Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency.

TLDR

Cancer metastasis is an inefficient process, and the steps responsible for this inefficiency and its variation across lung locations remain poorly understood. The study aims to quantify the early temporal and spatial progression of lung metastasis, document the persistence of solitary dormant cells, and demonstrate that metastatic inefficiency depends on initiation of growth in a subset of extravasated cells while continued growth favors specific tissue environments. Using B16F10 cells injected into mouse lungs, the authors sequentially measured overall and local cell survival and growth relative to lung surface and interior structures over time. They found that although most injected cells survive initial trapping and extravasation (74 % at day 3), a major loss occurs at first replication, leaving only a small fraction that ultimately form macroscopic tumors, with solitary cells remaining dormant; overall inefficiency is driven by post‑extravasation events, and by day 10 tumor growth preferentially.

Abstract

Cancer metastasis is an inefficient process. The steps in metastasis responsible for this inefficiency and how metastatic inefficiency can vary in different locations within an organ remain poorly understood. B16F10 cells were injected to target mouse lung, and at sequential times thereafter we quantified in lung the time course of: (a) overall cell survival and metastatic development; and (b) local cell survival and growth with respect to the lung surface and specific interior structures. We found high rates of initial survival of cells trapped in the lung circulation, extravasation into lung tissue, and subsequent survival of extravasated solitary cells (74% at day 3) before metastasis formation. However, at the time of initial replication of metastatic cells a major loss of cells occurred. Although only a small proportion of injected cells started to form metastases, most of these developed into macroscopic tumors. Solitary cells found at later times were dormant. Thus, overall metastatic inefficiency was largely due to postextravasation events affecting solitary cells. Regionally within the lung, cells and metastases were randomly distributed to day 4, but by day 10 preferential tumor growth was found along the lung surface and around arterial and venous vessels. Thus, trapping and early growth of injected cells was unaffected by location within the lung, whereas subsequent metastatic growth was enhanced in specific microenvironments. This study: (a) quantifies early temporal and spatial progression of metastasis in lung; (b) documents persistence of solitary dormant cells; and (c) shows that metastatic inefficiency depends on the initiation of growth in a subset of extravasated cells, whereas continued growth of metastases occurs preferentially in specific tissue environments.