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Molecular Roles of TGF-beta Signaling in Salivary Glands and Oral Cancer

TGF-β 信号传导在唾液腺和口腔癌中的分子作用

基本信息

批准号：
8553350
负责人：
Ashok Kulkarni
金额：
$ 58.16万
依托单位：
NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8553350
关键词：
AKT2 gene Affect Alcohol consumption Animal Model Animals Antineoplastic Agents Apoptosis Biological Markers CCND1 gene Cancer Diagnostics Cell Proliferation Cell physiology Cells Chromosomes, Human, Pair 10 Clinical Trials Communities Coupled Cytotoxic Chemotherapy Cytotoxin Development Disease Down-Regulation Embryonic Development Epigenetic Process Epithelium Exotoxins Extramural Activities Fibrosis Gene Targeting Genetic Genetic Polymorphism Genetic Predisposition to Disease Genomics Glioma Growth Factor Head and Neck Squamous Cell Carcinoma Head and neck structure Human Human Papillomavirus Immune Immune System Diseases Immunosuppression Induced Mutation Infiltration Inflammation Inflammatory Interleukin-13 Knock-out Knockout Mice Lesion Loss of Heterozygosity Malignant Neoplasms Mammals Metabolism Modeling Molecular Mus Mutation Myelogenous NF-kappa B Neoplastic Cell Transformation Oncogene Proteins Oncogenic PTEN gene PTEN protein Pain Pathway interactions Penetrance Phenotype Phosphorylation Physiological Processes Play Prevention strategy Process Protein Isoforms Proteomics Pseudomonas Reporting Research Research Personnel Risk Factors Role Route Saline Salivary Glands Signal Pathway Signal Transduction Sirolimus Squamous Cell Staging Stratum Basale Structure Suppressor-Effector T-Lymphocytes Survival Rate TGF Beta Signaling Pathway TGFBR1 gene Testing Therapeutic Tissues Tobacco Tooth structure Transforming Growth Factor beta Tumor Burden Tumor Promoters Tumor Suppressor Genes Tumor Suppressor Proteins Tumor Volume Tumorigenicity Wound Healing angiogenesis anti-cancer therapeutic base cancer cell cancer stem cell cancer therapy carcinogenesis cell growth craniofacial effective therapy high risk human FRAP1 protein human PIK3CA protein human TGFB1 protein improved in utero in vivo interleukin-13 receptor mTOR Inhibitor malignant mouth neoplasm malignant tongue neoplasm mineralization molecular array mouse model overexpression preclinical study prevent receptor expression senescence tumor tumor growth tumorigenesis

