Honsoul Kim

Inflammation-associated lymphangiogenesis: a double-edged sword?

Lymphangiogenesis and lymphatic vessel remodeling are complex biological processes frequently observed during inflammation. Accumulating evidence indicates that inflammation-associated lymphangiogenesis (IAL) is not merely an endpoint event, but actually a phenomenon actively involved in the pathophysiology of various inflammatory disorders. The VEGF-C/VEGFR-3 and VEGF-A/VEGF-R2 signaling pathways are two of the best-studied pathways in IAL. Methods targeting these molecules, such as prolymphangiogenic or antilymphatic treatments, were found to be beneficial in various preclinical and/or clinical studies. This Review focuses on the most recent achievements in the fields of lymphatic biology relevant to inflammatory conditions. Additionally, preclinical and clinical therapies that modulate IAL are summarized.

Stromal Vascular Fraction From Adipose Tissue Forms Profound Vascular Network Through the Dynamic Reassembly of Blood Endothelial Cells

Objective—Tremendous efforts have been made to establish effective therapeutic neovascularization using adipose tissue-derived stromal vascular fraction (SVF), but the efficiency is low, and underlying mechanisms and their interaction with the host in a new microenvironment are poorly understood. Methods and Results—Here we demonstrate that direct implantation of SVF derived from donor adipose tissue can create a profound vascular network through the disassembly and reassembly of blood endothelial cells at the site of implantation. This neovasculature successfully established connection with recipient blood vessels to form a functionally perfused circuit. Addition of vascular growth factors to the SVF implant improved the efficiency of functional neovasculature formation. In contrast, spheroid culture of SVF before implantation reduced the capacity of vasculature formation, possibly because of cellular alteration. Implanting SVF into the mouse ischemic hindlimb induced the robust formation of a local neovascular network and salvaged the limb. Moreover, the coimplantation of SVF prevented fat absorption in the subcutaneous adipose tissue graft model. Conclusion—Freshly isolated SVF can effectively induce new vessel formation through the dynamic reassembly of blood endothelial cells and could be applied to achieve therapeutic neovascularization for relieving ischemia and preventing fat absorption in an autologous manner.

Regulation and implications of inflammatory lymphangiogenesis

Lymphatic vessels (LVs) are highly dynamic structures that intimately interact with their surrounding microenvironment. They have a profound influence on the immune system and therefore can manipulate inflammatory processes. Inflammation is a major cause of adulthood lymphangiogenesis and LV remodeling. In turn, LVs can reciprocally manipulate inflammatory processes. For instance, LV growth and/or activation regulate antigen presentation and inflammatory cell recruitment to lymph nodes (LNs), and therefore critically affect adaptive immunity. The vascular endothelial growth factor (VEGF)-C-VEGF receptor-3 and VEGF-A-VEGF receptor-2 signaling pathways are particularly important in inflammatory lymphangiogenesis. LVs contribute to the pathophysiology of various inflammatory conditions. Knowledge of lymphatic biology can be applied to manipulate inflammatory disorders and divert immune responses. This review summarizes basic concepts of inflammation-relevant lymphatic biology, and describes recent progress and practical implications.

Can microvessel invasion of hepatocellular carcinoma be predicted by pre-operative MRI?

Microvessel invasion is a major prognostic factor in hepatocellular carcinoma (HCC) that influences the suitability of surgery, but rarely can be evaluated preoperatively. This study was performed to identify preoperative MRI findings that reflect histopathological microvessel invasion in hepatocellular carcinoma. Gadobenate dimeglumine-enhanced four-arterial phase dynamic study and hepatobiliary phase images of preoperative MRI of 70 HCC lesions were retrospectively reviewed. Tumor size (cm), peritumoral enhancement, tumor margins, and radiological capsule were analyzed as radiological parameters reflecting microvessel invasion and were compared with histopathological references. The chi-square test and the independent t-test were used for univariate analysis, and a logistic regression analysis was performed for multivariate analysis. In univariate analysis, tumor size (p = 0.030), peritumoral enhancement (p < 0.001), and tumor margins (p = 0.007) were associated with microvessel tumor invasion. However, in multivariate analysis irregular circumferential peritumoral enhancement only showed statistical significance (odds ratio 13.0), suggesting a high probability of microvessel invasion of HCC. Irregular circumferential peritumoral enhancement on contrast-enhanced multi-arterial phase dynamic MRI could be a preoperative surrogate marker for microvessel tumor invasion.

