Id蛋白与肿瘤增殖和侵袭转移的关系

自1990年编码Id蛋白的基因从鼠造血细胞株中被克隆并发现以来,大量研究显示Id蛋白具有一些癌蛋白的属性,它们通过抑制细胞分化、推进细胞周期进程、诱导细胞增殖、抑制衰老,促进细胞存活而参与肿瘤的发生与发展。尤其对Id蛋白功能“缺失/获得”的研究进一步证实,Id蛋白参与人类肿瘤进程以及肿瘤增殖、侵袭转移等恶性潜能。Id蛋白在肿瘤侵袭转移中的作用为恶性肿瘤预后估计提供了新的指标、为Id蛋白靶向肿瘤治疗策略提供新的思路。     

Comprehensive Analysis of Recent Biochemical and Biologic Findings Regarding a Newly Discovered Protein-PELP1/MNAR

Estradiol (E2) and estrogen receptor (ER) signaling have been implicated in the development and progression of several cancers. Emerging evidence suggests that the status of ER coregulators in tumor cells plays an important role in hormonal responsiveness and tumor progression. Proline, glutamic acid, and leucine-rich protein-1 (PELP1/MNAR)—a novel ER coactivator that plays an essential role in the ER’s actions and its expression—is deregulated in several hormonal responsive cancers. The precise function of PELP1/MNAR in cancer progression remains unclear, but PELP1 appears to function as a scaffolding protein, coupling ER with several proteins that are implicated in oncogenesis. Emerging evidence suggests that PELP1/MNAR increases E2-mediated cell proliferation and participates in E2-mediated tumorigenesis and metastasis.     

Normalization of the tumor microenvironment: evidence for tissue inhibitor of metalloproteinase-2 as a cancer therapeutic

Matrix metalloproteinases (MMPs) are members of the Metzincin family of proteases responsible for degrading the extracellular matrix (ECM). In early studies, MMP degradation of the sub-epithelial basement membrane was thought to be tumor cell autonomous and contribute to the invasive behavior of malignant cells. It is now recognized that MMPs have multiple roles that can either promote or inhibit tumor progression and metastasis. The endogenous inhibitors of the MMPs are the tissue inhibitors of metalloproteinases (TIMPs). Early studies on the tumor microenvironment revealed TIMP function to be principally through the inhibition of MMPs, thereby blocking tumor cell migration and invasion. However, data from a number of laboratories are now reporting that TIMPs have direct cellular functions, independent of their MMP inhibitory activity. The TIMPs can modulate normal tissue physiology and development, as well as pathology and progression in a variety of acute and chronic disease states. In this review, we briefly describe the role of MMPs and TIMPs in ECM turnover and formation of the tumor microenvironment. Based on the evidence presented, we postulate that TIMP-2 and other soluble components of the normal ECM may provide a novel therapeutic approach to cancer treatment through “normalization” of the tumor microenvironment.     

Adoptive immunotherapy prevents prostate cancer in a transgenic animal model

Cancer-related mortality can be decreased by prevention, early detection and improved therapies. Although animal models should be used to evaluate the success of cancer therapies, their usefulness is controversial. Many cancer therapies that have cured tumors in mice have not met with similar success when attempted in humans. Current animal models rely mainly on inoculating cell lines into animals, a method that does not reproduce the natural development of the tumor, both for the kinetics of induction and the anatomical site concerned. In this study, we have used an SV40 T-antigen-transgenic mouse model of prostate cancer in which the tumor spontaneously develops orthotopically with a disease progression that closely resembles the progression of human prostate cancer. We have used this model to test the suitability of adoptive cellular immunotherapy. Transfer of naive cells obtained from a T-antigen-negative congenic animal had significant but partial effects: it prevented development of malignant tumors, leaving just minor foci of residual tumor and/or hyperplasia. Adoptive transfer of memory lymphocytes specific for T-antigen, which is a prostatic self antigen in this model, prevented tumor development and progression without affecting the morphology and function of involved tissues. Treated animals were able to breed, and their survival was greatly increased. These results strongly suggest that adoptive immunotherapy should be successful in treating early stages of human prostate cancer.     

