Influential partnership (original) (raw)

In the early stages of multiple myeloma (MM) — an incurable B-cell cancer usually confined to bone marrow — malignant cells depend on bone-marrow stroma to supply the signals necessary for growth and survival. A surprising discovery by Louis Staudt and colleagues reveals that overexpression of the c-MAF oncogene is a common event in MM, which increases cell proliferation and interaction between tumour and stromal cells.

The authors used DNA microarrays to study a panel of primary MM tumours and MM cell lines. c-MAF was overexpressed in 50% of the samples studied, but not in normal plasma cells, indicating that c-MAF overexpression is a common event in MM. By comparing gene profiles from MM cells that did or did not express c-MAF, they showed that expression of the cell-adhesion protein integrin β7, the cell-cycle regulator cyclin D2 and the chemokine receptor CCR1 was increased in the presence of c-MAF. The expression of these three proteins was shown to be upregulated by c-MAF.

The cyclin D2 promoter contains a c-MAF binding site and was activated by c-MAF in luciferase reporter assays, so c-MAF might affect cell-cycle progression. To investigate this further, they expressed c-MAF in MM cells that are normally deficient in this protein and saw increased cell division and DNA synthesis. By contrast, division of c-MAF-positive cells was decreased by a dominant-negative c-MAF. So, as there was no increase in cell death, c-MAF seems to increase cell-cycle entry. The same was found in vivo, as dominant-negative c-MAF prevented c-MAF-expressing MM cells from forming tumours in immunodeficient mice.

The interaction with bone marrow stroma is particularly important for MM development, but what mediates this interaction? Integrin β7 is induced by c-MAF in MM cells and binds E-cadherin, which is detected on the surface of stromal cells, so do c-MAF-expressing MM cells bind E-cadherin? Cells constitutively expressing c-MAF adhered to E-cadherin-coated plates, whereas cell lines that lacked expression of c-MAF did not. Similarly, the adhesion of cells expressing c-MAF to bone marrow stroma was increased by 2.5–3.5-fold, compared with cells that did not express c-MAF. Antibodies to E-cadherin and integrin β7 blocked these interactions, confirming that c-MAF enhances adhesion of myeloma cells to bone-marrow stroma through interactions between integrin β7 and E-cadherin.

One of the ways that stromal cells affect MM cells is by expressing growth factors. Staudt and colleagues found that the expression of vascular endothelial growth factor (VEGF), which regulates tumour growth and angiogenesis, was increased when stromal cells were co-cultured with c-MAF-expressing MM cells. This response was dependent on the interaction between integrin β7 and E-cadherin as antibodies abolished this induction.

So, c-MAF alters MM–stromal-cell interactions and increases VEGF expression, which is important for MM growth. It also enhances proliferation through the production of cyclin D1. Whether CCR1 also has an effect on MM cells remains to be determined. This important discovery has begun to unravel the complex biology of MM and has identified a new class of oncogenes that increase interactions between tumour and stromal cells. Targeting c-MAF could therefore provide future therapies for MM.

ORIGINAL RESEARCH PAPER

  1. Hurt, E. M. et al. Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma. Cancer Cell 5, 191–199 (2004)
    Article CAS Google Scholar

Download references

Authors

  1. Emma Croager
    You can also search for this author inPubMed Google Scholar

WEB SITE

Louis Staudt's lab

Rights and permissions

About this article

Cite this article

Croager, E. Influential partnership.Nat Rev Cancer 4, 248 (2004). https://doi.org/10.1038/nrc1324

Download citation