Abstract
The extracellular matrix (ECM) is a major component of tumors and a significant contributor to cancer progression. In this study, we use proteomics to investigate the ECM of human mammary carcinoma xenografts and show that primary tumors of differing metastatic potential differ in ECM composition. Both tumor cells and stromal cells contribute to the tumor matrix and tumors of differing metastatic ability differ in both tumor- and stroma-derived ECM components. We define ECM signatures of poorly and highly metastatic mammary carcinomas and these signatures reveal up-regulation of signaling pathways including TGFβ and VEGF. We further demonstrate that several proteins characteristic of highly metastatic tumors (LTBP3, SNED1, EGLN1, and S100A2) play causal roles in metastasis, albeit at different steps. Finally we show that high expression of LTBP3 and SNED1 correlates with poor outcome for ER(-)/PR(-)breast cancer patients. This study thus identifies novel biomarkers that may serve as prognostic and diagnostic tools. DOI: http://dx.doi.org/10.7554/eLife.01308.001.
Highlights
With an estimated number of new cases in 2008 of 1.3 million worldwide, breast cancer is the second most frequent cancer worldwide and claimed the lives of over 39,000 patients in the United States in 2012 alone
We demonstrate in this study that a proteomics-based discovery approach can define extracellular matrix (ECM) signatures of tumors of differing metastatic potential
We show that the tumor ECM is derived from both the tumor and stromal cells and that tumors of differing metastatic potential differ in both the tumor- and stroma-derived ECM
Summary
With an estimated number of new cases in 2008 of 1.3 million worldwide (http://globocan.iarc.fr), breast cancer is the second most frequent cancer worldwide and claimed the lives of over 39,000 patients in the United States in 2012 alone. Most cancer deaths (∼90%) are due to the metastatic colonization of distant organs by the tumor cells. In order to progress, a tumor needs to be surrounded by a permissive environment and, to metastasize, tumor cells need to find or create a favorable niche (seed and soil theory) (Paget, 1889; Ribatti et al, 2006; Erler and Weaver, 2009; Comen, 2012). To create such a niche, tumor cells either directly alter the microenvironment, or instruct local or recruited stromal cells to do so. The nature of the tumor microenvironment or gene expression profile of the stromal cells has been used to define
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