Clinical and experimental evidence suggests that tumor cells shed into the
circulation from solid cancers are ineffective in forming distant metastasi
s unless the cells are able to respond to growth conditions offered by the
secondary organs. To identify the phenotypic properties that are specific f
or such growth response, we injected carcinoma cells, which had been recove
red from bone marrow micrometastases in a breast cancer patient who was cli
nically devoid of overt metastatic disease and established in culture, into
the systemic circulation of immunodeficient rats. The animals developed me
tastases in the central nervous system, and metastatic tumor cells were iso
lated with immunomagnetic beads coated with an antibody that was reactive w
ith human cells. The segregated cell population was compared with the injec
ted cells by means of differential display analysis, and two candidate frag
ments were identified as upregulated in the fully metastatic cells, The fir
st was an intracellular effector molecule involved in tyrosine kinase signa
ling, known to mediate nerve growth factor-dependent promotion of cell surv
ival. The second was a novel gene product (termed candidate of metastasis-1
), presumably encoding a DNA-binding protein of helix-turn-helix type. Cons
titutive expression of candidate of metastasis-1 seemed to distinguish brea
st cancer cells with metastatic potential from cells without metastatic pot
ential. Hence, our experimental approach identified factors that may mediat
e the growth response of tumor cells upon establishment in a secondary orga
n and, thereby, contribute to the metastatic phenotype.