以往曾认为在乳腺肿瘤中的两类细胞——快速增长的恶性细胞和它们周围的正常细胞——独立存在，互不干扰。最近的研究证据表明，表面正常的细胞能促进肿瘤内细胞恶变，但这两类细胞间如何相互影响有待解答。一项由美国俄亥俄州立大学癌症研究人员主持的研究有助于解开这个谜团。它首次表明，如果肿瘤外围正常细胞缺失一种PTEN基因，将会改变肿瘤周围环境以促进肿瘤生长。
纤维细胞是包围在肿瘤组织外的一类主要细胞。该项新研究表明，当纤维细胞中的PTEN基因缺失，它将迅速改变肿瘤环境的结构和生化组成。例如，纤维蛋白胶原增多，炎症细胞促使巨噬细胞迁移到肿瘤组织，肿瘤血管的数目也增多了：所有这些都有利于肿瘤的增长。俄亥俄州立大学综合癌症中心分子生物学和癌症遗传学项目主任Michael Ostrowski称，新研究提示，周围成纤维细胞中的PTEN 基因对抑制癌症的发展发挥重要作用。为了证实这一点，研究人员将小鼠乳腺成纤维细胞中的PTEN 基因敲除，结果发现PTEN调控另外一个基因Ets2。
当PTEN 丢失时，Ets2调节肿瘤周围环境发生的变化。研究人员称，这种动物模型模拟了人类乳腺癌的许多特征，因此它可以帮助评估在联合治疗中靶向肿瘤环境中缺陷细胞和癌细胞实验药物的疗效。
论文并列第一作者，俄亥俄州立大学综合癌症中心分子病毒学Gustavo Leone副教授称，新研究揭示了PTEN基因在肿瘤环境中的新作用，这将会促使乳腺癌的全新治疗方案和其他一些肿瘤靶标药物的产生。这些发现也将会增进人们对乳腺癌及其它一些受到局部组织环境影响的疾病的了解，其中包括自身免疫性疾病、肺纤维化和神经退行性疾病。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature 461, 1084-1091 (22 October 2009) | doi:10.1038/nature08486
Pten in stromal fibroblasts suppresses mammary epithelial tumours
Anthony J. Trimboli1,2,14, Carmen Z. Cantemir-Stone3,14, Fu Li1,3,14, Julie A. Wallace3, Anand Merchant3, Nicholas Creasap1,2, John C. Thompson1,2, Enrico Caserta1,2, Hui Wang1,2, Jean-Leon Chong1,2, Shan Naidu1,2,4, Guo Wei1,3, Sudarshana M. Sharma3, Julie A. Stephens5, Soledad A. Fernandez5, Metin N. Gurcan6, Michael B. Weinstein1,2, Sanford H. Barsky7,15, Lisa Yee8, Thomas J. Rosol4, Paul C. Stromberg4, Michael L. Robinson9,15, Francois Pepin10,11, Michael Hallett10,11, Morag Park10,12, Michael C. Ostrowski3,13 & Gustavo Leone1,2,13
1 Department of Molecular Genetics, College of Biological Sciences,
2 Department of Molecular Virology, Immunology and Medical Genetics,
3 Department of Molecular and Cellular Biochemistry, College of Medicine,
4 Department of Veterinary Biosciences, College of Veterinary Medicine,
5 Center for Biostatistics, Office of Health Sciences,
6 Department of Biomedical Informatics,
7 Department of Pathology and,
8 Department of Surgery, School of Medicine, The Ohio State University, Columbus, Ohio 43210, USA
9 Center for Molecular and Human Genetics, Columbus Children's Research Institute, Columbus, Ohio 43205, USA
10 Department of Biochemistry, Rosalind and Morris Goodman Cancer Center,
11 McGill Center for Bioinformatics,
12 Department of Oncology, McGill University, Québec H3A 1A1, Canada
13 Tumor Microenvironment Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA
14 These authors contributed equally to this work.
15 Present addresses: Department of Pathology, University of Nevada School of Medicine, Reno, Nevada 89557, and Nevada Cancer Institute, Las Vegas, Nevada 89135, USA (S.H.B.); Department of Zoology, Miami University, Oxford, Ohio 45056, USA (M.L.R.).
Correspondence to: Michael C. Ostrowski3,13Gustavo Leone1,2,13 Correspondence and requests for materials should be addressed to M.C.O. or G.L.
The tumour stroma is believed to contribute to some of the most malignant characteristics of epithelial tumours. However, signalling between stromal and tumour cells is complex and remains poorly understood. Here we show that the genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumours. This was associated with the massive remodelling of the extracellular matrix (ECM), innate immune cell infiltration and increased angiogenesis. Loss of Pten in stromal fibroblasts led to increased expression, phosphorylation (T72) and recruitment of Ets2 to target promoters known to be involved in these processes. Remarkably, Ets2 inactivation in Pten stroma-deleted tumours ameliorated disruption of the tumour microenvironment and was sufficient to decrease tumour growth and progression. Global gene expression profiling of mammary stromal cells identified a Pten-specific signature that was highly represented in the tumour stroma of patients with breast cancer. These findings identify the Pten–Ets2 axis as a critical stroma-specific signalling pathway that suppresses mammary epithelial tumours.
