Growth regulation of cancer metastases by their host organ.

Abstract

We analyzed mechanisms responsible for organ-specific metastasis by using two melanoma sublines derived from the same mouse tumor, of which one colonizes the lungs (Flo) and the other colonizes the liver (L8) after intravenous injection. Both lines were obtained by selective growth in lung or liver after injection of tumor cells into a tail vein or portal vein. Contrary to common concepts, the cells of the liver-colonizing melanoma line do not accumulate preferentially in the liver after intravenous administration in vivo. However, the selective survival and proliferation of these melanoma cells in the target organ (liver) may be explained by the unexpected observation that they can be specifically stimulated to proliferate in the presence of hepatocytes, whereas the cells of the lung-colonizing line cannot. Growth promotion under coculture conditions in vitro was monitored both by thymidine incorporation into DNA and by increase in cell numbers. The proliferative stimulus is not mediated by an easily diffusible factor but rather depends upon direct contact between liver cells and those tumor cells that metastasize to that particular organ.It is common clinical experience that a malignant primary cancer, although shedding viable cells throughout the body, will only give rise to gross metastases in certain specific tissues (1,2) and that the specific nature of these secondary sites depends upon the histological origin of the primary tumor. Apparently, the host tissue must be able to reciprocate this recognition in some way, if only passively (3).Some progress in explaining the general mechanisms of metastasis has been made recently through the recognition of autocrine motility factors that induce pseudopodia formation and hence exploratory cell migration (4). Earlier advances were made with variant and mutant cells that had different degrees of metastatic ability correlating with cell-surface alterations (5). Later, variants of metastasizing mouse melanoma cells were selected with preference for the liver (6). Fusion of nonmetastatic tumor cells with reticuloendothelial cells can also give rise to metastatic hybrids having distinct site specificities (7).This phenomenon has some interesting analogies with other homing and tissue interaction systems such as the inhibitory regulation of a melanoma by embryonic skin (8), the growth stimulation of neuroblastoma cells by neonatal sympathetic ganglia (9), fetal fat tissue and its supportive interaction with numerous fetal epithelia (10), and the stimulation by human melanoma and carcinomas of fibroblasts to produce hyaluronate (11).We show here that a specific interaction occurs between adult hepatocytes and liver-metastasizing melanoma cells resulting in the stimulation of the proliferation of the tumor cells. MATERIALS AND METHODSIn Vivo Experiments. Organ specificity. An organ-specific mouse melanoma of the F1 line of B16 melanoma cells (from I. J. Fidler, Houston) was isolated by administration into the portal vein, recovery and growth of liver colonies in ...

Purification and characterization of a Mr ∼66,000 lung‐derived (paracrine) growth factor that preferentially stimulates the in vitro proliferation of lung‐metastasizing tumor cells

“…Others have also found that lung-conditioned medium [ 1 1 ,I 21 or lung extracts [ 131 preferentially enhanced the growth of lung-metastasizing cell lines. Enhancement of the growth of metastatic cells was also observed when such cells were in contact with cells from the target organ [14]. Here we report on the purification and some of the properties of a growth factor from porcine and rat lung-conditioned medium that differentially stimulates the growth of lung-metastasizing tumor cells.…”

Differential influence of organ site on three subpopulations of a single mouse mammary tumor at two distinct steps in metastasis

“…The more tumor cells delivered to an organ, the more likely it is that metastases will result. That other factors are also involved in organ selective metastasis is clear, since metastases form in ectopic tissues in a specific manner (Kinsey, 1960;Hart and Fidler, 1980) and tumors transplanted into identical sites metastasize to different sites (Sugarbaker, 1952;Nicolson et al, 1978;Tao et al, 1979;Barnett and Eccles, 1984;Shearman and Longenecker, 1981;Brodt, 1986;Murphy et al, 1988;Chan et al, 1988;Sargent et al, 1988).…”

Influence of Hepatocyte Growth Factor/Scatter Factor on the Metastatic Phenotype of B16 Melanoma Cells

“…Melanoma cells were plated with the hepatocytes at a ratio 1:100, and 6 h later HGF/SF was added at 50 ng/ ml. Four days later cells were pulse-labelled for 2 h with 1 ÌCi/ml of 3 H-bromodeoxyuridine (Amersham, specific activity 37 Ci/mmol), and processed to measure the incorporated radioactivity [5,6]. The amount taken up by melanoma cells in coculture with hepatocytes was determined after subtraction of radioactivity incorporated by hepatocytes alone under the same culture conditions.…”

“…To this purpose, we have selected in vivo a B16 melanoma cell line (B16-LS9), showing an increased ability to colonize the liver of syngeneic mice [5]. Neither specific adhesion, nor increased retention in the liver could explain the liver specificity, which appeared rather to rely on paracrine growth effects [5][6][7].…”