Tumor Microenvironment in Cancer Progression

癌症进展中的肿瘤微环境

• 批准号: 8349476
• 负责人: Rosandra Kaplan
• 金额: $ 26.46万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/8349476
• 关键词: Acute Lymphocytic Leukemia; Adhesions; Adult; Area; Bone Marrow; Brain; Breast Carcinoma; Cell Survival; Cell physiology; Cells; Cessation of life; Characteristics; Childhood Lymphoma; Clinical; Colon Carcinoma; Communication; Development; Disease; Disseminated Malignant Neoplasm; Distant; Endothelial Cells; Event; Ewings sarcoma; Fibroblasts; Future; Gene Expression Profiling; Gene Proteins; Genetic; Goals; Growth; Hematopoietic; Human; Immune; Individual; Investigation; Laboratories; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Metastatic Lesion; Modeling; Molecular; Mus; Mutation; Nature; Neoplasm Metastasis; Neuroblastoma; Organ; Patients; Pattern; Pediatric Neoplasm; Phase; Phenotype; Population; Primary Neoplasm; Process; Recruitment Activity; Regenerative Medicine; Rhabdomyosarcoma; Role; Sampling; Seeds; Site; Soil; Stem cells; Stromal Neoplasm; Tissues; Work; angiogenesis; anticancer research; bone; cancer cell; cancer therapy; cancer type; cell motility; chemokine; design; effective therapy; genetic profiling; human tissue; improved; insight; lung Carcinoma; lymph nodes; malignant breast neoplasm; medulloblastoma; melanoma; metastatic process; mouse model; neglect; neoplastic cell; new therapeutic target; novel; novel strategies; prevent; prognostic; response; stem; theories; therapy design; translational study; tumor; tumor growth; tumor progression

Our laboratory is focused on understanding the role of the tumor microenvironment in cancer progression. Despite many great strides in cancer research, metastasis, the most devastating phase of tumor progression, remains poorly defined. Traditionally, theories of metastasis describe a multi-step process involving tumor cells accumulation of multiple genetic alterations promoting motility, growth and an invasive phenotype. However, genetic insights now suggest that metastatic propensity exists much earlier in tumor growth than was previously appreciated. Moreover, identification of genetic profiles intrinsic to the tumor cell that correlate with aggressive metastatic disease does not, in itself, reveal all details of the molecular and cellular events by which invasion and metastasis occurs, or of how it is orchestrated. Our work has caused a paradigm shift in understanding the stepwise events in metastatic disease. We focus on metastasis as an active process involving communication between the primary tumor and the entire host representing a systemic phenomenon with localized chemokine gradients being established in response to mobilization of bone marrow-derived cells to tissue-specific sites. Primary tumor growth and metastatic progression are preferentially dependent on the microenvironment in which these tumor cells reside. It has also long been recognized that the preferential colonization of cancer to specific tissues such as lymph nodes, bone, lung and brain are in part determined by the nature of the microenvironment within these distant organs as initially proposed by Stephen Paget. More recently, details of the early changes occurring within distant tissue stroma, involving the creation of a supportive microenvironment permissive for metastatic growth, have been recognized. The host genetic makeup within cells such as endothelial cells, hematopoietic cells, fibroblasts and immune cells all contribute to the growth and migration of tumors cells. Understanding the interaction between cancer cells and their supportive stromal components at sites of future metastasis, and the molecular cross-talk that is conducive to establishment of secondary tumor growth is now paramount. This work may reveal targets for novel therapeutic and prognostic strategies to treat and prevent metastatic cancer. We plan to study the specific cell populations including resident cells and recruited cell populations that are present in distant host sites of metastasis early in the metastatic cascade prior to full blown vascularized metastatic lesions and through development to established vascularized metastases. Further we will characterize the molecular and cellular changes within the pre-metastatic niche sites. We aim to discover novel expression patterns by gene expression profiling of murine and human metastatic tissue. We can then compare different metastatic tissue sites as well as the bone marrow changes that occur in murine models of metastasis as well as patients with malignancy. These studies will also help improve our understanding of adult stem and progenitor cells and their response to cancer progression. Analysis of the pathological impact on adult tissue specific stem cells may help to devise novel strategies for regenerative medicine as well as cancer therapies. It is our goal to use these unique approaches to improve effective therapies for patients with cancer progression.

我们的实验室致力于了解肿瘤微环境在癌症进展中的作用。尽管癌症研究取得了许多重大进展，但肿瘤进展中最具破坏性的阶段——转移仍然没有得到明确的定义。传统上，转移理论描述了一个多步骤的过程，涉及肿瘤细胞积累多种基因改变，促进运动、生长和侵袭表型。然而，现在的遗传学研究表明，肿瘤生长过程中转移倾向的存在比以前认为的要早得多。此外，对与侵袭性转移性疾病相关的肿瘤细胞固有的遗传图谱的识别本身并不能揭示发生侵袭和转移的分子和细胞事件或其如何精心策划的所有细节。我们的工作引起了对转移性疾病逐步事件的理解的范式转变。我们关注转移作为一个主动过程，涉及原发肿瘤和整个宿主之间的通讯，代表一种系统现象，局部趋化因子梯度是响应骨髓源性细胞动员到组织特异性位点而建立的。原发性肿瘤的生长和转移进展优先取决于这些肿瘤细胞所在的微环境。人们早就认识到，癌症优先定植于特定组织，如淋巴结、骨骼、肺和大脑，部分取决于这些远处器官内微环境的性质，正如斯蒂芬·佩吉特最初提出的那样。最近，人们已经认识到远处组织基质内发生的早期变化的细节，包括创建允许转移生长的支持性微环境。 内皮细胞、造血细胞、成纤维细胞和免疫细胞等细胞内的宿主基因组成都有助于肿瘤细胞的生长和迁移。了解癌细胞与其在未来转移部位的支持基质成分之间的相互作用，以及有利于继发性肿瘤生长建立的分子串扰现在至关重要。这项工作可能揭示治疗和预防转移性癌症的新治疗和预后策略的目标。我们计划研究特定的细胞群，包括常驻细胞和招募的细胞群，这些细胞群存在于转移级联的早期，在血管化转移病灶完全成熟之前，并通过发展形成已建立的血管化转移。此外，我们将表征转移前生态位点内的分子和细胞变化。我们的目标是通过小鼠和人类转移组织的基因表达谱来发现新的表达模式。然后我们可以比较不同的转移组织部位以及小鼠转移模型以及恶性肿瘤患者中发生的骨髓变化。这些研究还将有助于提高我们对成体干细胞和祖细胞及其对癌症进展的反应的了解。分析对成体组织特异性干细胞的病理影响可能有助于设计再生医学和癌症治疗的新策略。我们的目标是利用这些独特的方法来改善癌症进展患者的有效治疗。