Abstract
Objective:Super-resolution ultrasound localization microscopy (ULM) has unprecedented vascular resolution at clinically relevant imaging penetration depths. This technology can potentially screen for the transient microvascular changes that are thought to be critical to the synergistic effect(s) of combined chemotherapy-antiangiogenic agent regimens for cancer.Methods:In this paper, we apply this technology to a high-throughput colorectal carcinoma xenograft model treated with either the antiangiogenic agent sorafenib, FOLFOX-6 chemotherapy, a combination of the two treatments, or vehicle control.Results:Longitudinal ULM demonstrated morphological changes in the antiangiogenic treated cohorts, and evidence of vascular disruption caused by chemotherapy. Gold-standard histological measurements revealed reduced levels of hypoxia in the sorafenib treated cohort for both of the human cell lines tested (HCT-116 and HT-29). Therapy resistance was associated with an increase in tumor vascular fractal dimension as measured by a box-counting technique on ULM images.Conclusion:These results imply that the morphological changes evident on ULM signify a functional change in the tumor microvasculature, which may be indicative of chemo-sensitivity.Significance:ULM provides additional utility for tumor therapy response evaluation by offering a myriad of morphological and functional quantitative indices for gauging treatment effect(s).
Highlights
Metastatic colorectal cancer is the third leading cause of cancer-related mortality in the United States [1]
We present the results of ultrasound localization microscopy (ULM) imaging applied to a combined chemotherapy/AA regimen on a human CRC tumor xenograft model engrafted into the chorioallantoic membrane (CAM) of chicken embryos
In the Materials and Methods section, we introduce the chicken embryo tumor xenograft model of human CRC, describe the preparation and dosing of AA and chemotherapeutic agents, and describe the microbubble injection, ultrasound imaging acquisition, and super-resolution processing techniques used for ULM of this tumor model
Summary
Metastatic colorectal cancer (mCRC) is the third leading cause of cancer-related mortality in the United States [1]. Several phase II and III clinical trials have demonstrated an improvement in patient outcome and longer, progression-free survival for mCRC patients treated with a combination AA/chemotherapy regimen versus chemotherapy alone [3]–[6]. The addition of AA agents is thought to be essential to the efficacy of this combined therapy in part via the phenomenon of vascular normalization [7], where the selective remodeling of chaotic intratumoral vasculature can alleviate interstitial hypertension, improving blood flow and the delivery of chemotherapeutics inside the tumor [8] while simultaneously relieving a hypoxic tumor microenvironment known to promote chemotherapy resistance [9]. Combination therapies are associated with decreased treatment tolerability and increased side effects and adverse events, leading to a higher incidence of treatment discontinuation and dose reduction that may obscure a synergistic benefit [10]. Accurate predictors of biologic response to AA therapy are of vital clinical significance to mCRC as they permit the early identification of non-responders, sparing patients from unnecessary toxicity and medical expenses, and can potentially allow for individualized treatment strategies to optimize therapeutic stratification by serially identifying and measuring patient responses before a survival benefit is observed
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