Early Steps In Cancer Metastasis New Concepts From In Vivo Videomicroscopy PDF Download

Metastasis is the major contributor to cancer-related deaths. However, it is an inefficient process. Cancer is also noted for long periods of dormancy, and metastases can occur many years after treatment. The biology of metastatic inefficiency and tumor dormancy are poorly understood. The goal of these studies was to identify early steps in the metastatic process that contribute to metastatic inefficiency and dormancy. We used in vivo imaging and quantification techniques, including: (1) high-resolution in vivo videomicroscopy, to observe early steps in metastasis; (2) a cell "accounting" technique, to quantify cell survival. We used endogenous (Green Fluorescent Protein) and exogenous (fluorescent nanospheres) markers to label cancer cells for in vivo visualization. Using GFP-expressing cells we demonstrated the utility of this labelling procedure to assess sequential steps of early metastasis. We identified an apparently dormant sub-population of single cells in vivo. We developed an experimental approach, using fluorescent nanospheres, to monitor cell division in vivo, and quantified survival and growth of cells of high and poor metastatic potential. We found that large numbers of injected cells survived in secondary organs. A small sub-population of injected cells started to proliferate, but not all early micrometastases continued to grow. We identified a surprisingly large population of dormant but viable solitary cells, which persisted in an undivided state for a long time period after injection. Dormant cells were detected for both highly and poorly metastatic cell lines. We hypothesized that these cells would remain unaffected by cytotoxic chemotherapy. We tested this using an in vivo chemotherapy model, and found that this treatment successfully reduced the metastatic burden in mice injected with the highly metastatic cell line. However, the numbers of solitary dormant cells were unaffected by this treatment, in mice injected with either of the cell lines. Thus, in this model, solitary dormant cells were unaffected by cytotoxic chemotherapy that targets dividing cells. If such dormant cells are present in cancer patients, they could contribute to dormancy and tumor recurrence, and they would not be susceptible to current cytotoxic therapeutic strategies.