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Engineered Fibroblasts as Cell Therapy to Treat Colorectal Cancer via Tumor Stroma Stabilization

工程成纤维细胞作为细胞疗法通过肿瘤基质稳定治疗结直肠癌

基本信息

批准号：
10065260
负责人：
Wei-Hung Jung
金额：
$ 4.7万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10065260
关键词：
3-Dimensional Affect Antineoplastic Agents Architecture Autologous Transplantation Biochemical Cancer Etiology Cancer Model Carcinoma Cell Therapy Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Coin Collagen Colon Colorectal Cancer Colorectal Neoplasms Cross-Linking Reagents Deposition Dermal Development Diffusion Doctor of Philosophy Drops Drug Delivery Systems Early Diagnosis Engineering Enzymes Etiology Extracellular Matrix Fibroblasts Genes Genetic Engineering Genome Health Implant In Vitro Integrins Lead Length Link Malignant Neoplasms Malignant neoplasm of ovary Mechanics Mediating Mus Neoplasm Metastasis Pathologic Pathway interactions Pattern Phenotype Play Proteomics Research Research Project Grants Role Signal Pathway Squamous cell carcinoma Stromal Cells Survival Rate System Testing Therapeutic Therapeutic Effect Time Tissues Training Transglutaminases Translating Transportation Treatment Efficacy Woman anti-cancer biophysical properties cancer cell cancer type clinical application colorectal cancer treatment crosslink cytokine effective therapy efficacy testing exosome extracellular vesicles genipin improved improved outcome in vivo malignant breast neoplasm mechanical force men metastatic colorectal mouse model promoter screening therapeutic evaluation trait treatment strategy tumor tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY Cancer cells, extracellular matrix (ECM) and carcinoma-associated fibroblasts (CAFs) are three critical factors contributing to tumor progression in colorectal cancer and squamous cell carcinoma, among other cancer types. CAFs are often associated with the development of high-grade malignancies of poor prognoses because CAFs secrete metastasis-promoting cytokines and abnormally deposit collagen, facilitating integrin- dependent cancer invasion and forming hindrance of anti-cancer drug delivery. Despite the detailed studies about the role of CAFs in tumor progression, the mechanism by which stromal cells become CAFs is still not clear: how normal fibroblasts in stroma are transformed to CAFs during early stages of cancer? In this project, I will test the hypothesis that cancer cells facilitate CAF induction by mechanically reorganizing extracellular matrix and thus breaking down the diffusion barrier of CAF-inducing factors. A coculture system containing colorectal cancer spheroids and multiple types of stromal cells as the testing platform will be constructed for the preliminary tests. If proven valid, I will use my hypothesis to develop new treatments where ECM remodeling is suppressed to decrease the rate of tumor progression in colorectal cancer. Two treatment strategies will be tested: (1) direct applying ECM crosslinking agents in the tumor microenvironment; (2) implanting genetically engineered fibroblasts secreting ECM crosslinking enzymes and other anti-cancer biomolecules. Colorectal cancer mouse models will be used to evaluate the efficacy of the new treatments.

项目概要癌细胞、细胞外基质（ECM）和癌相关成纤维细胞（CAF）是三个关键的细胞导致结直肠癌和鳞状细胞癌等肿瘤进展的因素癌症类型。 CAF 通常与预后不良的高级恶性肿瘤的发生有关因为 CAF 会分泌促进转移的细胞因子并异常沉积胶原蛋白，从而促进整合素依赖性癌症侵袭并形成抗癌药物递送障碍。尽管进行了详细的研究关于CAFs在肿瘤进展中的作用，基质细胞变成CAFs的机制仍不清楚明确：在癌症早期阶段，基质中的正常成纤维细胞如何转化为 CAF？在这个项目中，我将检验癌细胞通过机械重组细胞外促进 CAF 诱导的假设基质，从而打破 CAF 诱导因子的扩散障碍。共培养系统包含构建结直肠癌球体和多种基质细胞检测平台初步测试。如果被证明有效，我将利用我的假设来开发新的治疗方法，其中 ECM 抑制重塑以降低结直肠癌的肿瘤进展速度。两次治疗将测试策略：（1）在肿瘤微环境中直接应用ECM交联剂； (2) 植入分泌 ECM 交联酶和其他抗癌物质的基因工程成纤维细胞生物分子。结直肠癌小鼠模型将用于评估新疗法的疗效。