Human bone marrow-derived mitogenic stimulation selective for breast carcinoma and neuroblastoma cells

In patients with neuroblastoma (NB) or breast carcinoma (BC), metastatic disease in the bone marrow (BM) is observed more frequently than at any other site, and a high incidence of BM metastases in these patients is associated with advanced disease and poor prognosis. These observations suggest the presence of BM micro-environmental elements that are favorable for NB and BC tumor cell growth. The influence of normal human BM cell-derived conditioned medium (CM) on clonogenic growth of BC and NB cell lines was investigated in vitro. The effects obtained were compared with those on tumor cells with a lower potential for BM metastasis. CM from unstimulated cultures of normal, healthy, low-density BM cells reproducibly and markedly augmented clonogenic growth of 3 BC and 3 NB cell lines. In contrast, growth of cell lines established from human tumors with differing metastatic propensity was unaffected by BM CM. Initial characterization, using crude BM CM, indicated that mitogenic activity (i) is mediated by peptides released by the non-adherent fraction of low-density BM cells and (ii) is not abolished by neutralizing antibodies against various cytokines known to be produced by BM cells and to regulate hematopoietic cell growth. Our observations suggest that certain specific peptides in the BM micro-environment may be responsible for the preferential growth of NB and BC metastases in BM.