Role of Fibroblasts in Cancer

成纤维细胞在癌症中的作用

基本信息

批准号：
8098527
负责人：
RAGHU KALLURI
金额：
$ 4.67万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-10 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8098527
关键词：
Ablation Address Alleles Angiogenic Switch Applications Grants Attenuated Biochemical Biological Breast Cancer Cell Cancer Model Carcinoma Cells Cytoskeletal Proteins Data Endothelial Cells Environment Extracellular Matrix Extracellular Matrix Proteins Extracellular Protein Family Fibroblasts Genetic Growth Growth Factor Healed Knowledge Laboratories Liver Lung Malignant Neoplasms Mammary Neoplasms Mediating Mediator of activation protein Metastatic Lesion Metastatic Neoplasm to the Liver Methods Modeling Mus Mutant Strains Mice Neoplasm Metastasis Nodule Pericytes Phenotype Play Population Population Heterogeneity Primary Neoplasm Production Proteins Research Rest Role Seeds Smooth Muscle Actin Staining Method Soil Stromal Cell-Derived Factor 1 Techniques Tenascin Testing Thymidine Kinase Time Transgenic Mice Vascular Endothelial Growth Factors Vascular Permeabilities abstracting angiogenesis cancer cell cell motility chemokine density design healing insight mouse Fsp1 protein mouse model promoter reconstitution research study response to injury tumor tumor growth tumor progression

项目摘要

Abstract Tumors are known as wounds that do not heal - implying that cells involved in angiogenesis and injury response, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Our knowledge regarding the role of the resting and the activated fibroblasts (also known as carcinoma-associated fibroblasts, CAF) in cancer is still evolving. Fibroblast production of growth factors, chemokines and extracellular matrix likely facilitates the angiogenic recruitment of endothelial cells and pericytes. Moreover, the precise role of fibroblasts in the recruitment and the formation of metastasis is completely unknown. Therefore, this grant application is focused on the role of fibroblast in cancer progression, with specific emphasis on metastasis. Emerging data from other laboratories and our own preliminary data suggest that fibroblasts are a heterogeneous population. In the tumor microenvironment, we have now identified a population of CAF that are positive for fibroblast specific protein-1 (FSP1) but not for alpha-smooth muscle actin (alphaSMA). Our studies demonstrate for the first time that not all CAF are alpha SMA+. Additionally, specific ablation of FSP1+/alphaSMA- fibroblasts using transgenic mice, which harbor FSP1 promoter driven thymidine kinase protein (FSP1-tk), demonstrate that FSP1+ fibroblasts are critical for the formation of metastasis without a significant impact on the growth of angiogenic primary tumors. Furthermore, we demonstrate that VEGF, SDF-1 and Tenascin-C, might mediate the formation of metastatic nodules.To further evaluate the role of these fibroblasts in the formation of metastasis, we propose the following aims in this proposal: 1. To evaluate the contribution of FSP1+ fibroblasts in the growth of primary tumors and recruitment of metastasis, 2. To address the contribution of VEGF produced by FSP1+ fibroblasts in the growth of primary tumors and the formation of metastasis, 3. To investigate the contribution of SDF-1, produced by FSP1+ fibroblasts, a downstream effector of VEGF, in the formation of metastasis, and 4. To study the contribution of Tenascin-C, a FSP1+ fibroblast-produced extracellular matrix protein, in the organization of metastasis nodules. Successful completion of experiments proposed in this grant application will provide crucial insights into the role of FSP1+ fibroblasts as key determinants for the organization of metastasis. Narrative Cancer cells are not the only constituent cells within a primary tumor and secondary metastasis. Other cells including fibroblasts are found inside the primary tumor and secondary metastatic nodules. The role of such fibroblasts in cancer progression and metastasis is unknown. This proposal addresses the role of fibroblasts in facilitating metastasis.

