Begell House Inc.
Critical Reviews™ in Eukaryotic Gene Expression
CRE
1045-4403
22
2
2012
Ciliary Epithelium: An Underevaluated Target for Therapeutic Regeneration
87-95
10.1615/CritRevEukarGeneExpr.v22.i2.10
Chandrika
Abburi
Department of Neurology, Post Graduate Institute of Medical Education and Research (PGIMER), Neuroscience Research Laboratory, Chandigarh-160012, India
Akshay
Anand
Neuroscience Research Lab, Post Graduate Institute of Medical Education and Research, Chandigarh, India
stem cells
ciliary epithelium
retina
vascular niche
The purpose of stem cells in various organs of vertebrates is to replenish dying cells or to replace damaged tissues. However, a few organs have reasonable, while others have very limited regenerative, capacity. Until the last two decades, the organs such as brain, heart, and kidneys were known to lack regenerative capacity for lack of resident stem cell population. However, with advancement of techniques and an increase in scientific communication, new discoveries have brought novel concepts and data to discover and manipulate these valuable resources. Much focus has been devoted to understanding the regulation and maintenance of these stem cells. We discuss the preclinical data emerging from retino-vascular interactions useful in the exploitation of ciliary epithelium−derived stem cells for therapeutic regeneration.
Paracrine Sonic Hedgehog Signaling Derived from Tumor Epithelial Cells: A Key Regulator in the Pancreatic Tumor Microenvironment
97-108
10.1615/CritRevEukarGeneExpr.v22.i2.20
Xuqi
Li
Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University , Xi'an 710061, Shaanxi, China
Qingyong
Ma
Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China
Wanxing
Duan
Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China
Han
Liu
Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China
Hongqin
Xu
Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China
Erxi
Wu
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105
pancreatic cancer
Sonic hedgehog
tumor microenvironment
stroma
Activation of the hedgehog (Hh) signaling pathway is involved in embryo development and tumorigenesis. While normal pancreatic tissue exhibits little Hh pathway activity, patients with pancreatic adenocarcinoma have high levels of Hh pathway signaling in both the tumor epithelia and the surrounding stromal tissue. Hh ligands expressed by pancreatic cancers promote tumor growth indirectly by activating Hh signaling in the surrounding stroma. This paracrine activation of Hh signaling in the tumor microenvironment provides a more favorable environment for tumor cellular proliferation, metastasis, and resistance to therapy. Taken together, these findings are of valuable implications for the use of Hh pathway inhibitors currently in development and inhibition of the Hh pathway paracrine loop in pancreatic cancer.
Thymosin β4: A Potential Molecular Target for Tumor Therapy
109-116
10.1615/CritRevEukarGeneExpr.v22.i2.30
Yongtao
Xiao
Shanghai Institute of Pediatric Research, Shanghai, China;Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition,China
Yingwei
Chen
Department of Gastroenterology, Shanghai Jiao Tong University, School of Medicine, Xin Hua Hospital, Shanghai, China;Shanghai Institute of Pediatric Research, Shanghai, China;Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition
Jie
Wen
Shanghai Institute of Pediatric Research, Shanghai, China
Weihui
Yan
Shanghai Institute of Pediatric Research, Shanghai, China
Kejun
Zhou
Shanghai Institute of Pediatric Research, Shanghai, China;Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition,China
Wei
Cai
Shanghai Institute of Pediatric Research, Shanghai, China ; Department of Pediatric Surgery, Shanghai Jiao Tong University, School of Medicine, Xin Hua Hospital, Shanghai, China
thymosin β4
inflammation
cell migration
inflammation
actin sequestering
cancer therapy
Thymosin β4 (Tβ4), a 5 kDa protein, has been demonstrated to play an important role in a variety of biological activities, such as actin sequestering, cellular motility, migration, inflammation, and damage repair. Recently, several novel findings provided compelling evidence that Tβ4 played a key role in facilitating tumor metastasis and angiogenesis. It has been found that Tβ4 expressed increasingly in a number of metastatic tumors, which was associated with an increased expression of a known angiogenic factor, vascular endothelial growth factor. Thus, Tβ4 provided a potential target of opportunity for cancer management, especially for cancer metastasis therapy.
Targeting the Regulatory Machinery of BIM for Cancer Therapy
117-129
10.1615/CritRevEukarGeneExpr.v22.i2.40
Hisashi
Harada
Department of Oral and Craniofacial Molecular Biology, Massey Cancer Center, Virginia Commonwealth University Health Sciences System, Richmond VA, 23298
Steven
Grant
Department of Medicine, Division of Hematology/Oncology, Massey Cancer Center, Virginia Commonwealth University Health Sciences System, Richmond VA, 23298
BIM
regulation
BCL-2
apoptosis
transcription
translation
BIM represents a BH3-only proapoptotic member of the BCL-2 family of apoptotic regulatory proteins. Recent evidence suggests that in addition to its involvement in normal homeostasis, BIM plays a critical role in tumor cell biology, including the regulation of tumorigenesis through activities as a tumor suppressor, tumor metastasis, and tumor cell survival. Consequently, BIM has become the focus of intense interest as a potential target for cancer chemotherapy. The control of BIM expression is complex, and involves multiple factors, including epigenetic events (i.e., promoter acetylation or methylation, miRNA), transcription factors, posttranscriptional regulation, and posttranslational modifications, most notably phosphorylation. Significantly, the expression of BIM by tumor cells has been shown to play an important role in determining the response of transformed cells to not only conventional cytotoxic agents, but also to a broad array of targeted agents that interrupt cell signaling and survival pathways. Furthermore, modifications in BIM expression may be exploited to improve the therapeutic activity and potentially the selectivity of such agents. It is likely that evolving insights into the factors that regulate BIM expression will ultimately lead to novel BIM-based therapeutic strategies in the future.
