Tumor Microvascular Permeability Research Articles

Dynamic Contrast Enhanced MRI Mapping of Vascular Permeability for Evaluation of Breast Cancer Neoadjuvant Chemotherapy Response Using Image-to-Image Conditional Generative Adversarial Networks.

Dynamic contrast enhanced (DCE) MRI is a non-invasive imaging technique that has become a quantitative standard for assessing tumor microvascular permeability. Through the application of a pharmacokinetic (PK) model to a series of T1-weighed MR images acquired after an injection of a contrast agent, several vascular permeability parameters can be quantitatively estimated. These parameters, including Ktrans, a measure of capillary permeability, have been widely implemented for assessing tumor vascular function as well as tumor therapeutic response. However, conventional PK modeling for translation of DCE MRI to PK vascular permeability parameter maps is complex and time-consuming for dynamic scans with thousands of pixels per image. In recent years, image-to-image conditional generative adversarial network (cGAN) is emerging as a robust approach in computer vision for complex cross-domain translation tasks. Through a sophisticated adversarial training process between two neural networks, image-to-image cGANs learn to effectively translate images from one domain to another, producing images that are indistinguishable from those in the target domain. In the present study, we have developed a novel image-to-image cGAN approach for mapping DCE MRI data to PK vascular permeability parameter maps. The DCE-to-PK cGAN not only generates high-quality parameter maps that closely resemble the ground truth, but also significantly reduces computation time over 1000-fold. The utility of the cGAN approach to map vascular permeability is validated using open-source breast cancer patient DCE MRI data provided by The Cancer Imaging Archive (TCIA). This data collection includes images and pathological analyses of breast cancer patients acquired before and after the first cycle of neoadjuvant chemotherapy (NACT). Importantly, in good agreement with previous studies leveraging this dataset, the percentage change of vascular permeability Ktrans derived from the DCE-to-PK cGAN enables early prediction of responders to NACT.

Nonoxidized MXene Quantum Dots Prepared by Microexplosion Method for Cancer Catalytic Therapy

AbstractNanocatalysts based on Fenton or Fenton‐like reactions for amplification of intracellular oxidative stress has become a frontier research area of tumor precise therapy. However, the major translational challenges are low catalytic efficiency, poor biocompatibility, and even potential toxicities. Here, a Ti‐based material with excellent biocompatibility is proposed for cancer treatment. The nonoxidized MXene‐Ti3C2Tx quantum dots (NMQDs‐Ti3C2Tx) are successfully prepared by a self‐designed microexplosion method. Surprisingly, it has an apparent inhibitory and killing effect on cancer cells, and excellent biocompatibility with normal cells. Moreover, the suppression rate of NMQDs‐Ti3C2Tx on xenograft tumor models can reach 91.9% without damaging normal tissues. Mechanistically, the Ti3+ of NMQDs‐Ti3C2Tx can react with H2O2 in the tumor microenvironment and high‐efficiently produce excessive toxic hydroxyl radicals to increase tumor microvascular permeability to synergistically kill cancer cells. This work should pave the way for tumor catalytic therapy applications of Ti‐based material as a promising and safer route.

Numerical modeling of high-intensity focused ultrasound-mediated intraperitoneal delivery of thermosensitive liposomal doxorubicin for cancer chemotherapy

Although intraperitoneal chemotherapy (IPC) has been suggested as a promising method for the management of peritoneal dissemination (PD) of ovarian or colorectal cancers, the actual clinical use of this method has been restricted due to such problems as poor drug penetration into the tumor and high side effects. It is, therefore, necessary to develop new strategies to improve the efficacy of this approach. In the present work, a new strategy is proposed based on intraperitoneal (IP) injection of thermosensitive liposomal doxorubicin (TSL-Dox) with triggered release by mild hyperthermia induced by high intensity focused ultrasound (HIFU). A computational model is developed to evaluate the proposed drug delivery system. Results show an order of magnitude increase in drug penetration depth into the tumor compared to the conventional IP delivery. Furthermore, the effects of thermal conditions applied to the tumor, TSL size, tumor vessel permeability, and tumor size are investigated. Results indicate an improved efficiency of the drug delivery by expanding the heated region, yet, it increases the risk of unintentional TSL drug load release in the peritoneal cavity. Results also indicate that smaller TSLs have better treatment outcome. However, there is a significant reduction in treatment efficacy for TSLs with sizes smaller than the vessel wall pore size. Thus, tuning the size of TSL should be based on the tumor microvascular permeability. The simulation results suggest that the TSL-Dox delivery system in smaller tumors is far advantageous than larger ones. Results of our model can be used as guidelines for future preclinical studies.

