Decorin expression is associated with predictive diffusion MR phenotypes of anti-VEGF efficacy in glioblastoma

Abstract

Previous data suggest that apparent diffusion coefficient (ADC) imaging phenotypes predict survival response to anti-VEGF monotherapy in glioblastoma. However, the mechanism by which imaging may predict clinical response is unknown. We hypothesize that decorin (DCN), a proteoglycan implicated in the modulation of the extracellular microenvironment and sequestration of pro-angiogenic signaling, may connect ADC phenotypes to survival benefit to anti-VEGF therapy. Patients undergoing resection for glioblastoma as well as patients included in The Cancer Genome Atlas (TCGA) and IVY Glioblastoma Atlas Project (IVY GAP) databases had pre-operative imaging analyzed to calculate pre-operative ADCL values, the average ADC in the lower distribution using a double Gaussian mixed model. ADCL values were correlated to available RNA expression from these databases as well as from RNA sequencing from patient derived mouse orthotopic xenograft samples. Targeted biopsies were selected based on ADC values and prospectively collected during resection. Surgical specimens were used to evaluate for DCN RNA and protein expression by ADC value. The IVY Glioblastoma Atlas Project Database was used to evaluate DCN localization and relationship with VEGF pathway via in situ hybridization maps and RNA sequencing data. In a cohort of 35 patients with pre-operative ADC imaging and surgical specimens, DCN RNA expression levels were significantly larger in high ADCL tumors (41.6 vs. 1.5; P = 0.0081). In a cohort of 17 patients with prospectively targeted biopsies there was a positive linear correlation between ADCL levels and DCN protein expression between tumors (Pearson R2 = 0.3977; P = 0.0066) and when evaluating different targets within the same tumor (Pearson R2 = 0.3068; P = 0.0139). In situ hybridization data localized DCN expression to areas of microvascular proliferation and immunohistochemical studies localized DCN protein expression to the tunica adventitia of blood vessels within the tumor. DCN expression positively correlated with VEGFR1 & 2 expression and localized to similar areas of tumor. Increased ADCL on diffusion MR imaging is associated with high DCN expression as well as increased survival with anti-VEGF therapy in glioblastoma. DCN may play an important role linking the imaging features on diffusion MR and anti-VEGF treatment efficacy. DCN may serve as a target for further investigation and modulation of anti-angiogenic therapy in GBM.

Hypoxia-Driven M2-Polarized Macrophages Facilitate Cancer Aggressiveness and Temozolomide Resistance in Glioblastoma

“…M2 macrophage VEGF-dependently contributes to GBM aggressiveness, and M2 macrophage is also involved in regulating chemoresistance in cancers. In addition, VEGF has been verified as a critical growth factor that increases drug resistance in multiple cancers [ 43 , 44 ], and we next explored whether M2 macrophage increased TMZ resistance in GBM through VEGF. To this end, the hypoxic M2-CM with or without VEGF deletion was cocultured with the GBM cells, and the cells were subsequently subjected to TMZ treatments.…”

Validation of diffusion MRI as a biomarker for efficacy using randomized phase III trial of bevacizumab with or without VB-111 in recurrent glioblastoma

“…The biological basis of these diffusion MR phenotypes has also been under recent investigation. 5 , 20 Specifically, we have noted that ADC L is significantly correlated with increased DNA, RNA, and protein expression of decorin, a small proteoglycan that both modulates angiogenesis and alters viscosity of the extracellular matrix, and this relationship is preserved in patient derived xenograft (PDX) models. 5 Data suggest decorin may be a multifaceted antiangiogenic agent, 21–24 as it interferes with thrombospondin-1, 25 suppress endogenous tumor cell production of VEGF 22 , 26 and VEGF-A, 27 the therapeutic targets of bevacizumab, and binds with a high affinity to VEGFR1/2.…”

“… 5 , 20 Specifically, we have noted that ADC L is significantly correlated with increased DNA, RNA, and protein expression of decorin, a small proteoglycan that both modulates angiogenesis and alters viscosity of the extracellular matrix, and this relationship is preserved in patient derived xenograft (PDX) models. 5 Data suggest decorin may be a multifaceted antiangiogenic agent, 21–24 as it interferes with thrombospondin-1, 25 suppress endogenous tumor cell production of VEGF 22 , 26 and VEGF-A, 27 the therapeutic targets of bevacizumab, and binds with a high affinity to VEGFR1/2. 28 Decorin also concurrently modulates the stiffness of the extracellular matrix by binding with various macromolecules and activating specific matrix metalloproteinases (MMPs), 22 which may explain the relationship between increased decorin expression and increased ADC L , a measure of water mobility (or viscosity) within the tumor tissue.…”

Neural Tissue Homeostasis and Repair Is Regulated via CS and DS Proteoglycan Motifs

“…MayDay, a ∼12 kDa N-terminal chemotactic factor, generated by macrophage-induced MMP-12 cleavage of decorin, recruits mesenchymal stem cells (MSCs) to damaged tissue regions in vitro and in vivo , promoting tissue repair ( Dempsey et al, 2020 ). In situ hybridization (ISH) has localized decorin in areas of microvascular proliferation within gliomas and may be a therapeutic target in anti-angiogenic therapy ( Patel et al, 2020 ) or approaches targeting TGF-β activity in tumors ( Birch et al, 2020 ). Decorin protects neuronal tissue from the damaging effects of anti-oxidants and neuroinflammation following TBI by inactivation and has anti-tumor activity by inhibiting glioma cell migration ( Yao et al, 2016 ).…”