Prostate Cancer and Parasitism of the Bone Hematopoietic Stem Cell Niche
131-148
10.1615/CritRevEukarGeneExpr.v22.i2.50
Chunyan
Yu
Department of Urology, School of Medicine, University of Michigan, Ann Arbor, MI; Tianjin Key Laboratory of Cellular and Molecular Immunology; Key Laboratory of Educational Ministry of China;Department of Immunology, School of Basic Medical Sciences
Yusuke
Shiozawa
Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI
Russell S.
Taichman
Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI
Laurie K.
McCauley
Department of Periodontics/Prevention/Geriatrics, School of Dentistry, University of Michigan; Department of Pathology, Medical School, University of Michigan
Kenneth J.
Pienta
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, Ml 48109-0680
Evan T.
Keller
Department of Urology, School of Medicine, University of Michigan, 1500 E. Medical Center Dr., Room 5308 CCGCB, Ann Arbor, MI 48105, USA; Center for Translational Medicine, Guangxi Medical University, Nanning, China
cancer stem cell
monocytes
prostate cancer
hematopoietic stem cell
microenvironment
A subpopulation of men that appear cured of prostate cancer (PCa) develop bone metastases many years after prostatectomy. This observation indicates that PCa cells were present outside of the prostate at the time of prostatectomy and remained dormant. Several lines of evidence indicate that there are disseminated tumor cells (DTCs) in the bone marrow at the time of prostatectomy. DTCs parasitize the bone microenvironment, where they derive support and impact the microenvironment itself. These DTCs appear to be a heterogeneous population of PCa cells; however, some of them appear to have some aspects of a cancer stem cell (CSC) phenotype as they can develop into clinically detectable metastases. The concept of CSC is controversial; however, several markers of CSC have been identified for PCa, which may represent cells of either basal or luminal origin. These DTCs have now been shown to compete for the hematopoietic stem cell niche in bone, where they may be placed in a dormant state. Interaction with a variety of host factors, including cytokine and cells, may impact the metastatic development and progression, including the dormant state. For example, myeloid cells have been shown to impact both the premetastatic niche and established tumors. Understanding the concepts of how PCa successfully parasitizes the bone microenvironment is paramount toward identifying therapeutic candidates to prevent or diminish PCa bone metastases.
The Effects of Nrf2 on Tumor Angiogenesis: A Review of the Possible Mechanisms of Action
149-160
10.1615/CritRevEukarGeneExpr.v22.i2.60
Suna
Zhou
Department of Radiotherapy, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Thoracic Oncology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University
Wenguang
Ye
Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an,Shaanxi, China
Mingxin
Zhang
Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an,Shaanxi, China
Jun
liang
Department of Radiotherapy, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
Nrf2
tumor angiogenesis
mechanism
To date, preclinical and clinical data have shown that various cancer patients benefit from antiangiogenic therapy because of the important role of angiogenesis in the tumor development process. NF-E2−related factor 2 (Nrf2) is recognized as a key transcription factor of genes coding for various antioxidant and cytoprotective enzymes, and Nrf2 plays important roles during tumor progression. Recent studies have begun to explore the role of Nrf2 in tumor angiogenesis, which may be to promote the advancement of tumor antiangiogenic therapy. This article reviews the Nrf2-related pathways involved in tumor angiogenesis and summarizes the possible mechanisms of Nrf2 action as a pro-angiogenic factor in tumor progression.
PAX Proteins and Fables of Their Reconstruction
161-177
10.1615/CritRevEukarGeneExpr.v22.i2.70
Darrell Alan
Underhill
Department of Oncology, School of Cancer, Engineering & Imaging Sciences, Faculty of Medicine & Dentistry, University of Alberta, 2328 Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, Canada
paired box
homeodomain
transcription factor
DNA-binding domain
developmental biology
phylogenetics
The PAX proteins derive their name from the "paired box," a region of homology first described between the Drosophila paired (Prd) and gooseberry (Gsb) proteins and later found to encode a sequence-specific DNA-binding activity. Both Prd and Gsb also contain a homeodomain, and this combination of DNA-binding domains is conserved in ancestral predecessors, reflecting an early "homeodomain-capturing" event. In addition, the prototypic PAX protein was thought to contain 2 additional features, namely the octapeptide (or eh1) motif and PHT (or OAR) domain−both modulate PAX regulatory activity but are not unique to the PAX family. Together with gene duplications and mutagenesis, a domain loss model accounts for the distinct architecture and sequence of extant PAX proteins. Despite the disparate evolutionary history of these 4 conserved motifs, there is a remarkable level of interplay that is modulated by discrete sequences elsewhere in the protein. Here, the implications with respect to the evolution of PAX protein structure and activity are discussed, it is suggested that the sum of these constituent domains is more than the contribution of individual parts. When combined with alternative splicing and posttranslational modifications, this model confers an extraordinary degree of functional diversity to even highly related PAX proteins.