VEGFR-1 targeted DNAzyme via transcatheter arterial delivery influences tumor vasculature assessed through dynamic contrast-enhanced magnetic resonance imaging.

DNAzymes are synthetic single-stranded DNA oligonucleotides that bind and cleave target mRNA in a sequence-specific manner. Although the therapeutic potential has been demonstrated in both preclinical and clinical settings, the efficient delivery and invivo assessment of the DNAzyme efficacy remain the vital unsolved issue. In the present study, we examined the feasibility of using transcatheter arterial chemoembolization (TACE) strategy to deliver a DNAzyme targeting VEGFR-1 and monitoring its effect on tumor angiogenesis invivo via dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). In a rabbit liver cancer model (VX2), we showed that the DNAzyme was efficiently delivered into the tumor by TACE. DCE-MRI revealed that the VEGFR-1-targeted DNAzyme affected the tumor vasculature through inhibiting VEGFR-1 expression invivo, which was reflected by a reduction of Ktrans and Kep, the parameters of tumor microvascular permeability. Our findings offer an efficient strategy of delivery and assessment of the VEGFR-1 DNAzyme, and further demonstrate the feasibility of DNAzyme for cancer therapy.

EBV-LMP1 targeted DNAzyme enhances radiosensitivity by inhibiting tumor angiogenesis via the JNKs/HIF-1 pathway in nasopharyngeal carcinoma.

LMP1, which is encoded by the Epstein-Barr virus, is proposed to be one of the major oncogenic factors involved in nasopharyngeal carcinoma (NPC). Previous studies demonstrated that down-regulation of LMP1 by LMP1-targeted DNAzyme (DZ1) increases the radiosensitivity of NPC. However, the mechanism by which DZ1 contributes to this radiosensitivity remains unclear. In this study, we determined whether a DZ1 blockade of LMP1 expression has an overall positive effect on the radiotherapy of NPCs by repressing HIF-1/VEGF activity and to investigate the mechanisms underlying LMP1-induced HIF-1 activation in NPC cells. The results showed that DZ1 inhibited the microtubule-forming ability of HUVECs co-cultured with NPC cells, which occurs with the down-regulation of VEGF expression and secretion. Moreover, LMP1 increases phosphorylated JNKs/c-Jun signaling, which is involved in the regulation of HIF-1/VEGF activity. After silencing LMP1 and decreasing phosphorylation of JNKs, NPC cells exhibited an enhanced radiosensitivity. Furthermore, in vivo experiments revealed a significant inhibition of tumor growth and a marked reduction of the Ktrans parameter, which reflects the condition of tumor micro-vascular permeability. Taken together, our data suggested that VEGF expression is increased by LMP1 through the JNKs/c-Jun signaling pathway and indicated that DZ1 enhances the radiosensitivity of NPC cells by inhibiting HIF-1/VEGF activity.

Therapeutic Evaluation of Epstein-Barr Virus-encoded Latent Membrane Protein-1 Targeted DNAzyme for Treating of Nasopharyngeal Carcinomas

