Lung metastasis genes couple breast tumor size and metastatic spread

Abstract

The association between large tumor size and metastatic risk in a majority of clinical cancers has led to questions as to whether these observations are causally related or whether one is simply a marker for the other. This is partly due to an uncertainty about how metastasis-promoting gene expression changes can arise in primary tumors. We investigated this question through the analysis of a previously defined ''lung metastasis gene-expression signature'' (LMS) that mediates experimental breast cancer metastasis selectively to the lung and is expressed by primary human breast cancer with a high risk for developing lung metastasis. Experimentally, we demonstrate that the LMS promotes primary tumor growth that enriches for LMS ؉ cells, and it allows for intravasation after reaching a critical tumor size. Clinically, this corresponds to LMS ؉ tumors being larger at diagnosis compared with LMS ؊ tumors and to a marked rise in the incidence of metastasis after LMS ؉ tumors reach 2 cm. Patients with LMS-expressing primary tumors selectively fail in the lung compared with the bone or other visceral sites and have a worse overall survival. The mechanistic linkage between metastasis gene expression, accelerated tumor growth, and likelihood of metastatic recurrence provided by the LMS may help to explain observations of prognostic gene signatures in primary cancer and how tumor growth can both lead to metastasis and be a marker for cells destined to metastasize.cancer ͉ genomics ͉ oncogenesis T he consistent association of large tumor size, rapid growth rate, and metastatic risk in a majority of cases of clinical cancer suggests that the molecular bases of these phenomena may be linked (1-3). However, the nature of this link remains unresolved. Conventional models of metastasis envision rare metastatically competent variants emerging by chance as primary tumors grow, causally linking growth with likelihood of metastatic relapse (4, 5). In this view, genes that control primary tumor growth operate independently of stochastically acquired metastasis genes. Alternative models posit that prometastatic gene expression events are acquired early during tumorigenesis and may overlap with the genes that promote primary tumor growth, making tumor size a marker for metastatic risk (6). These alternative models form a teleological basis for using gene expression signatures from primary tumors to forecast whether patients are at high risk for micrometastatic disease. However, despite several reports on the success of gene signatures from primary tumors to predict development of distant spread (7-12), tumor size remains an independent prognostic factor on multivariate analysis (9). Thus, to what degree conventional versus alternative models can explain the acquisition of a metastatic phenotype remains unclear.One of the difficulties in addressing the fundamental question on how metastasis gene expression events are acquired relates to the genetically complex nature of the phenotype itself. It has long been believed that there are nume...

Assessing intratumor heterogeneity and tracking longitudinal and spatial clonal evolutionary history by next-generation sequencing

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Data driven derivation of cutoffs from a pool of 3,030 Affymetrix arrays to stratify distinct clinical types of breast cancer

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Enhancement of active MMP release and invasive activity of lymph node metastatic tongue cancer cells by elevated signaling via the TNF-α-TNFR1-NF-κB pathway and a possible involvement of angiopoietin-like 4 in lung metastasis

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