Myeloma is on the move

Mature plasma cells and myeloma cells migrate to the bone, and myeloma cells have the ability to metastasize to different bone marrow and extramedullary sites. Although macrophage inflammatory protein 1 α and monocyte chemoattractant protein 1 have been shown to induce migration of myeloma cells, and other chemokines and chemokine receptors have been implicated in myeloma cell movement, the mechanism(s) by which these cells move are not completely understood. In this issue, Qiang and colleagues (page 301) provide compelling evidence that insulin-like growth factor-1 (IGF-1), an already established growth and survival factor for myeloma in vitro, is also an inducer of myeloma cell migration.

Interest in IGFs and their effect on carcinogenesis has increased recently because high IGF-1 serum concentrations are associated with an increased risk of breast, prostate, colorectal, and lung cancers. Indications are that IGF-1 also plays a role in myeloma. In a recent case report, the conversion of monoclonal gammopathy of undetermined significance to overt myeloma occurred in strict temporal relationship with elevated serum IGF-1 levels.¹  In addition, serum IGF-1 levels have been linked to survival in myeloma.²  We have shown that IGF1R is the only gene significantly elevated in a comparison of microarray profiles of myeloma cells with and without chromosome 13 deletion, a dire prognostic feature,³  and more recent analysis has revealed that elevated expression of IGF1R is associated with an increased risk of mortality in myeloma patients treated with tandem stem cell transplants (our unpublished data, May 2003).

Ge and Rudikoff were the first to show that virtually all myeloma cell lines express IGF1R, and that ligand binding causes activation of phosphatidylinositol-3′-kinase (PI-3K), which in turn increases survival and proliferation.⁴  IGF-1 activates Akt and Bad, leading to apoptosis inhibition, and mitogen-activated protein kinase (MAPK), resulting in proliferation. Although Vanderkerken and colleagues have previously shown that IGF-1 is a bone marrow–derived chemoattractant for myeloma cells in the 5T2 model,⁵  in this issue, Qiang, Rudikoff, and colleagues show that IGF-1 mediates cell migration of human myeloma cells and that this is dependent on RhoA signaling. Interestingly, this same group has recently shown that a Wnt3A-induced shift in cell morphology is also RhoA-dependent.

In an independent study, Tai et al have shown that IGF-1 stimulates migration, but, in their hands, this is Akt-dependent.⁶  Tai et al⁶  and Qiang et al used different myeloma cell lines, which may account for the divergent findings of Akt involvement in IGF-1–induced cell migration. Given the molecular and clinical heterogeneity of myeloma, these differences could reflect molecular variation in the tumors from which the cell lines were originally derived. Alternatively, the disagreement may be explained by subtle differences in the experimental conditions or genetic changes that occurred in long-term cell cultures. Nevertheless, these discrepancies point to the potential problems of extrapolating data from cell lines to primary tumor biology. Data derived from cell lines must be interpreted with caution as these models are typically derived from end-stage disease and may use signaling pathways that are not relevant to primary tumor biology. Thus, it will be important to determine if primary isolates respond to IGF-1, if IGF-1 induces migration through RhoA and/or Akt, and, if this heterogeneity is confirmed, if it correlates with clinical features of the disease.

An important biologic question raised by Qiang and colleagues is how can IGF-1 induce proliferation and migration? The authors have put forth an intriguing model suggesting that local concentration gradients of IGF-1 determine whether a given cell will migrate or will proliferate.

The IGF-1 signaling cascade continues to be implicated in several aspects of myeloma biology and, as such, must be seriously considered as a potential new therapeutic target in this difficult-to-manage cancer.