The ability of the 10–23 DNAzyme to specifically cleave RNA with high efficiency has fuelled expectation that this agent may have useful applications for targeted therapy. Here, we, for the first time, investigated the antitumor and radiosensitizing effects of a DNAzyme (DZ1) targeted to the Epstein-Barr virus (EBV)-LMP1 mRNA of nasopharyngeal carcinoma (NPC) in patients. Preclinical studies indicated that the DNAzyme was safe and well tolerated. A randomized and double-blind clinical study was conducted in 40 NPC patients who received DZ1 or saline intratumorally, in conjunction with radiation therapy. Tumor regression, patient survival, EBV DNA copy number and tumor microvascular permeability were assessed in a 3-month follow-up. The mean tumor regression rate at week 12 was significantly higher in DZ1 treated group than in the saline control group. Molecular imaging analysis showed that DZ1 impacted on tumor microvascular permeability as evidenced by a faster decline of the Ktrans in DZ1-treated patients. The percentage of the samples with undetectable level of EBV DNA copy in the DZ1 group was significantly higher than that in the control group. No adverse events that could be attributed to the DZ1 injection were observed in patients.

Review of treatment assessment using DCE-MRI in breast cancer radiation therapy

As a noninvasive functional imaging technique, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is being used in oncology to measure properties of tumor microvascular structure and permeability. Studies have shown that parameters derived from certain pharmacokinetic models can be used as imaging biomarkers for tumor treatment response. The use of DCE-MRI for quantitative and objective assessment of radiation therapy has been explored in a variety of methods and tumor types. However, due to the complexity in imaging technology and divergent outcomes from different pharmacokinetic approaches, the method of using DCE-MRI in treatment assessment has yet to be standardized, especially for breast cancer. This article reviews the basic principles of breast DCE-MRI and recent studies using DCE-MRI in treatment assessment. Technical and clinical considerations are emphasized with specific attention to assessment of radiation treatment response.

Antiangiogenic and Antitumoral Effects Mediated by a Vascular Endothelial Growth Factor Receptor 1 (VEGFR-1)-Targeted DNAzyme

Antiangiogenesis is a promising antitumor strategy that inhibits tumor vascular formation to suppress tumor growth. DNAzymes are synthetic single-strand deoxyribonucleic acid (DNA) molecules that can cleave ribonucleic acids (RNAs). Here, we conducted a comprehensive in vitro selection of active DNAzymes for their activity to cleave the vascular endothelial growth factor receptor (VEGFR-1) mRNA and screened for their biological activity in a matrigel tube-formation assay. Among the selected DNAzymes, DT18 was defined as a lead molecule that was further investigated in several model systems. In a rat corneal vascularization model, DT18 demonstrated significant and specific antiangiogenic activity, as evidenced by the reduced area and vessel number in VEGF-induced corneal angiogenesis. In a mouse melanoma model, DT18 was shown to inhibit B16 tumor growth, whereas it did not affect B16 cell proliferation. We further assessed the DT18 effect in mice with established human nasopharyngeal carcinoma (NPC). A significant inhibition of tumor growth was observed, which accompanied downregulation of VEGFR-1 expression in NPC tumor tissues. To evaluate DT18 effect on vasculature, we performed dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) on the human NPC xenograft mice treated with DT18 and showed a reduction of the parameter of K(trans) (volume constant for transfer of contrast agent), which reflects the condition of tumor microvascular permeability. When examining the safety and tolerability of DT18, intravenous administration of Dz18 to healthy mice caused no substantial toxicities, as shown by parameters such as body weight, liver/kidney function, and histological and biochemical analyses. Taken together, our data suggest that the anti-VEGFR-1 DNAzyme may be used as a therapeutic agent for the treatment of cancer, such as NPC.

The effects of ulinastatin on systemic inflammation, visceral vasopermeability and tissue water content in rats with scald injury

