Project #3: Fibrillogenesis Mediated Phenotype Switching of Breast Cancer Cells

项目

• 批准号: 9449733
• 负责人: Archana Varadaraj
• 金额: $ 22.81万
• 依托单位: NORTHERN ARIZONA UNIVERSITY
• 依托单位国家: 美国
• 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/9449733
• 关键词: Accounting; Address; Affect; African American; Aggressive behavior; Anoikis; Apoptotic; Autophagocytosis; Behavior; Binding; Biological; Biological Assay; Breast; Breast Cancer Cell; Breast Carcinoma; Breast Epithelial Cells; C-terminal; Carcinoma; Cell Hypoxia; Cell Line; Cell Nucleus; Cell Survival; Cells; Cessation of life; Coculture Techniques; Collagen; Communities; Coupled; Cues; Cultured Cells; Data; Diagnosis; Disease; Duct (organ) structure; Endocytosis; Endothelial Cells; Environment; Epithelial; Epithelial Cells; Epithelial-Stromal Communication; Ethnic group; Event; Extracellular Matrix; Fibronectins; Future; Genetic Transcription; Glycoproteins; Goals; Heparin; Hypoxia; Hypoxia Inducible Factor; Immunoassay; In Vitro; Incidence; Label; Lobule; MCF10A cells; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Metabolism; Metastatic to; Minority; Molecular; Molecular Target; Neoplasm Metastasis; Pathway interactions; Peptides; Phenotype; Play; Polymers; Population; Premalignant; Property; Proteins; Race; Regulation; Research; Rhodamine; Role; Series; Testing; Therapeutic; Tumor Cell Invasion; Vascular Endothelial Growth Factors; Woman; Work; angiogenesis; cancer cell; cancer health disparity; cancer heterogeneity; cell behavior; fibrillogenesis; health equity; insight; malignant breast neoplasm; malignant phenotype; migration; mimetics; mortality; novel; polymerization; prevent; response; therapy resistant; tumor; tumor progression; uptake

PROJECT SUMMARY Epithelial-stromal interactions are critical determinants of epithelial cell behavior in a tumor. While the stromal microenvironment and alterations in the stromal extracellular matrix (ECM), influences invasive and migratory properties at the invasive front, the role of the epithelial matrix in influencing cancer cell behavior are less well understood. Extracellular matrix (ECM) perturbations in epithelial cancers contribute to metastatic spread accounting for 80% of the cancer-related deaths worldwide. The molecular cues that affect the ECM and precede stromal influences on epithelial cell metastasis, is a critical first step at identifying pathways that can be molecularly targeted in the future. The overarching goal of this project is to determine whether alterations in the extracellular matrix of cancer epithelial cells can sufficiently alter cancer cell invasion, migration and metastatic propensity. Fibronectin (FN) matrix dysregulation in response to hypoxia using hypoxia mimetics and 1% O2 will be investigated in the MCF10A progression series to determine whether cellular responses in the three cell lines alternate between premalignant and malignant phenotypes or preinvasive and invasive phenotypes. During low O2 levels in the cells, Hypoxia-inducible factor (HIF)-1α and HIF2α proteins undergo stabilization and translocate to the nucleus to enable transcription of genes involved in cell survival, angiogenesis, and metabolism. An angiogenic transcriptional target of HIFα is VEGF (Vascular endothelial growth factor), which interacts with the C-terminal Heparin-II domain of the FN protein. Using non-contacting and contacting transwell assays, with endothelial cells, the role of FN fibrillogenesis in binding VEGF or releasing VEGF to promote angiogenesis will be determined. While breast cell lines are used in this study, the project goal applies to epithelial cancer cell invasion and migration and hypoxia- mediated angiogenesis that depend on FN fibrillogenesis. The long-term goal of this study is to provide new information on unfavorable FN matrix changes that can be perhaps stabilized that in combination with existing therapeutic strategies will help alleviate cancer cell aggression.

项目摘要 上皮-基质相互作用是肿瘤中上皮细胞行为的关键决定因素。而 基质微环境和基质细胞外基质（ECM）的改变，影响侵袭性 和迁移特性，上皮基质在影响癌细胞中的作用， 行为不太清楚。上皮癌中的细胞外基质（ECM）扰动 导致转移性扩散，占全球癌症相关死亡的80%。的 影响ECM并先于间质影响上皮细胞转移的分子线索，是一种 关键的第一步是确定未来可以分子靶向的途径。 本项目的首要目标是确定是否在细胞外基质的改变， 癌上皮细胞可以充分改变癌细胞的侵袭、迁移和转移倾向。 将使用低氧模拟物和1%O2对低氧反应的纤维连接蛋白（FN）基质失调进行研究。 在MCF 10A进展系列中进行了研究，以确定三种细胞中的细胞应答是否 细胞系在癌前和恶性表型或侵袭前和侵袭表型之间交替。 在细胞内低氧水平时，缺氧诱导因子（HIF）-1α和HIF 2 α蛋白质发生变化， 稳定并转移到细胞核以使参与细胞存活的基因能够转录， 血管生成和新陈代谢。HIFα的血管生成转录靶点是VEGF（Vascular Endothelial Growth Factor，VEGF）。 内皮生长因子），其与FN蛋白的C-末端肝素-II结构域相互作用。使用 非接触和接触transwell试验，与内皮细胞，FN纤维形成的作用， 将测定结合VEGF或释放VEGF以促进血管生成。虽然乳腺细胞系 在本研究中使用，项目目标适用于上皮癌细胞的侵袭和迁移以及缺氧- 介导的血管生成依赖于FN纤维形成。 这项研究的长期目标是提供新的不利FN基质变化的信息， 也许是稳定的，与现有的治疗策略相结合，将有助于减轻癌细胞 侵略