Intravascular location of breast cancer cells after spontaneous metastasis to the lung - PubMed (original) (raw)

Intravascular location of breast cancer cells after spontaneous metastasis to the lung

Christopher W Wong et al. Am J Pathol. 2002 Sep.

Abstract

In this study, we examined the hypothesis that early pulmonary metastases form within the vasculature. We introduced primary tumors in immunocompromised mice by subcutaneous injection of murine breast carcinoma cells (4T1) expressing green fluorescent protein. Isolated ventilated and perfused lungs from these mice were examined at various times after tumor formation by fluorescent microscopy. The vasculature was visualized by counterstaining with 1,1-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine (DiI)-acetylated low-density lipoprotein. These experiments showed that metastatic cells derived by spontaneous metastases were intravascular, and that early colony formation was intravascular. The location of the tumor cells was confirmed by deconvolution analysis. This work extends our previous study(1) that sarcoma cells injected intravenously form intravascular colonies to spontaneous metastasis and to a carcinoma model system. Many of the tumor cells seen were single implying that tumor cells may travel as single cells. These results support a model for pulmonary metastasis in mice in which 1) tumor cells can attach to lung endothelium soon after arrival; 2) surviving tumor cells proliferate intravascularly in this model; and 3) extravasation of the tumor occurs when intravascular micrometastatic foci outgrow the vessels they are in.

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Figures

Figure 1.

Figure 1.

Intravascular location of spontaneous lung metastases. 4T1 tumor cells that spontaneously metastasized into the lung were visualized by high-resolution digital video microscopy as described in Materials and Methods. In A, B, and F, the lung endothelium has been labeled with a red fluorescent dye, DiI-acetylated LDL. A: Solitary tumor cells (green) attached within the precapillary arterioles. B: Solitary tumor cell attached in a capillary. C: Colony of ∼10 cells within a blood vessel. The endothelial margins, indicated by arrows, are visible because of reflection and scattering of green fluorescent protein fluorescence from tumor cells. D: Large colony of tumor cells within the lung vasculature. E: Another large colony that probably has outgrown the vessel of initial attachment continues to exhibit intravascular growth along capillaries around alveoli (Alv). Note how the outline of the alveolar wall is formed by strings of green fluorescent protein-expressing tumor cells. F: Front projection of a three dimensional-reconstructed image of a small colony shows intravascular location. The endothelium was labeled with DiI-acetylated LDL (red). Fifty planes of a stack of images taken separately in the green and red fluorescence channels taken along the z axis spanning a depth of 50 μm were overlaid.

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