The aim of this study was to examine whether administration of ulinastatin inhibits pro-inflammatory mediators and ameliorate visceral vasopermeability both in a rat model of major burn, and also in rat cultured endothelial cells stimulated with permeability-evoking mediators. Plasma levels of tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), myeloperoxidase (MPO), microvascular permeability, and water content of organ tissues were evaluated in a rodent model of a 55% TBSA full-thickness scald injury. Microvascular permeability was also evaluated with a cultured pulmonary microvascular endothelial cells (PMECs) monolayer after stimulation with trypsin, bradykinin, histamine, prostaglandin E2 and burn serum. We found that the plasma levels of TNF-α, CRP, MPO, vascular permeability and water content of heart, lung, kidney, and small intestine tissues were significantly increased in animals after scald injury, and administration of ulinastatin lowered the levels TNF-α, CRP, MPO, vascular permeability and water content of those organ tissues. In vitro, ulinastatin lowered the levels of TNF-α, interleukin-6 (IL-6) and attenuated permeability in PMEC monolayers after being stimulated with burn serum or trypsin, but not by bradykinin, histamine or prostaglandin E2. These results indicate that ulinastatin attenuates the systemic inflammatory response and visceral vasopermeability both in vivo and vitro, and may serve as a therapeutic agent for prevention of systemic inflammatory response and leakage of fluid into tissue after major burn.

Retrospective Study of False-positive Breast Magnetic Resonance Images and Pathological Results in Taiwan

Background Breast magnetic resonance imaging (MRI) is extremely sensitive for detecting lesions, but certain characteristics of malignancies, such as the washout pattern of kinetic curves, are not specific. Correlations of false-positive MRI and specific pathological results are worthy of study. Methods From March 2008 to September 2011, 217 cases received biopsy after dedicated breast MRI in our department. Biopsies were recommended for suspected malignancies based on the overall analysis of early subtracted phase images, postenhanced curve patterns, color mapping, and tumor morphology. Results Twenty-nine percent of cases were false positive for malignancy, according to MRI. These lesions included radial scar, apocrine metaplasia, atypical ductal hyperplasia, sclerosing adenosis, intraductal papilloma, fibrocystic change, and mastitis. Conclusion The ability of tumor cells to induce vascularization occurs early in the cell transformation process; therefore, premalignant breast lesions may also induce vascularization to facilitate malignant transformation. As a noninvasive method, contrast-enhanced MRI has a potential role in estimating the degree of angiogenesis and tumor microvascular permeability of breast neoplasms.

Altered Angiogenesis in Caveolin-1 Gene–Deficient Mice Is Restored by Ablation of Endothelial Nitric Oxide Synthase

Caveolin-1 is an essential structural protein of caveolae, specialized plasma membrane organelles highly abundant in endothelial cells, where they regulate multiple functions including angiogenesis. Caveolin-1 exerts a tonic inhibition of endothelial nitric oxide synthase (eNOS) activity. Accordingly, caveolin-1 gene-disrupted mice have enhanced eNOS activity as well as increased systemic nitric oxide (NO) levels. We hypothesized that excess eNOS activity, secondary to caveolin deficiency, would mediate the decreased angiogenesis observed in caveolin-1 gene-disrupted mice. We tested tumor angiogenesis in mice lacking either one or both proteins, using in vitro, ex vivo, and in vivo assays. We show that endothelial cell migration, tube formation, cell sprouting from aortic rings, tumor growth, and angiogenesis are all significantly impaired in both caveolin-1-null and eNOS-null mice. We further show that these parameters were either partially or fully restored in double knockout mice that lack both caveolin-1 and eNOS. Furthermore, the effects of genetic ablation of eNOS are mimicked by the administration of the NOS inhibitor N-nitro-L-arginine methyl ester hydrochloride (L-NAME), including the reversal of the caveolin-1-null mouse angiogenic phenotype. This study is the first to demonstrate the detrimental effects of unregulated eNOS activity on angiogenesis, and shows that impaired tumor angiogenesis in caveolin-1-null mice is, at least in part, the result of enhanced eNOS activity.

Permeability to macromolecular contrast media quantified by dynamic MRI correlates with tumor tissue assays of vascular endothelial growth factor (VEGF)

