PLOD2 Is a Prognostic Marker in Glioblastoma That Modulates the Immune Microenvironment and Tumor Progression

Abstract

This study aimed to investigate the role of Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase 2 (PLOD2) in glioblastoma (GBM) pathophysiology. To this end, PLOD2 protein expression was assessed by immunohistochemistry in two independent cohorts of patients with primary GBM (n1 = 204 and n2 = 203, respectively). Association with the outcome was tested by Kaplan–Meier, log-rank and multivariate Cox regression analysis in patients with confirmed IDH wild-type status. The biological effects and downstream mechanisms of PLOD2 were assessed in stable PLOD2 knock-down GBM cell lines. High levels of PLOD2 significantly associated with (p1 = 0.020; p2< 0.001; log-rank) and predicted (cohort 1: HR = 1.401, CI [95%] = 1.009–1.946, p1 = 0.044; cohort 2: HR = 1.493; CI [95%] = 1.042–2.140, p2 = 0.029; Cox regression) the poor overall survival of GBM patients. PLOD2 knock-down inhibited tumor proliferation, invasion and anchorage-independent growth. MT1-MMP, CD44, CD99, Catenin D1 and MMP2 were downstream of PLOD2 in GBM cells. GBM cells produced soluble factors via PLOD2, which subsequently induced neutrophils to acquire a pro-tumor phenotype characterized by prolonged survival and the release of MMP9. Importantly, GBM patients with synchronous high levels of PLOD2 and neutrophil infiltration had significantly worse overall survival (p < 0.001; log-rank) compared to the other groups of GBM patients. These findings indicate that PLOD2 promotes GBM progression and might be a useful therapeutic target in this type of cancer.

RUNX1/CD44 axis regulates the proliferation, migration, and immunotherapy of gliomas: A single-cell sequencing analysis

“…A previous scRNA-seq analysis revealed SPP1/CD44-mediated crosstalk between macrophages and cancer cells in glioma ( 44 ). PLOD2 modulates the immune microenvironment and tumor progression of glioma, in which CD44 was the critical downstream molecule ( 45 ). Besides, CD44 was recently demonstrated to be associated with the M2-polarization of tumor-associated macrophages and immunosuppression of glioma ( 25 ).…”

Minoxidil weakens newly synthesized collagen in fibrotic synoviocytes from osteoarthritis patients

“…Therefore, evaluation of local and safe administration of targeted pharmacotherapeutics designed to weaken fibrous COL1 deposits in the synovium and neighboring fibro-sensitive structures such as the peri-articular musculature is critical to improve on the success of physical therapy, manual or device-assisted MUA, and arthroscopic lysis of adhesions. As an FDA-approved pharmacotherapeutic, elucidating the antifibrotic potential of MXD to modulate Pyd cross-linking in COL1 fibrous networks in fibroproliferative diseases such as idiopathic pulmonary fibrosis, renal disease, dermal scarring, and metastatic neoplasms in vitro needs further evaluation within the musculoskeletal arena beyond its shown effect on clubfoot fibroblasts [ 13 , 21 , 22 , 31 , 33 ].…”

Ivermectin Affects Neutrophil-Induced Inflammation through Inhibition of Hydroxylysine but Stimulation of Cathepsin G and Phenylalanine Secretion

“…The LH activity plays an important role in the ability of tumor cells to invade and metastasize through the modification of the extracellular matrix. A growing number of articles present increased LH expression as a prognostic marker associated with poor prognosis in patients with osteosarcoma [ 68 ], glioblastoma [ 27 ], oral squamous cell carcinoma [ 25 , 69 ], and other cancer diseases. Moreover, neutrophils that were attached to fibronectin in the presence of ivermectin did not secrete MMPs ( Figure 6 , Table 1 ).…”

“…In tumor cells, LH is also secreted and functions in the extracellular space [ 17 , 18 , 19 ], thus affecting cell migration and adhesion via modification of the extracellular matrix [ 20 ]. A growing number of studies demonstrate that LH activity correlates with the ability of tumor cells to invade and metastasize [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. By analogy with tumor cells, we hypothesize that the adhesion-induced increase in hydroxylysine release is associated with an increase in LH activity designed to promote neutrophil infiltration into tissues.…”