Baseline and contrast-enhanced ultrasound features of hepatic epithelioid angiomyolipoma

BACKGROUND: Recurrence or metastasis after surgery had been reported in hepatic epithelioid angiomylipoma (epi-AML). Most hepatic epi-AMLs were misdiagnosed with hepatocellular carcinoma or other hepatic tumors before surgery. OBJECTIVE: To describe the baseline and contrast-enhanced ultrasound (CEUS) features of hepatic epi-AMLs and to explore the potential ultrasonic features for prognosis. METHODS: The retrospective study enrolled 67 patients (56 females, 11 males) with 67 pathologically confirmed hepatic epi-AML lesions. All the lesions were examined by baseline ultrasound and 42 lesions were examined using CEUS with SonoVue (Bracco, Milan, Italy) before surgery. RESULTS: Baseline ultrasound features of hepatic epi-AMLs included heterogeneous echo (86.6%), well-defined border (68.7%), hypoecho (64.2%), regular morphology (62.7%), peripheral-tumor arc-shaped or ring-like vessels (53.7%), and low value of resistive index (0.51±0.08). CEUS features of hepatic epi-AMLs included arterial phase hyper-enhancement with smooth and well-defined margin (100%), peripheral-tumor ring-like vessels (57.1%), and intra-tumor vessels (52.4%). Some CEUS features, including arterial phase heterogeneously tortuous filling, intra-tumor vessels and peripheral-tumor ring-like vessels were more commonly found in hepatic epi-AMLs of uncertain malignant potential/malignant than in benign hepatic epi-AMLs (p < 0.05). CONCLUSIONS: Baseline ultrasound and CEUS features may be useful in diagnosis of hepatic epi-AML, and some CEUS features may be indicative of its malignant potential.

Recent advances of nanotechnology-based tumor vessel-targeting strategies

Tumor vessels can provide oxygen and nutrition for solid tumor tissue, create abnormal tumor microenvironment (TME), and play a vital role in the development, immune escape, metastasis and drug resistance of tumor. Tumor vessel-targeting therapy has become an important and promising direction in anti-tumor therapy, with the development of five anti-tumor therapeutic strategies, including vascular disruption, anti-angiogenesis, vascular blockade, vascular normalization and breaking immunosuppressive TME. However, the insufficient drug accumulation and severe side effects of vessel-targeting drugs limit their development in clinical application. Nanotechnology offers an excellent platform with flexible modified surface that can precisely deliver diverse cargoes, optimize efficacy, reduce side effects, and realize the combined therapy. Various nanomedicines (NMs) have been developed to target abnormal tumor vessels and specific TME to achieve more efficient vessel-targeting therapy. The article reviews tumor vascular abnormalities and the resulting abnormal microenvironment, the application of NMs in the tumor vessel-targeting strategies, and how NMs can improve these strategies and achieve multi-strategies combination to maximize anti-tumor effects. Graphical Abstract

Nucleolin Targeting by N6L Inhibits Wnt/β-Catenin Pathway Activation in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and resistant cancer with no available effective therapy. We have previously demonstrated that nucleolin targeting by N6L impairs tumor growth and normalizes tumor vessels in PDAC mouse models. Here, we investigated new pathways that are regulated by nucleolin in PDAC. We found that N6L and nucleolin interact with β-catenin. We found that the Wnt/β-catenin pathway is activated in PDAC and is necessary for tumor-derived 3D growth. N6L and nucleolin loss of function induced by siRNA inhibited Wnt pathway activation by preventing β-catenin stabilization in PDAC cells. N6L also inhibited the growth and the activation of the Wnt/β-catenin pathway in vivo in mice and in 3D cultures derived from MIA PaCa2 tumors. On the other hand, nucleolin overexpression increased β-catenin stabilization. In conclusion, in this study, we identified β-catenin as a new nucleolin interactor and suggest that the Wnt/β-catenin pathway could be a new target of the nucleolin antagonist N6L in PDAC.

The Anti-Angiogenic Agent Lenvatinib Induces Tumor Vessel Normalization and Enhances Radiosensitivity in Hepatocellular Tumors

The evaluation of angiogenesis inhibitors requires the analysis of the precise structure and function of tumor vessels. The anti-angiogenic agents lenvatinib and sorafenib are multi-target tyrosine kinase inhibitors that have been approved for the treatment of hepatocellular carcinoma (HCC). However, the different effects on tumor vasculature between lenvatinib and sorafenib are not well understood. In this study we analyzed the effects of both drugs on vascular structure and function, including vascular normalization, and investigated whether the normalization had a positive effect on a combination therapy with the drugs and radiation using micro X-ray computed tomography with gold nanoparticles as a contrast agent, as well as immunohistochemical analysis and interstitial fluid pressure (IFP) measurement. In mice subcutaneously transplanted with mouse HCC cells, treatment with lenvatinib or sorafenib for 14 days inhibited tumor growth and reduced the tumor vessel volume density. However, analysis of integrated data on vessel density, rates of pericyte-covering and perfused vessels, tumor hypoxia, and IFP measured 4 days after drug treatment showed that treatment with 3 mg/kg of lenvatinib significantly reduced the microvessel density and normalized tumor vessels compared to treatment with 50 mg/kg of sorafenib. These results showed that lenvatinib induced vascular normalization and improved the intratumoral microenvironment in HCC tumors earlier and more effectively than sorafenib. Moreover, such changes increased the radiosensitivity of tumors and enhanced the effect of lenvatinib and radiation combination therapy, suggesting that this combination therapy is a powerful potential application against HCC.

Nanodrug Delivery Systems Modulate Tumor Vessels to Increase the Enhanced Permeability and Retention Effect

The use of nanomedicine for antitumor therapy has been extensively investigated for a long time. Enhanced permeability and retention (EPR) effect-mediated drug delivery is currently regarded as an effective way to bring drugs to tumors, especially macromolecular drugs and drug-loaded pharmaceutical nanocarriers. However, a disordered vessel network, and occluded or embolized tumor blood vessels seriously limit the EPR effect. To augment the EPR effect and improve curative effects, in this review, we focused on the perspective of tumor blood vessels, and analyzed the relationship among abnormal angiogenesis, abnormal vascular structure, irregular blood flow, extensive permeability of tumor vessels, and the EPR effect. In this commentary, nanoparticles including liposomes, micelles, and polymers extravasate through the tumor vasculature, which are based on modulating tumor vessels, to increase the EPR effect, thereby increasing their therapeutic effect.