The Cyclophilin A–CD147 complex promotes the proliferation and homing of multiple myeloma cells

Abstract

B-cell malignancies frequently colonizes the bone marrow (BM). The mechanisms responsible for this preferential homing are not entirely known. Using multiple myeloma (MM) as a model of a terminally differentiated B-cell malignancy that selectively colonizes the BM, we demonstrated that BM endothelial cells (BMECs), secrete cyclophilin A (eCyPA), which promotes migration, proliferation, and BM colonization of MM cells via binding to its receptor, CD147, on MM cells. The clinical and translational implications of this work are highlighted by the observation of significantly higher eCyPA levels in BM serum than in peripheral blood (PB) in MM persons, and that eCyPA-CD147 blockade supresses BM-homing and tumor growth in a mouse xenograft model of MM. eCyPA also promoted migration of CLL and LPL cells, two other B-cell malignancies that colonize the BM and express CD147. These findings offer a compelling rationale for exploring the eCyPA-CD147 axis as therapeutic target for these malignancies.

Immunomodulatory drugs disrupt the cereblon–CD147–MCT1 axis to exert antitumor activity and teratogenicity

“…This result suggests that CD147 and MCT1 destabilization may be indicative of IMiD response, similar to very low IKZF1 levels, which have been reported to correlate with poor responses to pomalidomide in relapsed or refractory MM 22 . In agreement with previous reports that demonstrate the importance of CD147 and MCT1 overexpression for MM cell proliferation and survival [16][17][18] , knockdown of CD147 and MCT1 by RNAi substantially decreased proliferation in both lenalidomide-sensitive and lenalidomide-resistant MM cell lines ( Fig. 3c and Supplementary Fig.…”

“…Indeed, the CD147-MCT1 complex is of vital importance for the regulation of cellular metabolism-particularly glycolysis, a major source of energy production in cancer cells 14,15 . Notably, expression of CD147 and MCT1 is upregulated in MM, and both proteins have been critically implicated in the proliferation and survival of MM cells [16][17][18] .Recently it was shown that lenalidomide enables CRBN to target the lymphoid transcription factors IKZF1 and IKZF3, as well as the kinase CK1-α, for proteasomal degradation 19-24 . These mechanisms presumably account for some of the effects of IMiDs in MM and del(5q) MDS.…”

The bone marrow microenvironment in health and disease at a glance

“…However, the homing of myeloma cells to bone marrow is dependent on their interaction with endothelial cells and the CXCR4-CXCL12 axis, as for leukemia cells. CD147 (basigin) on the surface of myeloma cells interacts with cyclophilin A secreted by endothelial cells, which contributes to myeloma cell migration (Zhu et al, 2015). Bone marrow stroma cells produce endothelial growth factor A (VEGFA), which increases microvessel density and has been linked to a worse outcome in MM (Iwasaki et al, 2002).…”

Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration

“…During end-stage of MM, malignant cells can survive and proliferate outside the microenvironment of the BM. The chemokine receptor CXCR4 and the CD147 receptor, which are up-regulated in MM plasmacells, have shown involvement in the recruitment of these cells to the BM [26]. …”