Significance of tumor self-seeding as an augmentation to the classic metastasis paradigm

Evaluation of: Kim M-Y, Oskarsson T, Acharyya S et al.: Tumor self-seeding by circulating cancer cells. Cell 139, 1315-1326(2009). Augmenting our understanding that metastasis involves the spread of tumor cells to distant sites, this study describes an overlooked phenomenon - the seeding of metastases to the primary tumor itself. An aggressive population of circulating tumor cells (OTCs) within the primary tumor, which has already surmounted the challenge of entering and exiting the circulation, is revealed. The self-seeding principle was demonstrated using mice implanted with both 'recipient' unlabeled nonaggressive tumors and with homotypic 'donor' tumors, consisting of green fluorescent protein-labeled metastatic variants. When the donor tumor implants were instead nonaggressive, labeled cells isolated from the recipient tumors also exhibited strong self-seeding potential when re-implanted as donors, demonstrating selection for and amplification of a metastatic phenotype. The isolated CTC population possessed gene classifiers for all typical metastatic sites (bone, lung and brain). Metastatic and indolent populations could both chemoattract metastatic cells, while the CTCs demonstrated infiltrative capacity. CTCs were found to enhance primary tumor growth, probably through stromal paracrine effects. A self-seeding mechanism, driven by tumor chemoattraction and CTC infiltration, is concluded to play a critical role in tumor malignancy.