Abstract
BackgroundTumor metastases pose the greatest threat to a patient's survival, and thus, understanding the biology of disseminated cancer cells is critical for developing effective therapies.MethodsMicroarrays and immunohistochemistry were used to analyze primary breast tumors, regional (lymph node) metastases, and distant metastases in order to identify biological features associated with distant metastases.ResultsWhen compared with each other, primary tumors and regional metastases showed statistically indistinguishable gene expression patterns. Supervised analyses comparing patients with distant metastases versus primary tumors or regional metastases showed that the distant metastases were distinct and distinguished by the lack of expression of fibroblast/mesenchymal genes, and by the high expression of a 13-gene profile (that is, the 'vascular endothelial growth factor (VEGF) profile') that included VEGF, ANGPTL4, ADM and the monocarboxylic acid transporter SLC16A3. At least 8 out of 13 of these genes contained HIF1α binding sites, many are known to be HIF1α-regulated, and expression of the VEGF profile correlated with HIF1α IHC positivity. The VEGF profile also showed prognostic significance on tests of sets of patients with breast and lung cancer and glioblastomas, and was an independent predictor of outcomes in primary breast cancers when tested in models that contained other prognostic gene expression profiles and clinical variables.ConclusionThese data identify a compact in vivo hypoxia signature that tends to be present in distant metastasis samples, and which portends a poor outcome in multiple tumor types.This signature suggests that the response to hypoxia includes the ability to promote new blood and lymphatic vessel formation, and that the dual targeting of multiple cell types and pathways will be needed to prevent metastatic spread.
Highlights
Tumor metastases pose the greatest threat to a patient's survival, and understanding the biology of disseminated cancer cells is critical for developing effective therapies
Recent evidence suggests that tumor endothelial cell interactions are important for determining patient outcomes as evidenced by the promising results from clinical trials that use bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor (VEGF) [7,8]
It has been shown that the expression profile of primary tumors without metastases can be highly predictive of the development of future metastases [9,10,11,12,13]
Summary
Tumor metastases pose the greatest threat to a patient's survival, and understanding the biology of disseminated cancer cells is critical for developing effective therapies. Metastases are the main cause of mortality for patients with breast cancer. Genomic profiling of human tumors and model systems has identified important features concerning metastasis biology. It has been shown that the expression profile of primary tumors without metastases can be highly predictive of the development of future metastases [9,10,11,12,13]. Cell line and murine models have demonstrated many different genes as being important for breast tumor metastasis, including Twist [16], Snail [3], and CXCL12 [17]. We compare primary breast tumors, regional metastases, and distant metastases with each other and show that distant metastasis samples are distinct and provide unique signatures that predict poor outcomes in primary tumors
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