Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated death worldwide. Angiogenesis, the process of formation of new blood vessels, is required for cancer cells to obtain nutrients and oxygen. HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth, progression, invasion, and metastasis. Current anti-angiogenic therapies target mainly tyrosine kinases, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), and are considered effective strategies for HCC, particularly advanced HCC. However, because the survival benefits conferred by these anti-angiogenic therapies are modest, new anti-angiogenic targets must be identified. Several recent studies have determined the underlying molecular mechanisms, including pro-angiogenic factors secreted by HCC cells, the tumor microenvironment, and cancer stem cells. In this review, we summarize the roles of pro-angiogenic factors; the involvement of endothelial cells, hepatic stellate cells, tumor-associated macrophages, and tumor-associated neutrophils present in the tumor microenvironment; and the regulatory influence of cancer stem cells on angiogenesis in HCC. Furthermore, we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC. A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.

The formation of amyloid plaques usually occurs in the early-stage of Alzheimer’s disease (AD). Stimulated emission depletion (STED) imaging provided a powerful tool for visualizing amyloid structures on the nanometer scale. However, many commercial probes adopted in detecting amyloid fibrils are inapplicable to STED imaging, owing to their unmatched absorption and emission wavelengths, small Stokes’ shift, easy photo-bleaching, etc. Herein, we demonstrated a polarity-activated STED probe based on an intramolecular charge transfer donor (D)-π-acceptor (A) compound. The electron-rich carbazole group and the electron-poor pyridinium bromide group, linked by π-conjugated thiophen-bridge, ensure strong near infrared (NIR) emission with a Stokes’ shift larger than 200 nm. The tiny change in polarity before and after binding with amyloid plaques leads to a transition from weakly emission charge-transfer (CT) state (Φ < 0.04) to highly emissive locally-excited (LE) state (Φ = 0.57), giving rise to a fluorescence Turn-On probe. Together with large Stokes’ shift, good photostability and high depletion efficiency, the super-resolution imaging of the formation and morphology of amyloid fibrils in vitro based on this probe was realized with a lateral spatial resolution better than 33 nm at an extremely low depletion power. Moreover, the ex-vivo super-resolution imaging of (E)-1-butyl-4(2-(5-(9-ethyl-9H-carbazol-3-yl)thiophen-2-yl)vinyl) pyridinium bromide (CTPB) probe in Aβ plaques in the brain slices of a Tg mouse was demonstrated. This research provides a demonstration of the super resolution imaging probe of amyloid fibrils based on polarity-response mechanism, providing a new approach to the development of future amyloid probes.