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

Cancer metastasis is an inefficient process. The steps in metastasis respon sible for this inefficiency and how metastatic inefficiency can vary in dif ferent locations within an organ remain poorly understood. B16F10 cells wer e injected to target mouse lung, and at sequential times thereafter we quan tified in lung the time course of: (a) overall cell survival and metastatic development; and (b) local cell survival and growth with respect to the lu ng 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 replicatio n of metastatic cells a major loss of cells occurred. Although only a small proportion of injected cells started to form metastases, most of these dev eloped into macroscopic tumors. Solitary cells found at later times were do rmant. Thus, overall metastatic inefficiency was largely due to postextrava sation events affecting solitary cells. Regionally within the lung, cells a nd metastases were randomly distributed to day 4, but by day 10 preferentia l tumor growth was found along the lung surface and around arterial and ven ous vessels. Thus, trapping and early growth of injected cells was unaffect ed by location within the lung, whereas subsequent metastatic growth was en hanced in specific microenvironments. This study: (a) quantifies early temp oral and spatial progression of metastasis in lung; (b) documents persisten ce of solitary dormant cells; and (c) shows that metastatic inefficiency de pends on the initiation of growth in a subset of extravasated cells, wherea s continued growth of metastases occurs preferentially in specific tissue e nvironments.