Extracellular matrix metalloprotease inducer stimulates fibroblast-mediated tumor growth in vivo

Extracellular matrix metalloprotease inducer (EMMPRIN) is a molecule expressed on the cell surface of tumor cells that has been shown to induce both tumor cells and fibroblasts to express matrix metalloproteases in vitro. We hypothesize that fibroblasts are stimulated by EMMPRIN to create a microenvironment favorable to tumor growth.

Case series review of laryngeal cancer and assessment of tumor cell lines in vivo.

EMMPRIN immunoreactivity in 33 pathologic specimens from patients with supraglottic laryngeal cancer was correlated with clinicopathologic features and survival. The CAL 27 cell line was transfected with EMMPRIN (CAL 27E) or a control vector (CAL 27). Cells were xenografted into the flank of severe combined immunodeficient (SCID) mice with or without a co-injection of normal dermal fibroblasts (NDFs).

Immunohistochemical detection of EMMPRIN in laryngeal cancer specimens demonstrated expression in all the tumors but not in adjacent, histologically normal mucosa. EMMPRIN membrane immunoreactivity (transmembrane EMMPRIN score) was associated with nodal positivity (P=.07), and it was associated with poorer survival (hazard ratio=2.4, 95% confidence interval 0.88, 6.55). As a categoric variable, higher EMMPRIN expression positively correlates with higher mortality. To determine whether EMMPRIN mediates tumor growth in vivo through fibroblast stimulation, EMMPRIN-expressing CAL 27 (CAL 27E) xenografted (n=20) onto the flank of SCID mice developed larger tumors than CAL 27 control vector transfected cells alone (n=20), but they were not significantly larger (P=.17). However, when CAL 27E cells were co-injected with NDFs, there was a statistically significant increase in tumor growth compared with the CAL 27 cells co-injected with NDFs (n=10, P=.0038).

As a cell surface expressed protein that promotes tumor growth and high expression in head and neck squamous cell carcinoma but not in normal tissue, EMMPRIN may be a good target for directed molecular therapy.