Extracellular matrix signatures of human mammary carcinoma identify novel metastasis promoters

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

eLife digest

Metastasis is the process whereby tumor cells spread within the body and is the cause of most deaths from cancer. This complex process involves several steps: first the cancer cells invade the tissues that surround the tumor; second, the cancer cells enter the blood stream and travel throughout the body; and third, the cancer cells seed the growth of new tumors in distant organs.

Within tissues, the extracellular matrix forms a complex scaffold of proteins that surrounds cells, to support and organize them: it also provides signals that control how much cells can multiply, how likely cells are to stick together or migrate, and even a cell’s chances of survival. Pathologists have used an accumulation of extracellular matrix proteins in tumors as a sign that the outcome of the disease will likely be unfavorable for a patient, and that treatment will be challenging. However, we still do not have a clear picture of the composition of the tumor extracellular matrix and we do not know all the details of how it affects tumor growth and metastasis.

Now, Naba et al. have explored these questions by injecting different types of human breast tumor cells into mice. Some of the cells were capable of spreading throughout the body and were said to have a high ‘metastatic potential’; others were less capable of spreading and were said to have a low metastatic potential. Naba et al. then analyzed the proteins that made up the extracellular matrix of the tumors that grew in the mice. Some proteins were found in both types of tumor; whereas some proteins were only found in the tumors with low metastatic potential and some were only found in the highly metastatic tumors. Naba et al. also demonstrated that both cancer cells and non-cancer cells—which are also found within the tumors—contributed to the production of the extracellular matrix in the tumor. Moreover, and somewhat surprisingly, the contributions from the non-cancer cells in the two types of tumors were also different.

Computational analysis predicted that the production of several extracellular matrix proteins in the highly metastatic tumors was under the control of signaling pathways that are involved in cancer progression. Furthermore, Naba et al. also demonstrated that several of the extracellular matrix proteins specific to highly metastatic tumors were required for the cancer to spread. These proteins are involved in different stages of the metastatic process, and some of them are commonly over-produced in tumors from patients with some of the worst chances of recovery.

If similar results are consistently observed in clinical samples from humans, the work of Naba et al. could help doctors to discriminate between tumors that will spread and those that will not, which should lead to improved patient care. The proteins and pathways associated with the highly metastatic tumors could be also investigated as potential drug targets.

DOI: http://dx.doi.org/10.7554/eLife.01308.002