Rectal Cancer: Comparison of Accuracy of Local-Regional Staging with Two- and Three-dimensional Preoperative 3-T MR Imaging

PURPOSE To compare the local-regional staging accuracy of the conventional two-dimensional (2D) T2-weighted imaging protocol and of the three-dimensional (3D) T2-weighted imaging protocol for preoperative magnetic resonance (MR) imaging in rectal cancer patients. MATERIALS AND METHODS This retrospective study was approved by the institutional review board, and a waiver of informed consent was obtained. A review was conducted of 109 preoperative 3-T MR images obtained with 2D and 3D T2-weighted imaging protocols in rectal cancer patients. Two radiologists independently assessed the radiologic findings for T and N category lesions, conspicuity of tumor margin, and image quality of 2D and 3D data. Interactive multiplanar reconstruction was performed for 3D data analysis. The linear weighted kappa values for T2-weighted imaging staging results (2D and 3D data) and histopathologic staging results were calculated and compared. Wilcoxon signed rank test was performed to compare tumoral conspicuity and overall image quality. RESULTS T category lesion staging accuracy values for 2D and 3D data, respectively, were 66.0% and 67.0% for reviewer 1 (P = .465) and 63.3% and 56.9% for reviewer 2 (P = .402). N category lesion staging accuracy values for 2D and 3D T2-weighted images, respectively, were 64.2% and 57.8% for reviewer 1 (P = .427) and 47.7% and 62.4% for reviewer 2 (P = .666). Tumor conspicuity was better for 2D T2-weighted imaging, but no significant difference in image quality was observed. CONCLUSION Preoperative MR imaging in rectal cancer patients for staging with conventional 2D and multiplanar reconstruction 3D T2-weighted imaging protocols showed no significant differences in accuracy of T and N category staging and overall image quality, as determined by degree of artifact. However, the 3D T2-weighted imaging protocol had limitations in regard to lesion conspicuity.

Angiopoietin-1 promotes endothelial differentiation from embryonic stem cells and induced pluripotent stem cells.

Angiopoietin-1 (Ang1) plays a crucial role in vascular and hematopoietic development, mainly through its cognate receptor Tie2. However, little is known about the precise role of Ang1 in embryonic stem cell (ESC) differentiation. In the present study, we used COMP-Ang1 (a soluble and potent variant of Ang1) to explore the effect of Ang1 on endothelial and hematopoietic differentiation of mouse ESCs in an OP9 coculture system and found that Ang1 promoted endothelial cell (EC) differentiation from Flk-1(+) mesodermal precursors. This effect mainly occurred through Tie2 signaling and was altered in the presence of soluble Tie2-Fc. We accounted for this Ang1-induced expansion of ECs as enhanced proliferation and survival. Ang1 also had an effect on CD41(+) cells, transient precursors that can differentiate into both endothelial and hematopoietic lineages. Intriguingly, Ang1 induced the preferential differentiation of CD41(+) cells toward ECs instead of hematopoietic cells. This EC expansion promoted by Ang1 was also recapitulated in induced pluripotent stem cells (iPSCs) and human ESCs. We successfully achieved in vivo neovascularization in mice by transplantation of ECs obtained from Ang1-stimulated ESCs. We conclude that Ang1/Tie2 signaling has a pivotal role in ESC-EC differentiation and that this effect can be exploited to expand EC populations.

Reversing the intractable nature of pancreatic cancer by selectively targeting ALDH-high, therapy-resistant cancer cells.

Human pancreatic ductal adenocarcinoma (PDAC) is a cancer with a dismal prognosis. The efficacy of PDAC anticancer therapies is often short-lived; however, there is little information on how this disease entity so frequently gains resistance to treatment. We adopted the concept of cancer stem cells (CSCs) to explain the mechanism of resistance and evaluated the efficacy of a candidate anticancer drug to target these therapy-resistant CSCs. We identified a subpopulation of cells in PDAC with CSC features that were enriched for aldehyde dehydrogenase (ALDH), a marker expressed in certain stem/progenitor cells. These cells were also highly resistant to, and were further enriched by, treatment with gemcitabine. Similarly, surgical specimens from PDAC patients showed that those who had undergone preoperative chemo-radiation therapy more frequently displayed cancers with ALDH strongly positive subpopulations compared with untreated patients. Importantly, these ALDH-high cancer cells were sensitive to disulfiram, an ALDH inhibitor, when tested in vitro. Furthermore, in vivo xenograft studies showed that the effect of disulfiram was additive to that of low-dose gemcitabine when applied in combination. In conclusion, human PDAC-derived cells that express high levels of ALDH show CSC features and have a key role in the development of resistance to anticancer therapies. Disulfiram can be used to suppress this therapy-resistant subpopulation.

