Abstract
Effects of M2 tumour-associated macrophages on the pathogenesis of diffuse large B cell lymphoma (DLBCL) are still controversial. Our data showed that the number of CD163-positive M2 macrophages correlated negatively with DLBCL prognosis. Macrophage depletion by clodronate liposomes significantly suppressed tumour growth in a xenograft mouse model of DLBCL using OCI-Ly3 cells. Moreover, M2 polarization of macrophages induced legumain expression in U937 cells. Exogenous legumain promoted degradation of fibronectin and collagen I, which was abolished by administration of a legumain inhibitor RR-11a. Overexpression of legumain in Raw 264.7 cells also induced tube formation of endothelial cells in matrigel. In the xenograft mouse model of DLBCL, decreased fibronectin and collagen I, as well as increased legumain expression and angiogenesis were found at the late stage tumours compared with early stage tumours. Co-localization of legumain and fibronectin was observed in the extracellular matrix of tumour tissues. Administration of the legumain inhibitor to the xenograft DLBCL model suppressed tumour growth, angiogenesis and collagen deposition compared with the control. Taken together, our results suggest that M2 tumour-associated macrophages affect degradation of the extracellular matrix and angiogenesis via overexpression of legumain, and therefore play an active role in the progression of DLBCL.
Highlights
Whether a higher ratio of CD163- or CD68-positive macrophages can serve as a predictive index for a poorer prognosis of Diffuse large B cell lymphoma (DLBCL) is still controversial
The percentage of M2 TAMs in low risk groups was significantly lower than that in the high risk group as evaluated by the international prognostic index (IPI) (Fig. 1C, 9.459 ± 1.014% vs 14.34 ± 1.634, p = 0.0099). These findings suggest that the ratio of CD163-positive M2 TAMs correlates positively with the disease progression and prognosis of DLBCL
Several lines of evidence support that a high ratio of M2 polarized macrophages (M2 TAMs) leads to a poor outcome of DLBCL
Summary
Accumulating data have identified legumain expression in a variety of tumour types, suggesting a role in tumour progression[13]. A recent study on the crystal structure revealed multi-branched and context-dependent activation processes of legumain, suggesting broad roles in addition to its primary role as an endolysosomal cysteine proteinase[16]. TAMs have been found to express abundant amounts of legumain. A vaccine or inhibitor against legumain significantly eliminates M2 TAMs and inhibits tumour growth and metastases in murine tumour models[17,18]. Legumain was involved in angiogenesis and tumour progression via extracellular matrix (ECM) remodelling.
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