抽象的肿瘤被称为无法愈合的伤口——这意味着细胞参与血管生成和损伤反应，例如内皮细胞和成纤维细胞，在进展、生长和癌症扩散。我们关于静息和活化成纤维细胞（也称为癌症相关成纤维细胞（CAF）仍在不断发展。成纤维细胞产生生长因子，趋化因子和细胞外基质可能促进内皮细胞的血管生成募集周细胞。此外，成纤维细胞在招募和转移形成中的确切作用是完全未知。因此，这项拨款申请的重点是成纤维细胞在癌症进展中的作用，特别强调转移。来自其他实验室的新数据和我们自己的初步数据表明成纤维细胞是一个异质群体。在肿瘤微环境中，我们现在鉴定出一群对成纤维细胞特异性蛋白 1 (FSP1) 呈阳性但对 α-smooth 呈阳性的 CAF 群体肌肉肌动蛋白（αSMA）。我们的研究首次证明并非所有 CAF 都是 α SMA+。此外，使用含有 FSP1 的转基因小鼠对 FSP1+/alphaSMA- 成纤维细胞进行特异性消融启动子驱动的胸苷激酶蛋白 (FSP1-tk)，证明 FSP1+ 成纤维细胞对于转移的形成对血管原发性肿瘤的生长没有显着影响。此外，我们证明 VEGF、SDF-1 和 Tenascin-C 可能介导转移结节的形成。为了进一步评估这些成纤维细胞在转移形成中的作用，我们提出以下目标：该提案： 1. 评估FSP1+成纤维细胞在原发性肿瘤生长中的贡献和转移灶的募集，2. 解决 FSP1+ 成纤维细胞产生的 VEGF 在生长中的贡献 3.研究SDF-1的贡献，SDF-1是由 FSP1+ 成纤维细胞（VEGF 的下游效应子）在转移形成中的作用，以及 4. 研究 Tenascin-C（一种 FSP1+ 成纤维细胞产生的细胞外基质蛋白）在组织中的贡献转移结节。成功完成本拨款申请中提出的实验将提供对 FSP1+ 成纤维细胞作为转移组织关键决定因素的作用的重要见解。叙述癌细胞不是原发性肿瘤和继发性转移瘤内的唯一组成细胞。其他细胞包括在原发性肿瘤和继发性转移结节内发现的成纤维细胞。这样的作用成纤维细胞在癌症进展和转移中的作用尚不清楚。该提案阐述了成纤维细胞在促进转移。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Depletion of S100A4+ stromal cells does not prevent HCC development but reduces the stem cell-like phenotype of the tumors.

S100A4 基质细胞的耗竭并不能阻止 HCC 的发展，但会减少肿瘤的干细胞样表型。

DOI：
发表时间：
2018
期刊：
影响因子：
12.8
作者：
Jiao, Jingjing;González, Álvaro;Stevenson, Heather L;Gagea, Mihai;Sugimoto, Hikaru;Kalluri, Raghu;Beretta, Laura
通讯作者：
Beretta, Laura

Interaction between the extracellular matrix and lymphatics: consequences for lymphangiogenesis and lymphatic function.

DOI：
10.1016/j.matbio.2010.08.001
发表时间：
2010-10
期刊：
Matrix biology : journal of the International Society for Matrix Biology
影响因子：
0
作者：
Wiig, Helge;Keskin, Doruk;Kalluri, Raghu
通讯作者：
Kalluri, Raghu

Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2.

靶向缺氧肿瘤中的血管周细胞可通过血管生成素-2 增加肺转移。

DOI：
10.1016/j.celrep.2015.01.035
发表时间：
2015-02-24
期刊：
Cell reports
影响因子：
8.8
作者：
Keskin D;Kim J;Cooke VG;Wu CC;Sugimoto H;Gu C;De Palma M;Kalluri R;LeBleu VS
通讯作者：
LeBleu VS

Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer.

上皮到间质的转变对于转移来说是可有可无的，但会在胰腺癌中诱导化疗耐药。

DOI：
发表时间：
2015-11-26
期刊：
影响因子：
64.8
作者：
Zheng, Xiaofeng;Carstens, Julienne L;Kim, Jiha;Scheible, Matthew;Kaye, Judith;Sugimoto, Hikaru;Wu, Chia;LeBleu, Valerie S;Kalluri, Raghu
通讯作者：
Kalluri, Raghu

Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis.

组织纤维化的细胞机制。