CCN1: a sticky issue in myeloma

In this issue of Blood, Johnson et al report that patients with high CCN1 levels in their marrow who were treated in the Total Therapy 3 trial have a prolonged overall survival and better progression-free survival than patients with lower levels of CCN1.¹ 

The authors show that CCN1 is produced by mesenchymal stromal cells and not myeloma cells in the myeloma microenvironment and that CCN1 decreases myeloma cell growth at high concentrations, blocks osteoclastogenesis, and enhances osteoblastogenesis (see figure). Finally, they report that patients with monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic myeloma (AMM) who have high levels of CCN1 demonstrate a longer time of progression to active myeloma than those patients with lower CCN1 levels. Thus, this paper identifies CCN1 as both an important factor in the progression from MGUS/AMM to myeloma and a prognostic factor for myeloma patients, even those with high-risk myeloma, and provides a potential new target for enhancing the survival of myeloma patients.

CCN1 is 1 of a 6-member family of cysteine-rich matricellular proteins that share structural homology and have diverse effects on cells, including regulation of cell adhesion, cell migration, proliferation, differentiation, survival, angiogenesis, wound repair, and inflammation.²  Most of these family members bind integrins on the cell surface of target cells to induce their effects, and several of these family members have a role in bone turnover and solid tumor skeletal metastasis. CCN3, for example, which impairs normal osteoblast differentiation, has been implicated in enhancing osteosarcoma metastasis, but in other cancers it suppresses tumor progression.³  CCN1 is overexpressed in ∼30% of invasive breast cancers and is associated with bone metastasis and chemoresistance.⁴  Additionally, CCN1 has been shown to be a survival and proangiogenic factor that increases mesenchymal stem cell expansion and osteoblast differentiation.² 

Until recently, the role of CCN1 in myeloma has been relatively unknown. Using immunohistochemistry techniques, Santra et al reported that CCN1 is detectable in lymphoid and myeloid cells, but not myeloma cells in bone marrow biopsies from myeloma patients.⁵  More recently, Dotterweich et al reported that mesenchymal cells from myeloma patients express CCN1 and that CCN1 promotes splicing, transcription, and expression of CCN1 in myeloma cells.⁶  They further showed that CCN1 enhances survival of the IN-6 myeloma cell line in the absence of interleukin-6 and suggested that CCN1 may support myeloma cell viability and enhance myeloma bone disease. This is in contrast to the current article, which finds that CCN1 decreases myeloma cell numbers at high concentrations and that CCN1 inhibited osteoclastogenesis and stimulated osteoblastogenesis in a preclinical model of myeloma.

Several mechanisms might explain CCN1’s capacity to enhance the survival of myeloma patients and prevent the progression of patients with MGUS and AMM to active myeloma. Crockett et al showed that CCN1 inhibits osteoclastogenesis by a mechanism that is independent of α_vβ₃ integrin.⁷  Osteoclasts can support the growth of primary myeloma cells through cell to cell contact and produce a variety of soluble factors that stimulate the growth of myeloma cells, in particular, interleukin-6. Osteoclasts also release growth factors from the bone matrix that further enhance the growth and chemoresistance of myeloma cells.⁸  CCN1 also directly stimulates osteoblast precursor proliferation and differentiation.⁹  Li et al have shown in preclinical models of myeloma that enhanced osteoblast differentiation inhibits the growth of primary myeloma cells and bone destruction via decorin production.¹⁰  Further, the effects of CCN1 on the marrow microenvironment in patients with MGUS/AMM may also prevent the “microenvironmental switch” that may be at least in part involved in the progression of MGUS patients to active myeloma. This seems likely as myeloma cells from patients with MGUS and active myeloma share the same chromosomal abnormalities.

Results of the current study suggest that increasing local CCN1 levels in patients with active myeloma offers a new approach for enhancing survival and prolonging response to treatment of patients with active myeloma, as well as slowing the progression of patients with MGUS/AMM to active myeloma. Further, CCN1 appears to be a very useful marker for stratifying patients with MGUS/AMM and active myeloma to allow more appropriate risk-adapted therapy and follow-up for these patients.