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

Abstract

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.

Figure 1-6935

DCCs and tumors and metastases formed by retrieved cells. A–C: Scattered fluorescing cancer cells detected by microscopy of the surface of the spleen (A), kidney (B), and liver (C). D–F: Frozen sections show individual cancer cells deeper within the spleen (D), kidney (E), and liver (F). Fluorescence microscopy confirmed that labeled cancer cells (G) lay outside blood vessels (asterisk) in the tissues, although they were not identifiable in adjacent H&E-stained sections (H). In G a RFP-labeled tumor cell is bright red, background autofluorescence is pale green. Subsequent panels show pulmonary metastases (I) and mammary carcinomas generated by reinoculated fluorescent DCCs, retrieved from spleen (J) and bone marrow (K and L).