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

Abstract

Tumor subpopulations 66c14, 168FARN, and 4T07 are drug-resistant variants selected from sister subpopulations derived from a single mouse mammary tumor. These subpopulations are heterogeneous in their capacities to form experimental metastatic growth in the lungs and liver. Initial survival kinetics of arrested cells, determined by the clearance of 125IUdR-labelled cells, and subsequent growth rates, determined by sequential recovery of clonogenic tumor cells from occult metastases, both correlated with organ-colonizing potential as determined by necropsy. The growth rates of these 3 subpopulations were determined in vitro in monolayer and in situ in the subcutis, in the liver following intrasplenic injection, and in the lung following intravenous injection. Clonogenic potential of all 3 lines was similar in vitro (54-59%). Growth rates in vitro (population doubling times 16.5-21 hr) and in the subcutis (tumor volume doubling times 5.2-7.4 days) were similar for the 3 subpopulations, but differed significantly in the liver and lungs. For line 4T07, the most metastatic line to both lung and liver, population doubling times in vitro and in the lung and liver were similar, ranging from 17 to 26 hr. For lines 66c14 and 168FARN, the growth rates in lungs and livers were much slower than in vitro. Line 66c14, which is relatively more metastatic to the lungs, grew much faster in the lung (39 hours) than in the liver (91 hr), but line 168FARN, which is relatively more metastatic to the liver, grew at a faster rate in the liver (37 hr) than in the lung (63 hr). Thus, 3 tumor subpopulations (seeds) derived from a single tumor were differentially affected by host organ factors (soil) at 2 distinct stages in the metastatic process.

Raman spectroscopy can differentiate malignant tumors from normal breast tissue and detect early neoplastic changes in a mouse model

“…A highly malignant BALB/c tumor cell line (4T1) was used in this study. 12 Eleven BALB/c (Taconic Farms, Germantown, NY) female mice (6-to 8-weeks old) were injected subcutaneously at the nipple of the 5th mammary gland on one side, with a suspension of 1 3 10 5 4T1 tumor cells. All mice developed tumor nodules at the injection site.…”

Melphalan sensitivity as a function of progressive metastatic growth in two subpopulations of a mouse mammary tumour

“…In order for tumour cells injected intravenously to form lung colonies, the cells must be arrested and retained in the lung, extravasate, and replicate in lung parenchyma. Previous studies with line 4T07 using similar colony-forming assays have shown that it arrests and grows in lung in a characteristic time-dependent manner which can be related to these several steps of metastasis (Aslakson et al, 1991a(Aslakson et al, , 1991b. The majority (>80%) of line 4T07 cells injected i.v.…”

“…Agents which inhibit metastasis are usually evaluated by determining their effect on the final outcome of this metastatic sequence, either by the overall effect on survival or by comparing the number or size of metastatic nodules which develop in treated vs control animals. By using a series of mouse mammary tumour cell lines with selectable markers, we have been able to follow the development of experimental lung and liver metastases from cell injection through the appearance of visible nodules (Aslakson et al, 1991a), and have described immunological treatments which inhibit lung colonisation at two different steps in the metastatic sequence (Aslakson et al, 1991b). These tumour cell lines were selected from sister subpopulations derived from a single mouse mammary tumour.…”

“…These tumour cell lines were selected from sister subpopulations derived from a single mouse mammary tumour. Both the parent subpopulations and several of the lines with selectable markers have been extensively characterised, and have been shown to differ in many characteristics, including sensitivity to several chemotherapeutic drugs Miller et al, 1989a;Miller et al, 1989b;Miller et al, 1991), ability to metastasise from a subcutaneous site (Miller et al, 1983), and ability to form experimental metastases in lung and liver (Aslakson et al, 1991a). We have chosen to use this model system to examine the sensitivity to chemotherapy of these tumour cells at various steps in the metastatic sequence and in subcutaneous tumours.…”

Complementation of two related tumour cell classes during experimental metastasis tagged with different histochemical marker genes

“…Heterogeneity of tumour cell subpopulations and their cooperation in contributing to malignant tumour progression have been studied in only a few systems (Aslakson et al, 1991;Hart & Saini, 1992;Heppner & Miller, 1983;Maghazachi et al., 1988;Miller et al, 1980;Miller & Heppner, 1990). Interactions among subpopulations of tumour cells could very well determine the outcome of metastasis (Hart et al, 1989;Miller & Heppner, 1990).…”