To correlate dynamic MRI assays of macromolecular endothelial permeability with microscopic area-density measurements of vascular endothelial growth factor (VEGF) in tumors. This study compared tumor xenografts from two different human cancer cell lines, MDA-MB-231 tumors (n=5), and MDA-MB-435 (n=8), reported to express respectively higher and lower levels of VEGF. Dynamic MRI was enhanced by a prototype macromolecular contrast medium (MMCM), albumin-(Gd-DTPA)35. Quantitative estimates of tumor microvascular permeability (K(PS); μl/min × 100 cm(3)), obtained using a two-compartment kinetic model, were correlated with immunohistochemical measurements of VEGF in each tumor. Mean K(PS) was 2.4 times greater in MDA-MB-231 tumors (K(PS)=58 ± 30.9 μl/min × 100 cm(3)) than in MDA-MB-435 tumors (K(PS)=24 ± 8.4 μl/min × 100 cm(3)) (p<0.05). Correspondingly, the area-density of VEGF in MDA-MB-231 tumors was 2.6 times greater (27.3 ± 2.2%, p<0.05) than in MDA-MB-435 cancers (10.5 ± 0.5%, p<0.05). Considering all tumors without regard to cell type, a significant positive correlation (r=0.67, p<0.05) was observed between MRI-estimated endothelial permeability and VEGF immunoreactivity. Correlation of MRI assays of endothelial permeability to a MMCM and VEGF immunoreactivity of tumors support the hypothesis that VEGF is a major contributor to increased macromolecular permeability in cancers. When applied clinically, the MMCM-enhanced MRI approach could help to optimize the appropriate application of VEGF-inhibiting therapy on an individual patient basis.

Monitoring Response to Antiangiogenic Therapy in Non–Small Cell Lung Cancer Using Imaging Markers Derived from PET and Dynamic Contrast-Enhanced MRI

With antiangiogenic agents, tumor shrinkage may be absent, despite survival benefit. The present study assessed the predictive value of molecular imaging for the identification of survival benefit during antiangiogenic treatment with bevacizumab and erlotinib in patients with advanced non-small cell lung cancer. Patients were evaluated using an imaging protocol including CT, 18F-FDG PET, H2(15)O PET, and dynamic contrast-enhanced MRI to derive measurements on tumor size, glucose metabolism, perfusion, and microvascular permeability. The percentage change in imaging parameters after 3 wk of treatment as compared with baseline was calculated and correlated with progression-free survival (PFS). Forty-four patients were included, and 40 underwent CT and 18F-FDG PET at both time points. Complete datasets, containing all imaging modalities, were available for 14 patients. Bevacizumab and erlotinib treatment resulted in decreased metabolism, perfusion, and tumor size. A decrease in standardized uptake value or tumor perfusion of more than 20% at week 3 was associated with longer PFS (9.7 vs. 2.8 mo, P=0.01, and 12.5 vs. 2.9 mo, P=0.009, respectively). Whole-tumor Ktrans (the endothelial transfer constant) was not associated with PFS, but patients with an increase of more than 15% in the SD of tumor Ktrans values-that is, an increase in regions with low or high Ktrans values-after 3 wk had shorter PFS (2.3 vs. 7.0 mo, P=0.008). A partial response, according to the response evaluation criteria in solid tumors (RECIST), at week 3 was also associated with prolonged PFS (4.6 vs. 2.9 mo, P=0.017). However, 40% of patients with a partial response as their best RECIST response still had stable disease at week 3. In these cases tumor perfusion was already decreased and Ktrans heterogeneity showed no increase, indicating that the latter parameters seem to be more discriminative than RECIST at the 3-wk time point. PET and dynamic contrast-enhanced MRI were able to identify patients who benefit from bevacizumab and erlotinib treatment. Molecular imaging seems to allow earlier response evaluation than CT.

Characterization of tumor microvascular structure and permeability: comparison between magnetic resonance imaging and intravital confocal imaging

Solid tumors are characterized by abnormal blood vessel organization, structure, and function. These abnormalities give rise to enhanced vascular permeability and may predict therapeutic responses. The permeability and architecture of the microvasculature in human osteosarcoma tumors growing in dorsal window chambers in athymic mice were measured by confocal laser scanning microscopy (CLSM) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Dextran (40 kDa) and Gadomer were used as molecular tracers for CLSM and DCE-MRI, respectively. A significant correlation was found between permeability indicators. The extravasation rate K(i) as measured by CLSM correlated positively with DCE-MRI parameters, such as the volume transfer constant K(trans) and the initial slope of the contrast agent concentration-time curve. This demonstrates that these two techniques give complementary information. Extravasation was further related to microvascular structure and was found to correlate with the fractal dimension and vascular density. The structural parameter values that were obtained from CLSM images were higher for abnormal tumor vasculature than for normal vessels.

