Gene Delivery Vehicles for Cancer Gene Therapy

用于癌症基因治疗的基因递送载体

• 批准号: 7584056
• 负责人: Frank C. Marini
• 金额: $ 18.35万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-18 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7584056
• 关键词: Adenoviruses; Animals; Apoptotic; Beds; Behavior; Biodistribution; Biological; Bone Marrow; Breast Carcinoma; Breast Melanoma; Cell Communication; Cells; Characteristics; Data; Detection; Development; Disease; Elements; Engraftment; Exhibits; Extracellular Matrix; Fibroblast Growth Factor; Gene Delivery; Gene Expression; Gene-Modified; Goals; Green Fluorescent Proteins; Growth; Growth Factor; HSV-Tk Gene; Home environment; Homing; Image; Imaging Techniques; Immunocompetent; Immunodeficient Mouse; Immunohistochemistry; Implant; In Vitro; Injection of therapeutic agent; Interferon-beta; Label; Luciferases; Malignant Neoplasms; Mediator of activation protein; Mesenchymal Stem Cells; Metastatic Melanoma; Migration Assay; Mus; Neoplasm Metastasis; Normal Statistical Distribution; Oncogenes; PECAM1 gene; Phenotype; Platelet-Derived Growth Factor; Positron; Proliferating; Protein Tyrosine Kinase; Proteins; Radiolabeled; Reaction; Recruitment Activity; Reporter Genes; Research Design; Research Personnel; SCID Mice; Signal Transduction; Simplexvirus; Smooth Muscle Actin Staining Method; Solid Neoplasm; Stromal Cells; Stromal Neoplasm; System; Testing; Therapeutic; Thymidine Kinase; Tissues; Viral; Wound Healing; Xenograft procedure; beta-Galactosidase; cadherin 5; cancer cell; cell killing; cell stroma; cytokine; gene delivery system; gene therapy; in vivo; interest; luciferin; luminescence; malignant breast neoplasm; matrigel; mouse model; neoplastic cell; paracrine; programs; radiotracer; receptor; repaired; response; subcutaneous; therapeutic gene; tomography; tumor; tumor growth; tumor xenograft; vector; viral gene delivery

DESCRIPTION (provided by applicant): Stromal cells provide structural support for malignant cells, modulate the tumor microenvironment, and influence phenotypic behavior as well as the aggressiveness of the malignancy. In response, the tumor provides growth factors, cytokines, and cellular signals that continually initiate new stromal reactions and recruit new cells into the microenvironment to further support tumor growth. It is not fully understood how stroma influences the neoplastic cells, but there is evidence for involvement of soluble paracrine factors, extracellular matrix formation, and direct cell-to-cell interaction. Therefore, it might be possible to manipulate the tissue stroma cells and thereby interfere with the stroma-tumor interactions for therapeutic benefit. The prerequisite for this approach is that stromal cells be accessible to therapeutic manipulation. We have previously demonstrated that bone marrow-derived mesenchymal stem cells (MSC) integrate into solid tumors as stromal elements and contribute to the development of tumors. Importantly, MSC are precursors of structural and supportive tissues and have been implicated in the repair of damaged tissues and in wound healing. Of interest is that the tumor microenvironment appears to exhibit cytokine profiles and cellular signals similar to those characteristics of wounded or damaged tissues. Given this, we hypothesized that MSC would home to and selectively proliferate in the tumor microenvironment and that gene-modified MSC could be used as cellular vehicles to deliver gene products into tumors. Preliminary data suggests that MSC home to and participate in tumor stroma formation in both subcutaneous and metastatic tumor xenografts in mice. Additionally, once homed to tumor beds, MSC proliferate rapidly and integrate. Migration assays have identified apoptotic cells as a potent attractant of MSC in vitro. Our proposed studies aim at understanding the factors that influence MSC homing and selective proliferation in the tumor microenvironment. Additionally, our goals focus on optimizing the cellular delivery of therapeutic genes into the stroma of metastatic and subcutaneous tumor xenografts. Specific Aim 1: To determine the biodistribution and selective proliferation of intravenously administered MSC in the stromal microenvironment, to identify cellular mediators that may enhance the selective proliferation and engraftment of MSC, and determine the phenotype and fate of MSC that have engrafted and proliferated in the tumor microenvironment. Specific Aim 2: To investigate the tumor targeting ability and normal distribution of MSC in vivo utilizing noninvasive imaging techniques. Specific Aim 3: To determine which of several viral gene delivery systems + MSC results in optimal tumor growth inhibition and cell killing. Additionally, to determine the effect of MSC + vector specifically targeted to breast cancer or metastatic melanoma in vivo, on the growth of tumors in immunocompetent and immunodeficient mice.

