Expression of CD74, the Receptor for Macrophage Migration Inhibitory Factor, in Non-Small Cell Lung Cancer

Abstract

Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that is overexpressed in lung cancer. The MIF receptor was recently discovered and found to be the invariant chain of the HLA class II molecule, CD74. We hypothesized that the expression of this receptor-ligand pair in lung cancer is associated with the angiogenic activity and level of CXC chemokine expression in human specimens of non-small cell lung cancer. We, therefore, performed immunolocalization of CD74 and compared it with the localization of MIF in non-small cell lung cancer to determine their respective locations, as well as the relationship between the co-expression of MIF-CD74 and angiogenic CXC chemokines with tumor angiogenesis. We found intense CD74 expression by immunohistochemistry in 57 of 70 tumors with minimal to no staining in the remaining 13 tumors. Comparing the localization of CD74 with its putative ligand, MIF, we found that CD74 and MIF were co-expressed in tumors in close proximity, and that co-expression of the MIF-CD74 pair was associated with both higher levels of tumor-associated angiogenic CXC chemokines (ie, the ELR score) and greater vascularity compared with tumors in which MIF-CD74 co-expression was not present. We also found that MIF induced angiogenic CXC chemokine expression in an autocrine manner in vitro , a function that was specifically inhibited by antibodies to CD74. (Am J Pathol

CD74 as a Potential Prognostic Marker in Glioblastoma

“…Furthermore, our data confirmed worst prognosis for high-grade glioblastoma with high levels of CD74 expression. However, our data suggest that CD74 expression alone is not an independent marker for poor prognosis and it requires the expression of MIF for tumor pathogenesis, as previously reported in other studies (4,7,16,17,18) . Although we did not perform co-localization staining for MIF-CD74 in this retrospective study, evidence of MIF and CD74 co-localization reported in several other studies (7,8,9,10,11,12,13,14) .…”

“…Postoperative KPS scores have superior predictive capabilities for overall survival in glioblastoma patients and should replace preoperative KPS scores when estimating prognosis (20) . Similar to previous association studies of CD74 expression and survival in other cancers, KaplanMeier overall survival analyses for CD74 expression levels revealed a significant association between high CD74 expression and poorer prognosis (log-rank test, P = 0.05) (7,10,11) . Furthermore, our data confirmed worst prognosis for high-grade glioblastoma with high levels of CD74 expression.…”

“…The binding of MIF to the extracellular domain of CD74 is necessary as an initial step in the MIF signaling cascade (4) resulting in tumor vascularization and the promotion of neoplastic Fig. (3) cell proliferation and survival via ERK1/2-MAPK pathway (7) . Uni-and multi-variate analysis for CD74 expression in this study revealed a significant association for age, preoperative KPS, and post-operative KPS score, with overall survival, supporting the empirical evidence seen in the majority of the cancers.…”

“…MIF and CD74 form complexes with the cysteine-Xcysteine (CXC)-chemokine receptors CXCR2 on myeloid cells and CXCR4 on T cells (8) . The overexpression of MIF and/or CD74 has thought to enhance tumor growth in several human neoplasms, including breast cancer (9) , pancreatic cancer (10) , lung cancer (7) , and thyroid carcinoma (11) . Targeted therapies for CD74 that are currently under investigation includes Milatuzumab, a humanized MAB that recognizes CD74, which was able to stabilize advanced multiple myeloma (12) .…”

“…MIF signals upstream of cytokines via receptor binding in CD74-dependent pathways (4) . The pro-inflammatory cytokine MIF and its receptor CD74 (4) are associated with tumor vascularization (7) and the promotion of neoplastic cell proliferation and survival via ERK1/2-MAPK (extracellular signal-regulated protein kinases 1/2 and mitogen-activated protein kinase) pathway (7) . MIF can activate the extracellular signal-regulated kinase phosphorylation via CD74 and CD44, where CD44 activates non-receptor tyrosine kinases (4) .…”