Volume controlled apparatus for neonatal tidal liquid ventilation

Conventional gas ventilation is often unsuccessful for premature neonatal patients suffering from respiratory distress syndrome (RDS). For such patients, liquid ventilation (LV) with perfluorocarbon (PFC) liquids has been proposed. By eliminating the air-liquid interface in saccules (the premature gas exchange structures), where scarce or absent surfactant production exists, pulmonary instability is avoided, lung compliance is improved, and atelectatic saccules are recruited, ultimately lowering the saccular pressure. Tidal LV involves administrating a liquid tidal volume to the patient at each respiratory cycle, and therefore requires a dedicated circuital setup to deliver, withdraw, and refresh the PFC during the treatment. We have developed a prototype liquid breathing system (LBS). The apparatus comprises two subcircuits managed by a personal computer based control system. The ventilation subcircuit performs inspiration/expiration with two sets of peristaltic pumps. A system to evaluate the true inspired/expired volumes was devised that consists of two reservoirs equipped with pressure transducers measuring the hydraulic head of the fluid therein. Volume accuracy was +/- 0.3 ml. The refresh subcircuit properly processes the PFC by performing filtration (DFA, Pall, NY), oxygenation, CO2 scavenge, and heat exchange (SciMed 2500, Life Systems, MN). The new apparatus has been used in preliminary animal tests on five newborn mini pigs with induced acquired RDS. The PFC used was RM-101 (Miteni, Milano, Italy). The animals were successfully supported for 4 hours each. Mean arterial O2 pressure was 131.4 mm Hg (range 79.0-184.2), and mean arterial CO2 pressure was 64.8 mm Hg (range 60.0-73.4).     

The pros and cons of chemokines in tumor immunology

Innate and adaptive immune cells can intervene during tumor progression at different stages including initiation, angiogenesis, local spreading and distant metastasis formation. The net effect can be favorable or detrimental to tumor development, depending on the composition and activation status of the immune infiltrate. Chemokines can determine the distribution of immune cells in the tumor microenvironment and also affect stroma composition. Here we consider how a complex network of chemokines plays a key role in dictating the fate of a tumor. Although the field is in its infancy, we also highlight how targeting chemokines offers a tool to modulate the tumor environment with the aim of enhancing immune-mediated rejection of cancer.     

Pax3/Pax7 mark a novel population of primitive myogenic cells during development

Skeletal muscle serves as a paradigm for the acquisition of cell fate, yet the relationship between primitive cell populations and emerging myoblasts has remained elusive. We identify a novel population of resident Pax3+/Pax7+, muscle marker-negative cells throughout development. Using mouse mutants that uncouple myogenic progression, we show that these Pax+ cells give rise to muscle progenitors. In the absence of skeletal muscle, they apoptose after down-regulation of Pax7. Furthermore, they mark the emergence of satellite cells during fetal development, and do not require Pax3 function. These findings identify critical cell populations during lineage restriction, and provide a framework for defining myogenic cell states for therapeutic studies.     

The EGF/ErbB receptor family and apoptosis

The ErbB receptor family can activate a multitude of cell signaling pathways that involve many aspects of cellular function. The four members of the ErbB receptor family interact with diverse ligands and substrates, as well as with each other through cell surface heterodimerization. The sum of these diverse interactions is a signaling network that is complex but also finely regulated. Among the cellular functions influenced by ErbB signaling is cell survival. ErbB receptor signaling has been demonstrated to interact with all of the major mechanisms of cell death signaling in a manner that promotes cell survival. Survival factors such as Ras, PI3-K, Akt, and Bcl-x/-2 all have been shown to be activated by ErbB signaling (Fig. 5). ErbB abrogation of apoptotic signals has been shown to play an important role during embryonic tissue development, in normal adult tissue maintenance (e.g. mammary tissue, wound healing), and also in tumor development and progression. Although the majority of studies suggest that ErbB receptor family members are mediators of cell survival, there have been occasional reports suggesting that ErbB receptors can induce cell death under selected experimental conditions. While this apparent discrepancy remains unresolved, in many of these reports, cell death may be the result of anoikis in response to changes in the cytoskeleton associated with hyperstimulation of ErbB signaling. The notion that ErbB receptor family members function to promote cell survival is not a recent observation. However, how this family functions to prevent apoptosis is an area that only recently has been considered. The understanding of ErbB receptor signaling as it relates to the avoidance of apoptosis had profound implications for the treatment of solid tumors originating in multiple tissues, as well as for the treatment of neurodegenerative disease. Further elucidation of the complex relationships between ErbB receptor signaling networks and the apoptotic machinery is certain to yield biologically important and potentially life-saving information.     

