primary regulators, such as cyclin-dependent kinase inhibitor 1 (p21), might function as a switch that determines the outcome of KLF4 signaling. We also explore a clinical therapy strategy based on the systemic inactivation of KLF4 along with other factors to affect tumorigenesis both positively and negatively as a function of the genetic context.
Regulation of the Cancer Stem Cell Phenotype by Raf Kinase Inhibitor Protein via Its Association with Kruppel-Like Factor 4
107-118
10.1615/ForumImmunDisTher.2016017232
Stephanie
Wottrich
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
cell signaling
CSCs
EMT
KLF4
RKIP
As one of four core transcription factors whose expression is required to induce the pluripotent state, Kruppel-like factor 4 (KLF4) is a factor of utmost interest to the medical scientific community. Particularly, since the discovery of its unusual capability as an indispensable player along with three other factors in achieving this state, significant research has been conducted regarding unearthing the mechanisms by which KLF4 is required for cells to achieve such a state of plasticity. As dynamic as it is, however, the mechanism by which KLF4 carries out its functions is rooted in a number of different systematic regulatory pathways, such as immune function and wound healing among others, including its recently discovered roles that give rise to the embryonic stem cell phenotype and the cancer stem cell (CSC) phenotype. There is a sensitive equilibrium between KLF4 and other proteins as well as epigenetic factors and signals that determine the overall outcome of the functions of KLF4. However, as of yet, very few defined mechanistic pathways fully explain how and why KLF4 contributes specifically to the CSC phenotype. Instead, what is known is based largely on general trends and conjectural implications. The contrasting properties between KLF4 and the metastasis suppression and reversal of drug resistance mediated by Raf kinase inhibitor protein (RKIP) have led us to hypothesize that there might be cross talk between KLF4 and RKIP in CSCs. This brief review presents an overview of some studies reporting on the important role of RKIP in the regulation of the CSC phenotype via its association with KLF4.
KLF4 in Ovarian Cancer
119-126
10.1615/ForumImmunDisTher.2016017273
Junming
Yue
Department of Pathology and Laboratory Medicine and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163
Baojin
Wang
The Third Affiliated Hospital, Zhengzhou University, China
Ziyun
Du
Department of Pathology and Laboratory Medicine and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163
Lawrence M.
Pfeffer
Department of Pathology and Laboratory Medicine and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163
EMT
KLF4
ovarian cancer
The Kruppel-like factor 4 (KLF4) transcriptional factor functions as a tumor suppressor or oncogene in different human cancers. Ovarian cancer is one of the most aggressive malignancies in women. In this review, we discuss the role of KLF4 and the KLF4 regulatory network in ovarian cancer. KLF4 expression inhibits ovarian cancer cell proliferation, migration, invasion, and metastasis. KLF4 inhibits the epithelial-to-mesenchymal transition by directly binding to the promoter of E-cadherin in ovarian cancer cells. Moreover, KLF4 inhibits the cancer stem cell phenotype in ovarian cancer. KLF4 not only regulates microRNA expression but is also targeted by microRNAs. It is a potential biomarker for prognosis and drug targeting in ovarian cancer and may contribute to ovarian cancer metastasis and chemoresistance through a complex gene regulatory network.
The Transcription Regulator Kruppel-Like Factor 4 and Its Dual Roles of Oncogene in Glioblastoma and Tumor Suppressor in Neuroblastoma
127-139
10.1615/ForumImmunDisTher.2016017227
Swapan K.