Fluoroscopically guided placement of self-expandable metallic stents and stent-grafts in the treatment of acute malignant colorectal obstruction.

PURPOSE To evaluate the technical feasibility and clinical effectiveness of fluoroscopically guided placement of self-expandable metallic stents and stent-grafts for acute malignant colorectal obstruction. MATERIALS AND METHODS Radiologic images and clinical reports of 42 patients (22 men, 20 women; age range, 28-93 years; median age, 65.5 years) who underwent fluoroscopically guided colorectal stent insertion without endoscopic assistance for acute malignant obstruction were reviewed retrospectively. Eighteen patients received bare stents as a bridge to surgery. Twenty-four patients received 27 insertions of either a bare stent (n = 15) or a stent-graft (n = 12) for palliation. The obstruction was located in the rectum (n = 8), sigmoid (n = 17), descending colon (n = 8), splenic flexure (n = 3), and transverse colon (n = 6). RESULTS Clinical success, defined as more than 50% dilatation of the stent with subsequent symptomatic improvement, was achieved in 41 of the 42 patients (98%). No major procedure-related complications occurred. Minor complications occurred in eight of the 45 procedures (18%). No perioperative mortalities occurred within 1 month after surgery. In the palliative group, the median stent patency was 62 days (range, 0-1,014 days). There was no statistically significant difference in stent patency between the bare stents (range, 0-855 days; median, 68 days) and stent-grafts (range, 1-1,014 days; median, 81 days). CONCLUSIONS Fluoroscopically guided placement of self-expandable metallic stents and stent-grafts for the relief of acute malignant colorectal obstruction was technically feasible without endoscopic assistance-even in lesions proximal to the splenic flexure and transverse colon-and clinically effective in both bridge to surgery and palliative management.

Preoperative Radiologic and Postoperative Pathologic Risk Factors for Early Intra-Hepatic Recurrence in Hepatocellular Carcinoma Patients Who Underwent Curative Resection

Purpose The risk of hepatocellular carcinoma (HCC) recurrence must be considered ahead of surgery. This study was undertaken to identify pre-operative risk factors for early intrahepatic recurrence of HCC after curative resection in a large-scale. Materials and Methods We retrospectively reviewed the preoperative three-phase multi-detector CT (MDCT) and laboratory data for 240 HCC patients who underwent curative resection; tumor size, number, gross shape, capsule integrity, distinctiveness of tumor margin, portal vein thrombosis (PVT), alpha-fetoprotein level (AFP), and protein induced by vitamin K absence-II (PIVKA-II) levels were assessed. Surgical pathology was reviewed; tumor differentiation, capsule, necrosis, and micro-vessel invasion were recorded. Results HCC recurred in 61 patients within six months (early recurrence group), but not in 179 patients (control group). In univariate analysis, large tumor size (p = 0.018), shape (p = 0.028), poor capsule integrity (p = 0.046), elevated AFP (p = 0.015), and PIVKA-II (p = 0.008) were significant preoperative risk factors. Among the pathologic features, PVT (p = 0.023), Glissons capsule penetration (p = 0.033), microvascular invasion (p < 0.001), and poor differentiation (p = 0.001) showed statistical significance. In multivariate analysis, only the histopathologic parameters of microvascular invasion and poor differentiation achieved statistical significance. Conclusion Preoperative CT and laboratory parameters showed limited value, while the presence of microscopic vascular tumor invasion and poorly differentiated HCC correlated with higher risk of early recurrence after curative resection.

Dynamic enhancement pattern of HCC smaller than 3 cm in diameter on gadoxetic acid‐enhanced MRI: comparison with multiphasic MDCT

The dynamic enhancement pattern of HCCs smaller than 3 cm in diameter on gadoxetic acid‐enhanced magnetic resonance imaging (MRI) have not been extensively investigated. We aimed to evaluate the dynamic enhancement patterns of small HCCs (≤3 cm) on gadoxetic acid‐enhanced magnetic resonance imaging (MRI) and compare enhancement patterns with multiphasic multidetector computed tomography (MDCT) based on tumour cellular differentiation and size.