專題：Nature報導
以往曾認為在乳腺腫瘤中的兩類細胞——快速增長的惡性細胞和它們周圍的正常細胞——獨立存在，互不幹擾。最近的研究證據表明，表面正常的細胞能促進腫瘤內細胞惡變，但這兩類細胞間如何相互影響有待解答。一項由美國俄亥俄州立大學癌症研究人員主持的研究有助於解開這個謎團。它首次表明，如果腫瘤外圍正常細胞缺失一種PTEN基因，將會改變腫瘤周圍環境以促進腫瘤生長。
纖維細胞是包圍在腫瘤組織外的一類主要細胞。該項新研究表明，當纖維細胞中的PTEN基因缺失，它將迅速改變腫瘤環境的結構和生化組成。例如，纖維蛋白膠原增多，炎症細胞促使巨噬細胞遷移到腫瘤組織，腫瘤血管的數目也增多了：所有這些都有利於腫瘤的增長。俄亥俄州立大學綜合癌症中心分子生物學和癌症遺傳學項目主任Michael Ostrowski稱，新研究提示，周圍成纖維細胞中的PTEN 基因對抑制癌症的發展發揮重要作用。為了證實這一點，研究人員將小鼠乳腺成纖維細胞中的PTEN 基因敲除，結果發現PTEN調控另外一個基因Ets2。
當PTEN 丟失時，Ets2調節腫瘤周圍環境發生的變化。研究人員稱，這種動物模型模擬了人類乳腺癌的許多特徵，因此它可以幫助評估在聯合治療中靶向腫瘤環境中缺陷細胞和癌細胞實驗藥物的療效。
論文並列第一作者，俄亥俄州立大學綜合癌症中心分子病毒學Gustavo Leone副教授稱，新研究揭示了PTEN基因在腫瘤環境中的新作用，這將會促使乳腺癌的全新治療方案和其他一些腫瘤靶標藥物的產生。這些發現也將會增進人們對乳腺癌及其它一些受到局部組織環境影響的疾病的了解，其中包括自身免疫性疾病、肺纖維化和神經退行性疾病。（生物谷Bioon.com）
生物谷推薦原始出處：
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.