项目摘要

TGF-beta: inflammation, fibrosis, and cancer: The TGF-beta superfamily of multifunctional growth factors is involved in key processes such as cell proliferation, differentiation, embryonic development, carcinogenesis, immune dysfunction, inflammation, and wound healing. Three highly homologous isoforms of TGF-beta have been identified in mammals, and they share a common signaling pathway. Our primary focus has been to delineate the precise role of the TGF-beta signaling pathway in development, inflammation, and carcinogenesis. We initiated these studies in 1992 with TGF-beta1 knockout mice (Kulkarni et al., Proc. Natl. Acad. Sci. USA 90: 770-774, 1993). More than half of these mice died in utero, and those born alive developed multifocal and fatal inflammation, which prevented us from carrying out a detailed analysis of this isoform's cellular functions during various physiological processes. In order to overcome this problem, we have been testing strategies to generate conditional deletion, activation, or alteration of the TGF-beta1 signaling pathway. Molecular roles of TGF-beta signaling in head and neck squamous cell carcinogenesis(HNSCC): Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer. The underlying cellular and molecular mechanisms that contribute to the initiation and progression of HNSCC have not been completely delineated. Tobacco, alcohol consumption, and human papillomavirus (HPV) are the major risk factors associated with the development of HNSCC. These risk factors, together with genetic susceptibility, result in the accumulation of multiple genetic and epigenetic alterations in a multistep process of cancer development. In addition, the tumor microenvironment also contributes significantly to head and neck carcinogenesis. Recent advances in the understanding of the oncogenesis of HNSCC have revealed multiple deregulated signaling pathways. TGF-beta; and PTEN/PI3K/Akt/mTOR pathways are among the most frequently altered signaling routes. Both pathways play central roles in numerous cellular processes including metabolism, cell growth, apoptosis, survival, and differentiation, all of which ultimately contribute to HNSCC progression. The effects of TGF-beta signaling in carcinogenesis largely depend on the tissue of origin and the tumor type. In most types of human cancer, TGF-beta plays a paradoxical role in cancer development by acting as a tumor suppressor during the early stages, and as a tumor promoter during the later stages. Several reports have noted that mutations and polymorphisms of TGFBR1 and Smad signaling are associated with HNSCC, suggesting that TGF-beta functions as a potent tumor suppressor. However, it is not clear whether alterations in TGF-beta signaling act alone or in concert with those involving other pathways to promote a pro-oncogenic phenotype in advanced late-stage HNSCC. The PI3K/Akt pathway is important for suppressing apoptosis and promoting cell growth and proliferation. In HNSCC, hyperactivation of PI3K can be induced by mutations or by enhanced activity of its upstream activators, including the activation of Ras oncoproteins or inactivation of PTEN (phosphatase and tensin homolog deleted on chromosome 10). PTEN is a potent tumor suppressor gene and a negative regulator of the PI3K/Akt pathway. While PTEN mutations were identified in 0-16% of HNSCC, loss of PTEN expression was observed in 29% of tongue cancers, and loss of heterozygosity (LOH) of the PTEN locus was identified in 40% of HNSCCs. Additionally, 47% of HNSCC cases showed at least one molecular alteration in the PI3K/Akt pathway, including PI3KCA and AKT2 amplification, p110-alpha; overexpression, and PTEN protein downregulation. This suggests the critical role of PTEN/PI3K/Akt signaling pathways in the carcinogenesis of HNSCC. The studies from our previous mouse model indicate that there may be negative crosstalk between the TGF-beta1 tumor suppressor and the PI3K/Akt pathways. To further characterize the interactions between TGF-beta signaling and the PI3K/Akt pathway during the development of HNSCC, we conditionally deleted Tgfbr1 along with Pten to enhance PI3K/Akt pathway activation in mouse head and neck epithelia using the Cre-LoxP approach. Conditional activation of the PI3K/Akt pathway due to Pten deletion in mouse head and neck epithelia gives rise to hyperproliferation, but only a few lesions progress to HNSCC. However, Tgfbr1/Pten double-conditional knockout (2cKO) mice developed HNSCC with full penetrance. Tumors that developed in Tgfbr1/Pten 2cKO mice displayed pathological and molecular alterations that resembled human HNSCCs. The basal layer of head and neck epithelia, as well as in the tumors of Tgfbr1/Pten 2cKO mice, display enhanced cell proliferation, decreased apoptosis, and increased expression of CCND1. Furthermore, neoplastic transformation involves senescence evasion and is associated with increased expression of several markers of HNSCC cancer stem cells (CSCs). In addition, NF-κB pathway activation, inflammatory myeloid derived suppressor cell (MDSC) infiltration, angiogenesis and immune suppression in the tumor microenvironment, implicated in human HNSCC carcinogenesis, are induced in 2cKO mice. This suggests that the Tgfbr1/Pten 2cKO mice provide a model with multiple pathological and molecular alterations, suitable for preclinical studies of diagnostic cancer biomarkers and effective strategies for prevention and treatment of HNSCCs. Therapeutic approaches to treat HNSCC: Human cases of HNSCC show frequent alterations in components of both the TGF-beta and PI3K/Akt signaling pathways. With deletion of TGF-beta signaling and activation of the PI3K/Akt pathway, our double conditional knockout mouse model mimics some of the molecular changes seen in human cases of HNSCC. These mice can thereby serve as a unique mouse model of SCC to evaluate the tumorigenicity and effects of anti-cancer therapeutics. The tumors from the TβR1/Pten cKO mice are histopathologically indistinguishable from human HNSCCs and show similar molecular changes, such as increased phosphorylation of Akt, Stat3, and NF-kappaB. Additionally, tumors from our mouse model showed elevated expression of the interleukin-13 receptor IL-13Ralpha2, a unique cancer diagnostic marker that is expressed at high levels in about 30% of human HNSCCs. Based on this observation, targeted cytotoxic therapy against this cancer marker could be tested in TGFBR1/Pten cKO mice, since IL-13alpha2 is highly expressed on cancer cells but is lacking or minimally expressed on normal immune cells. First, primary cultures of the SCCs were treated with a targeted cytotoxin composed of IL-13 fused to the Pseudomonas Exotoxin (IL-13 PE), which is currently being used in clinical trials for glioma. After proving sensitivity to this cytotoxin treatment in vivo, the TGFBR1/Pten cKO mice were injected with IL-13 PE three weeks after tumor induction. Those treated with IL-13 PE showed better survival rates along with significantly reduced tumor burden in comparison to animals treated with only saline. This demonstrates the usefulness of the animal model in testing anti-cancer treatments. Interestingly, this anti-cancer treatment reduced IL-13 alpha-2u receptor expression in the tested mice. With elevated PI3K/Akt signaling, we also decided to treat the TGF-betaR1/Pten cKO mice with rapamycin, an mTOR inhibitor. This antineoplastic therapy reduced tumor volume and improved overall survival in the TGF-betaR1/Pten cKO mice.

tgf - β：炎症、纤维化和癌症；

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Manipulation of mouse embryonic stem cells for knockout mouse production.

DOI：
10.1002/0471143030.cb1913s44
发表时间：
2009-09
期刊：
Current protocols in cell biology
影响因子：
0
作者：
Limaye, Advait;Hall, Bradford;Kulkarni, Ashok B
通讯作者：
Kulkarni, Ashok B

Increased globotriaosylceramide levels in a transgenic mouse expressing human alpha1,4-galactosyltransferase and a mouse model for treating Fabry disease.

表达人 α1,4-半乳糖基转移酶的转基因小鼠和治疗法布里病的小鼠模型中三酰基神经酰胺水平升高。

DOI：
10.1093/jb/mvq125
发表时间：
2011
期刊：
Journal of biochemistry
影响因子：
2.7
作者：
Shiozuka,Chikara;Taguchi,Atsumi;Matsuda,Junichiro;Noguchi,Yoko;Kunieda,Takanori;Uchio-Yamada,Kozue;Yoshioka,Hidekatsu;Hamanaka,Ryoji;Yano,Shinji;Yokoyama,Shigeo;Mannen,Kazuaki;Kulkarni,AshokB;Furukawa,Koichi;Ishii,Satoshi
通讯作者：
Ishii,Satoshi

Conditional overexpression of TGF-beta1 disrupts mouse salivary gland development and function.