Genes that mediate breast cancer metastasis to lung
By means of in vivo selection, transcriptomic analysis, functional verification and clinical validation, here we identify a set of genes that marks and mediates breast cancer metastasis to the lungs. Some of these genes serve dual functions, providing growth advantages both in the primary tumour and in the lung microenvironment. Others contribute to aggressive growth selectively in the lung. Many encode extracellular proteins and are of previously unknown relevance to cancer metastasis.
... is is frequently a final and fatal step in the progression of solid malignancies. Tumour cell intravasation, survival in circulation, extravasation into a distant organ, angiogenesis and uninhibited growth constitute the metastatic process 1 . The molecular requirements for some of these steps may be tissue specific. Indeed, the proclivity that tumours have for specific organs, such as breast carcinomas for bone and lung, was noted more than a century ago 2 . The identity and time of onset of the changes that endow tumour cells with these metastatic functions are largely unknown and are a subject of debate. It is believed that genomic instability generates large-scale cellular heterogeneity within tumour populations, from which rare cellular variants with augmented metastatic abilities evolve through a darwinian selection process 2,3 . Work on experimental metastasis with tumour cell lines has demonstrated that reinjection of metastatic cell populations can lead to enrichment in the metastatic phenotype 4-6 . Recently, however, the existence of genes expressed by rare cellular variants that specifically mediate metastasis has been challenged 7 . Transcriptomic profiling of primary human carcinomas has identified gene expression patterns that, when present in the bulk primary tumour population, predict a poor prognosis for patients 8-10 . The existence of such signatures has been interpreted to mean that genetic lesions acquired early in tumor-igenesis are sufficient for the metastatic process, and that consequently no metastasis-specific genes exist. However, it is unclear whether these genes predicting metastatic recurrence are also functional mediators. The lungs and bones are frequent sites of breast cancer metastasis, and metastases to these sites differ in terms of their evolution, treatment, morbidity and mortality 11 . Reasoning that each organ places different demands on circulating cancer cells for the establishment of metastases,