No abstract

Primary tumors have been shown to prepare distal organs for later colonization of metastatic cells by stimulating organ-specific infiltration of bone marrow derived cells. Here we demonstrate that neutrophils accumulate in the lung prior to the arrival of metastatic cells in mouse models of breast cancer. Tumor-entrained neutrophils (TENs) inhibit metastatic seeding in the lungs by generating H2O2 and tumor secreted CCL2 is a critical mediator of optimal anti-metastatic entrainment of G-CSF-stimulated neutrophils. TENs are present in the peripheral blood of breast cancer patients prior to surgical resection but not in healthy individuals. Thus, while tumor-secreted factors contribute to tumor progression at the primary site, they concomitantly induce a neutrophil-mediated inhibitory process at the metastatic site.

Most metastatic cancers are incurable--a fact that underscores the limitations of our existing paradigms for understanding metastasis. In this Review, we use breast cancer to explore many of the enigmas revealed by these existing paradigms. Traditionally, metastatic models describe metastasis as a unidirectional process, whereby cancer cells leave a primary tumor and unidirectionally seed metastasis in regional lymph nodes or distant sites. By contrast, recent data indicate that metastasis is a multidirectional process whereby cancer cells can seed distant sites as well as the primary tumor itself. This later process, known as 'self-seeding,' has been validated in diverse experimental models. Here, we show that the self-seeding model may answer many of the mysteries inherent to cancer metastasis. Indeed, reframing our understanding of metastasis within the self-seeding model offers new opportunities for prevention and cure of metastatic cancer.