P5 - Gene-modified MSCs for Controlling Ovarian Cancer

P5 - 用于控制卵巢癌的基因修饰 MSC

• 批准号: 7961949
• 负责人: Frank C. Marini
• 金额: $ 17.98万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7961949
• 关键词: Adverse effects; Animal Model; Autologous; Beds; Behavior; Biodistribution; Bone Marrow; CD44 gene; Cell Communication; Cells; Characteristics; Chemosensitization; Clinical; Collaborations; Combination Drug Therapy; Data; Development; Dose; Elements; Engraftment; Exhibits; Extracellular Matrix; Gene-Modified; Goals; Growth Factor; Home environment; Homing; Human; Inflammation Mediators; Instruction; Interferon-beta; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mesenchymal Stem Cells; Modeling; Mus; Ovarian Carcinoma; Patients; Phase I Clinical Trials; Pre-Clinical Model; Production; Proliferating; Proteins; Reaction; Recruitment Activity; Refractory; Role; Route; Schedule; Signal Transduction; Solid Neoplasm; Staging; Stem cell transplant; Stromal Cells; Testing; Therapeutic; Tissues; Toxic effect; Wound Healing; Xenograft procedure; cancer cell; cancer therapy; cell motility; cellular engineering; chemotherapy; cytokine; interest; intraperitoneal; neoplastic cell; novel; ovarian neoplasm; paracrine; pre-clinical; receptor; repaired; response; stem cell population; subcutaneous; therapeutic gene; treatment strategy; tumor; tumor growth; tumor xenograft

PROJECT SUMMARY (See instructions): 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 stromal 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. Our preliminary data suggests that MSC home to and participate in tumor stroma formation in both subcutaneous and Intraperitoneal tumor xenografts in mice. Additionally, once homed to tumor beds, MSC proliferate rapidly and integrate. 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.

项目摘要（请参阅说明）： 基质细胞为恶性细胞提供结构支持，调节肿瘤微环境，并为 影响表型行为以及恶性肿瘤的侵略性。作为回应，肿瘤 提供生长因子，细胞因子和细胞信号，这些信号不断引发新的基质反应和 将新细胞募集到微环境中，以进一步支持肿瘤生长。尚不完全了解如何 基质会影响肿瘤细胞，但有证据表明可溶性旁分泌因子参与 细胞外基质形成，并直接细胞对细胞相互作用。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 这种方法的先决条件是可以通过治疗操作访问基质细胞。我们有 以前证明骨髓来源的间充质干细胞（MSC）整合到固体中 肿瘤作为基质元素，并有助于肿瘤的发展。重要的是，MSC是前体 结构性和支撑性组织，已与受损组织的修复和伤口有关 康复。有趣的是，肿瘤微环境似乎表现出细胞因子谱和细胞 信号类似于受伤或受损组织的特征。鉴于此，我们假设 MSC将在肿瘤微环境中选择并有选择地扩散，并且基因改性MSC 可以用作细胞车辆将基因产物输送到肿瘤中。我们的初步数据表明 MSC在皮下和腹膜内肿瘤中都可以参与肿瘤基质形成 小鼠的异种移植物。此外，一旦将其归入肿瘤床，MSC会迅速增殖并整合。我们的 拟议的研究旨在了解影响MSC归巢和选择性增殖的因素 肿瘤微环境。此外，我们的目标着重于优化治疗的细胞输送 转移和皮下肿瘤异种移植物的基因。