Vasculature-specific MRI reveals differential anti-angiogenic effects of a biomimetic peptide in an orthotopic breast cancer model

Abstract

Translational vasculature-specific MRI biomarkers were used to measure the effects of a novel anti-angiogenic biomimetic peptide in an orthotopic MDA-MB-231 human triple-negative breast cancer model at an early growth stage. In vivo diffusion-weighted and steady-state susceptibility contrast (SSC) MRI was performed pre-treatment and 2 weeks post-treatment in tumor volume-matched treatment and control groups (n = 5/group). Treatment response was measured by changes in tumor volume; baseline transverse relaxation time (T2); apparent diffusion coefficient (ADC); and SSC-MRI metrics of blood volume, vessel size, and vessel density. These vasculature-specific SSC-MRI biomarkers were compared to the more conventional, non-vascular biomarkers (tumor growth, ADC, and T2) in terms of their sensitivity to anti-angiogenic treatment response. After 2 weeks of peptide treatment, tumor growth inhibition was evident but not yet significant, and the changes in ADC or T2 were not significantly different between treated and control groups. In contrast, the vascular MRI biomarkers revealed a significant anti-angiogenic response to the peptide after 2 weeks—blood volume and vessel size decreased, and vessel density increased in treated tumors; the opposite was seen in control tumors. The MRI results were validated with histology—H&E staining showed no difference in tumor viability between groups, while peptide-treated tumors exhibited decreased vascularity. These results indicate that translational SSC-MRI biomarkers are able to detect the differential effects of anti-angiogenic therapy on the tumor vasculature before significant tumor growth inhibition or changes in tumor viability.

In vitro modeling of solid tumor interactions with perfused blood vessels

“…However, a major limitation of current cancer research is that it is very difficult to investigate the biophysical mechanisms underlying multifactorial processes, such as those which occur at the tumor-vascular interface, using conventional murine models. Moreover, although animal models have been used in biomedical research to understand tumor-vessel interactions by us [3][4][5] and others 6,7 , it has been difficult to unravel the tumor-vessel interactions, mass transport mechanisms through the vessels, and drug responsiveness in these models due to the natural complexity of live animals. In particular, it has been very challenging to isolate and control the relative contributions of biological and biophysical factors to tumor vessel interactions.…”

Regulation of the tumor immune microenvironment and vascular normalization in TNBC murine models by a novel peptide

“…Previously, AXT201 or peptides from the same class were found to stabilize the vasculature and inhibit tumor vessel density. 36 , 37 , 40 – 42 Based on these observations, we hypothesized that AXT201 treatment would reduce the vessel density of 4T1 tumors while increasing the perivascular coverage of the remaining vasculature. To investigate vessel density, tumors were isolated from mice after two weeks and stained by IHC for blood vessels using the CD31 marker ( Figure 3(a) ).…”

“…25,27,[31][32][33] Our work focuses on AXT201, a novel 20-mer anti-angiogenic peptide that belongs to a class of peptides for which we have demonstrated potent influences on tumor vasculature through the inhibition of VEGF signaling. [34][35][36][37] Moreover, peptides from this class inhibit several other tumor-promoting signaling pathways including HGF, IGF1R and PDGF and have been previously demonstrated to inhibit the growth and metastasis of mouse tumor xenografts, including TNBC models, and an autochthonous model of hepatocellular carcinoma by blocking the growth of blood and lymphatic vessels. 36,[38][39][40][41][42] We have confirmed these properties for AXT201 in the present study.…”

Contrast enhanced magnetic resonance imaging highlights neurovasculature changes following experimental traumatic brain injury in the rat

“…Vessel density, vessel size, ΔR 2 (CBV in small blood vessels) and ΔR 2 * (CBV in a broad range of vessels) images were calculated using MATLAB (R2018b, The MathWorks, Natick, MA) with formulae as described in Lin et al 13 , 22 . These transverse relaxation rate changes were then used used to investigate vessel size (ΔR 2 * /ΔR 2 ) and density (ΔR 2 /(ΔR 2 * ) 2/3 ) 23 , 24 . Regions of interest (ROI) were delineated in the ipsilateral and contralateral cortex and hippocampus and the median value for each image metric determined.…”