A mathematical model of tumor self-seeding reveals secondary metastatic deposits as drivers of primary tumor growth

TL;DR

This paper presents a mathematical model comparing primary and secondary seeding of circulating tumor cells, concluding secondary seeding is vastly more likely and significantly impacts tumor growth and treatment strategies.

Contribution

The study introduces a mathematical framework to distinguish between primary and secondary seeding, highlighting the dominance of secondary seeding in tumor progression.

Findings

Secondary seeding is several orders of magnitude more likely than primary seeding.

The model suggests secondary seeding significantly influences tumor evolution.

Proposes experimental methods to validate the model's predictions.

Abstract

Two models of circulating tumor cell (CTC) dynamics have been proposed to explain the phenomenon of tumor 'self-seeding', whereby CTCs repopulate the primary tumor and accelerate growth: Primary Seeding, where cells from a primary tumor shed into the vasculature and return back to the primary themselves; and Secondary Seeding, where cells from the primary first metastasize in a secondary tissue and form microscopic secondary deposits, which then shed cells into the vasculature returning to the primary. These two models are difficult to distinguish experimentally, yet the differences between them is of great importance to both our understanding of the metastatic process and also for designing methods of intervention. Therefore we developed a mathematical model to test the relative likelihood of these two phenomena in the subset of tumours whose shed CTCs first encounter the lung capillary bed, and show that Secondary Seeding is several orders of magnitude more likely than Primary seeding. We suggest how this difference could affect tumour evolution, progression and therapy, and propose several possible methods of experimental validation.