Dormant cancer cells retrieved from metastasis-free organs regain tumorigenic and metastatic potency.

This study shows that solitary, dormant human cancer cells, retrieved from metastasis-free organs of animals carrying spontaneously metastatic primary tumors, can reactivate their tumorigenic and metastatic potency. The tumors were produced by MDA-MB-435 CL16 breast cancer cells permanently labeled with green fluorescent protein and the neomycin resistance gene. This enabled unequivocal identification of tumor cells emerging from organ explants cultured in neomycin to eliminate nonneoplastic host cells. Rescued cells resumed proliferation and generated lines that were tumorigenic and metastatic in fresh animals. All resulting primary and secondary tumors were uniformly labeled. Cells recovered from bone marrows and spleens, where there were no metastases, were as tumorigenic and metastatic as cells recovered from lungs and lymph nodes, which are the preferred sites of colonization for this tumor line. This evidence that malignant growth of disseminated cancer cells is suspended indefinitely by microenvironmental conditions in metastasis-free organs, although it is still active in others of the same host, shows that neoplastic progression can be arrested and has far-reaching biological and clinical implications. Specifically, it predicts the existence of natural, nonimmune host mechanisms that stimulate or inactivate tumor growth in different anatomical sites, which may be exploitable for therapeutic benefit.

Tumor-stromal interactions reciprocally modulate gene expression patterns during carcinogenesis and metastasis.

This study used a unique xenogeneic breast cancer model to study the effects of tumor cells and neighboring host cells upon each other in tumor growth and metastasis. It exploited species differences between the interacting components to determine how the host influenced the tumor and vice versa. It was found that the gene expression profiles of highly and poorly metastatic clones from the same human breast carcinoma changed differentially when the cells were transferred from growth in vitro to the mammary gland. We describe novel sets of genes, validated by human-specific probes, which were induced in the 2 isogenic, but phenotypically different, tumor lineages by the mammary environment. Conversely, the tumor cells also induced changes in gene expression in the neighboring host stromal (i.e., mesenchymal) cell lineages, validated by mouse-specific probes. Reciprocal inductive interactions were also demonstrated in the tumor deposits formed preferentially in the lungs and lymph nodes by the highly metastatic tumor cells. Subtraction of the induced gene changes in the primary site from those in the metastases revealed that the number and magnitude of specific gene inductions in colonized organs were moderate. This finding indicates that the gene expression program causing metastasis has only limited flexibility and fits well with clinical observations that tumor cells form metastases preferentially in select organs, although tumor cells are scattered ubiquitously. This dependency on suitable host niches suggests new molecular therapeutic avenues that target genes in the host-support system that is manipulated by the malignant cells.