Role of Cripto-1 in Stem Cell Maintenance and Malignant Progression

Cripto-1 is critical for early embryonic development and, together with its ligand Nodal, has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Like other embryonic genes, Cripto-1 performs important roles in the formation and progression of several types of human tumors, stimulating cell proliferation, migration, epithelial to mesenchymal transition, and tumor angiogenesis. Several studies have demonstrated that cell fate regulation during embryonic development and cell transformation during oncogenesis share common signaling pathways, suggesting that uncontrolled activation of embryonic signaling pathways might drive cell transformation and tumor progression in adult tissues. Here we review our current understanding of how Cripto-1 controls stem cell biology and how it integrates with other major embryonic signaling pathways. Because many cancers are thought to derive from a subpopulation of cancer stem-like cells, which may re-express embryonic genes, Cripto-1 signaling may drive tumor growth through the generation or expansion of tumor initiating cells bearing stem-like characteristics. Therefore, the Cripto-1/Nodal signaling may represent an attractive target for treatment in cancer, leading to the elimination of undifferentiated stem-like tumor initiating cells.Embryonic development involves coordinated processes of proliferation of progenitor stem cells that carry the potential of self-renewal and subsequent differentiation into distinct cell lineages.¹ After fertilization, totipotent stem cells of the blastocyst give rise to all tissues. With subsequent cell divisions, stem cells retain their self-renewal capacity, but they become more restricted in their differentiation potential, becoming progenitor cells (adult or somatic stem cells) that give rise to differentiated somatic cells in specific tissues.¹Therefore, two fundamental properties characterize stem cells: self-renewal, the ability to maintain their identity through a long period of time, and multipotency, the ability to generate all differentiated cell types of a specific tissue. A stem cell that asymmetrically divides can generate a new stem cell and a committed daughter cell. In the adult, a pool of stem cells resides within specific microenvironments or niches in adult tissues and functions as an internal repair system, dividing to replenish specialized cells and also maintaining the normal turnover of regenerative organs, such as blood, skin, or intestinal epithelium.² Stem cells, therefore, are of interest for their potential use in regenerative medicine.Recent progress has identified potential molecular signatures of embryonic stem (ES) cells that delineate pathways that are used by somatic stem cells in the maintenance of self-renewal and in cell fate decisions.³ Among these markers of stemness, Cripto-1 represents an important component of a critical core pathway that is used by ES cells. In this review we highlight the role of Cripto-1 in stem cell self-renewal and differentiation with particular emphasis on the cross talk with other ES cell genes. Finally, re-expression of Cripto-1 in human cancers and its contribution to malignant progression is discussed.     

Modulating apoptosis as a target for effective therapy

Alterations in cell proliferation and cell death are essential determinants in the pathogenesis and progression of several diseases such as cancer, neurodegenerative disorders or autoimmune diseases among others. Complex networks of regulatory factors determine whether cells proliferate or die. Recent progress in understanding the molecular changes offer the possibility of specifically targeting molecules and pathways to achieve more effective and rational therapies. Drugs that target molecules involved in apoptosis are used as treatment against several diseases. Candidates such as TNF death receptor family, caspase inhibitors, antagonists of the p53-MDM2 interaction, NF-kappaB and PI3K pathways and Bcl-2 family members have been targeted as cancer cell killing agents. Moreover, apoptosis of tumor cells can also be achieved by targeting the inhibitor of apoptosis proteins, IAPs, in addition to the classical antiproliferative approach. Disruption of STAT activation and interferon beta therapy have been used as a treatment to prevent the progression of some autoimmune diseases. In models of Parkinson's, Alzheimer's and amyotrophic lateral sclerosis, blocking of Par-4 expression or function, as well as caspase activation, prevents neuronal cell death. Finally, it has been shown that gene therapy may be an encouraging approach for treatment of neurodegenerative disorders.     

Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia

Loss-of-function mutations in progranulin (GRN) cause ubiquitin- and TAR DNA-binding protein 43 (TDP-43)-positive frontotemporal dementia (FTLD-U), a progressive neurodegenerative disease affecting approximately 10% of early-onset dementia patients. Here we expand the role of GRN in FTLD-U and demonstrate that a common genetic variant (rs5848), located in the 3'-untranslated region (UTR) of GRN in a binding-site for miR-659, is a major susceptibility factor for FTLD-U. In a series of pathologically confirmed FTLD-U patients without GRN mutations, we show that carriers homozygous for the T-allele of rs5848 have a 3.2-fold increased risk to develop FTLD-U compared with homozygous C-allele carriers (95% CI: 1.50-6.73). We further demonstrate that miR-659 can regulate GRN expression in vitro, with miR-659 binding more efficiently to the high risk T-allele of rs5848 resulting in augmented translational inhibition of GRN. A significant reduction in GRN protein was observed in homozygous T-allele carriers in vivo, through biochemical and immunohistochemical methods, mimicking the effect of heterozygous loss-of-function GRN mutations. In support of these findings, the neuropathology of homozygous rs5848 T-allele carriers frequently resembled the pathological FTLD-U subtype of GRN mutation carriers. We suggest that the expression of GRN is regulated by miRNAs and that common genetic variability in a miRNA binding-site can significantly increase the risk for FTLD-U. Translational regulation by miRNAs may represent a common mechanism underlying complex neurodegenerative disorders.     

Localization of a novel tumor metastasis suppressor region on the short arm of human chromosome 2

Much of the lethality of malignant neoplasms is attributable directly to their ability to develop secondary growths in organs at a distance from the primary tumor mass, whereas few patients die from their primary neoplasm. Little is known about the molecular mechanism of tumor metastasis, however, which is controlled by a variety of positive and negative factors. In the search for metastasis suppressor genes, we have used the microcell-mediated chromosome transfer method and a rat prostate tumor model in SCID mice. When human chromosome 2 was introduced into the highly metastatic rat prostatic tumor cell, AT6.1, the metastatic ability of this cell was significantly (>99%) decreased in animals. An STS-based PCR analysis for 8 hybrid clones indicates that the suppressor activity is located in the p25-22 region of the chromosome. Furthermore, the AT6.1 cell with human chromosome 2 showed a reduced ability to invade Matrigel, suggesting that the suppressor activity is involved in the step of tumor invasion during the progression of prostate cancer. We have also examined the status of the suppressor region on chromosome 2 in human prostate cancer specimens and found that this region was often lost in high-grade tumors. These results suggest that the putative suppressor gene on chromosome 2 is functionally involved in the progression of human prostate cancer. Genes Chromosomes Cancer 28:285-293, 2000.     

The neurotrophic properties of progranulin depend on the granulin E domain but do not require sortilin binding

Progranulin (PGRN) is a growth factor involved in wound healing, inflammation, tumor growth, and neurodegeneration. Mutations in the gene encoding PGRN give rise to shortage of PGRN and cause familial frontotemporal lobar degeneration. PGRN exerts neurotrophic functions and binding of PGRN to the membrane receptor sortilin (SORT1) mediates the endocytosis of PGRN. SORT1-mediated uptake plays an important role in the regulation of extracellular PGRN levels. We studied the role of SORT1 in PGRN-mediated neuroprotection in vitro and in vivo. The survival-enhancing effect of PGRN seemed to be dependent on the granulin E (GRN E) domain. Pharmacologic inhibition of the GRN E–SORT1 interaction or deletion of the SORT1 binding site of GRN E did not abolish its neurotrophic function. In addition, the in vivo phenotype of PGRN knockdown in zebrafish embryos was not phenocopied by SORT1 knockdown. These results suggest that GRN E mediates the neurotrophic properties of PGRN and that binding to SORT1 is not required for this effect.