描述（由申请人提供）：基质细胞为恶性细胞提供结构支持，调节肿瘤微环境并影响表型行为以及恶性肿瘤的攻击性。作为反应，肿瘤提供了生长因子，细胞因子和细胞信号，这些信号不断引发新的基质反应，并将新细胞募集到微环境中，以进一步支持肿瘤生长。尚未完全了解基质如何影响肿瘤细胞，但是有证据表明可溶性旁分泌因子，细胞外基质形成以及直接的细胞间相互作用。因此，有可能操纵组织基质细胞，从而干扰基质肿瘤相互作用以获得治疗益处。这种方法的先决条件是可以通过治疗性操纵来访问基质细胞。我们先前已经证明，骨髓来源的间充质干细胞（MSC）作为基质元素整合到实体瘤中，并有助于肿瘤的发展。重要的是，MSC是结构性和支撑性组织的前体，并且与受损组织和伤口愈合的修复有关。有趣的是，肿瘤微环境似乎表现出类似于受伤或受损组织的特征的细胞因子特征和细胞信号。鉴于此，我们假设MSC可以在肿瘤微环境中选择并有选择地扩散，并且基因改性的MSC可以用作细胞车辆，以将基因产物输送到肿瘤中。初步数据表明，在小鼠皮下和转移性肿瘤异种移植物中，MSC供应并参与肿瘤基质形成。此外，一旦将其归入肿瘤床，MSC会迅速增殖并整合。迁移测定已将凋亡细胞确定为体外MSC的有效吸引剂。我们提出的研究旨在了解影响MSC归巢和肿瘤微环境中选择性增殖的因素。此外，我们的目标着重于优化治疗基因进入转移性和皮下肿瘤异种移植的基质的细胞递送。 具体目的1：确定基质微环境中静脉内施用的MSC的生物分布和选择性增殖，以鉴定可能增强MSC选择性增殖和植入的细胞介质，并确定在thumor Microeenvrironment中植入和扩散的MSC的表观型和命运。 特定目的2：研究利用非侵入性成像技术的肿瘤靶向能力和MSC的正态分布。 特定目的3：确定哪个病毒基因输送系统中的哪个 + MSC会导致最佳的肿瘤生长抑制和细胞杀伤。此外，为了确定针对体内乳腺癌或转移性黑色素瘤的MSC +载体的影响，对免疫能力和免疫缺陷小鼠的肿瘤生长。

项目成果

Tracking inflammation-induced mobilization of mesenchymal stem cells.

追踪炎症诱导的间充质干细胞动员。

• DOI: 10.1007/978-1-61779-943-3_15
• 发表时间: 2012
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Spaeth,ErikaL;Kidd,Shannon;Marini,FrankC
• 通讯作者: Marini,FrankC

Mesenchymal stem cells promote mammosphere formation and decrease E-cadherin in normal and malignant breast cells.

• DOI: 10.1371/journal.pone.0012180
• 发表时间: 2010-08-16
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Klopp AH;Lacerda L;Gupta A;Debeb BG;Solley T;Li L;Spaeth E;Xu W;Zhang X;Lewis MT;Reuben JM;Krishnamurthy S;Ferrari M;Gaspar R;Buchholz TA;Cristofanilli M;Marini F;Andreeff M;Woodward WA
• 通讯作者: Woodward WA