Ray
Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Building 2, Room C11, 6439 Garners Ferry Road, Columbia, SC 29209
KLF4
oncogene
glioblastoma
tumor suppressor
neuroblastoma
The Kruppel-like factor 4 (KLF4) gene is located on chromosome 9q31. All of the currently known 17 KLF transcription regulators that have similarity with members of the specificity protein family are distinctly characterized by the Cys2/His2 zinc finger motifs at their carboxyl terminals for preferential binding to the GC/GT box or the CACCC element of the gene promoter and enhancer regions. KLF4 is a transcriptional regulator of cell proliferation, differentiation, apoptosis, migration, and invasion, emphasizing its importance in diagnosis and prognosis of particular tumors. KLF4 has been implicated in tumor progression as well as in tumor suppression, depending on tumor types and contexts. Different studies so far strongly suggest that KLF4 acts as an oncogene in glioblastoma, which is the most malignant and prevalent brain tumor in human adult. It is now well established that the presence of glioblastoma stem cells (GSCs) in glioblastoma causes therapy resistance and progressive growth of the tumor. Because KLF4 is one of the key stemness factors in GSCs, it is likely that KLF4 contributes significantly to the survival of GSCs and the recurrence of glioblastoma. On the other hand, recent studies show that KLF4 can act as a tumor suppressor in human malignant neuroblastoma, which is a deadly tumor mostly in children, by inhibiting the cell cycle and activating the cell differentiation and death pathways. Our increasing understanding of the molecular mechanisms of the contrasting roles of KLF4 in glioblastoma and neuroblastoma is useful for superior diagnosis, therapy, and prognosis of these tumors of the nervous system.
Bifunctional Role of Kruppel-Like Factor 4 in Hematological Malignancies
141-151
10.1615/ForumImmunDisTher.2016017234
Mario
Morales-Martinez
Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center IMSS, Mexico City, Mexico
Luz A.
Franco-Cea
Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center IMSS, Mexico City, Mexico
Liliana
Moreno Vargas
Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico, Federico Gomez, SSA, Mexico City, Mexico
Otoniel
Martinez-Maza
UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles
Sara
Huerta-Yepez
Hospital Infantil de México Federico Gomez
Mario I.
Vega
Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center IMSS, Mexico City, Mexico; Department of Medicine, Hematology-Oncology Division, Greater Los Angeles VA Healthcare Center, David Geffen School of
Medicine, University of California, Los Angeles
KLF4
hematological malignances
Burkitt lymphoma
YY1
Kruppel-like factor 4 (KLF4) is a member of the KLF zinc-finger−containing transcription factor family. Reported experimental data have indicated that KLF4 is either an oncogene or tumor suppressor. Moreover, other observations have indicated the role of KLF4 in the regulation of apoptosis, proliferation, and differentiation of B cells and B-cell malignancies. Interestingly, in contrast to adult lymphomas and most solid tumors, we have shown that KLF4 is overexpressed in pediatric non-Hodgkin lymphoma (NHL) tumor tissues, and overexpression of this protein predicted unresponsiveness to cyclophosphamide, doxorubicin, vincristine, and prednisolone treatment. Furthermore, we have found that the transcription factor Ying Yang 1 (YY1) is overexpressed in B-NHL and correlated with the expression of KLF4. Accordingly, we suggest that coexpression of KLF4 and YY1 may result from the transcriptional regulation of KLF4 by YY1. Indeed, this hypothesis was tested in various experimental designs that used both cell lines and tumor tissues derived from patients. From these findings, it was depicted that KLF4 and YY1 are regulated by microRNA-7 and that the activation of KLF4 can suppresses the extrinsic apoptotic pathway by inhibiting activation and cleavage of caspases 7, 9, and 3. Therefore, the overexpression of KLF4 in lymphoma may be responsible, in part, for pathogenesis, malignancy, and drug resistance. We propose that both KLF4 and YY1 may be prognostic biomarkers in pediatric lymphoma. Furthermore, the clinical testing of inhibitors of KLF4 may be a promising novel treatment for lymphoma.
Kruppel-Like Factor 4: From Physiological Functions to Tumor Therapy
153-158
10.1615/ForumImmunDisTher.2016018257
Ruocong
Zhao
Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
Yunxin
Lai
Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
Peng
Li
Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
KLF4
leukemia
solid tumor
Kruppel-like factor 4 (KLF4) is a zinc finger transcription factor that can regulate diverse cellular physiological functions such as cell growth, death, differentiation, and migration. Recent studies have suggested that KLF4 can act as either a suppressor or oncogene for different types of cancers, ranging from solid tumors to leukemia, by regulating target genes involved in tumor cell proliferation, survival, metastasis, invasiveness, and the constitution of the tumor microenvironment. In most cancer types, KLF4 has shown the ability to inhibit tumor progression, thus raising the possibility that it may be a novel target for multiple types of cancer, including T-cell acute lymphoblastic leukemia, which lacks targeted drugs in clinical practice. A better understanding of the role of KLF4 in tumorigenesis will facilitate the application of this potential molecular target for tumor therapy.