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.
Highlights
We explore the association between DCN gene expression and diffusion MRI measurements in two large independent cohorts of GBM patients from The Cancer Genome Atlas (TCGA) and IVY Glioblastoma Atlas Project (IVY GAP)
Given the findings that (1) higher apparent diffusion coefficient (ADC) is associated with increased overall survival in patients treated with anti-VEGF therapy and (2) higher ADC is associated with higher levels of DCN expression we investigated whether DCN expression levels themselves were associated with differences in overall survival
Increased ADC on DWI of patients with glioblastoma is associated with increased RNA and protein expression of DCN, a proteoglycan that modulates the extracellular matrix (ECM) and has well established anti-angiogenic properties
Summary
Dept. of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, 924 Westwood Blvd, Suite 615, Los Angeles, CA 90024, USA. 2Dept. of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. 3Dept. of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. 4UCLA Neuro‐Oncology Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. 5Dept. of Pathology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. 6Dept. of Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. 7Dept. of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. 8Neuroscience Interdisciplinary Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. 9Dept. of Neurology, David Geffen School of Medicine, University of California Los. Pre-treatment diffusion-weighted magnetic resonance imaging (DWI or DW-MRI) estimates of the apparent diffusion coefficient (ADC) within the enhancing lesion have been shown to be predictive for survival benefit on anti-VEGF treatment in the recurrent setting in both single-center[16,17,18] and multicenter studies[19,20,21] suggesting a potential mechanistic link between water mobility within the tumor and anti-VEGF treatment efficacy Despite these observations, only a few, rather simplistic biologic associations based on changes in cell structure and density have been identified and associated with changes in measured ADC in the central nervous system. Since ADC is inversely correlated with fluid v iscosity[49,50] and tortuosity of the E CM51–55, it is conceivable that high DCN expression results in softer and less viscous tumors with decreased boundaries to the fluid within the extracellular space from DCM remodeling, resulting in a higher measured ADC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