CXCR4 and CXCR7 regulate angiogenesis and CT26.WT tumor growth independent from SDF‐1

Recent studies have shown that the chemokine stromal cell-derived factor (SDF)-1 and its receptor CXCR4 are involved in the metastatic process of colorectal cancer. The impact of SDF-1 on the stimulated metastatic growth during hepatectomy-associated liver regeneration is unknown. With the use of a heterotopic murine colon cancer model, we analyzed whether blockade of SDF-1 inhibits angiogenesis and extrahepatic growth of colorectal cancer after liver resection. Functional neutralization of SDF-1 by 1 mg/kg body weight anti-SDF-1 antibody only slightly delayed the initial tumor cell engraftment but also did not reduce the size of established extrahepatic tumors compared with controls. Tumor cell apoptosis was increased by anti-SDF-1 treatment only during the early 5-9-day period of tumor cell engraftment, but was found significantly decreased during the late phase of tumor growth. The initial delay of tumor cell engraftment was associated with an increase of tumor capillary density and microvascular permeability. This was associated with an increased vascular endothelial growth factor (VEGF) expression and an enhanced tumor cell invasion of the neighboring tissue. In contrast to the neutralization of SDF-1, blockade of the SDF-1 receptors CXCR4 and CXCR7 significantly reduced tumor capillary density and tumor growth. Thus, our study indicates that neutralization of SDF-1 after hepatectomy is not capable of inhibiting angiogenesis and growth of extrahepatic colorectal tumors, because it is counteracted by the compensatory actions through an alternative VEGF-dependent pathway.

Simultaneous imaging of tumor oxygenation and microvascular permeability using Overhauser enhanced MRI

Architectural and functional abnormalities of blood vessels are a common feature in tumors. A consequence of increased vascular permeability and concomitant aberrant blood flow is poor delivery of oxygen and drugs, which is associated with treatment resistance. In the present study, we describe a strategy to simultaneously visualize tissue oxygen concentration and microvascular permeability by using a hyperpolarized (1)H-MRI, known as Overhauser enhanced MRI (OMRI), and an oxygen-sensitive contrast agent OX63. Substantial MRI signal enhancement was induced by dynamic nuclear polarization (DNP). The DNP achieved up to a 7,000% increase in MRI signal at an OX63 concentration of 1.5 mM compared with that under thermal equilibrium state. The extent of hyperpolarization is influenced mainly by the local concentration of OX63 and inversely by the tissue oxygen level. By collecting dynamic OMRI images at different hyperpolarization levels, local oxygen concentration and microvascular permeability of OX63 can be simultaneously determined. Application of this modality to murine tumors revealed that tumor regions with high vascular permeability were spatio-temporally coincident with hypoxia. Quantitative analysis of image data from individual animals showed an inverse correlation between tumor vascular leakage and median oxygen concentration. Immunohistochemical analyses of tumor tissues obtained from the same animals after OMRI experiments demonstrated that lack of integrity in tumor blood vessels was associated with increased tumor microvascular permeability. This dual imaging technique may be useful for the longitudinal assessment of changes in tumor vascular function and oxygenation in response to chemotherapy, radiotherapy, or antiangiogenic treatment.

Regulation of Cripto-1 Signaling and Biological Activity by Caveolin-1 in Mammary Epithelial Cells

Human and mouse Cripto-1 (CR-1/Cr-1) proteins play an important role in mammary gland development and tumorigenesis. In this study, we examined the relationship between Cripto-1 and caveolin-1 (Cav-1), a membrane protein that acts as a tumor suppressor in the mammary gland. Cripto-1 was found to interact with Cav-1 in COS7 cells and mammary epithelial cells. Using EpH4 mouse mammary epithelial cells expressing Cr-1 (EpH4 Cr-1) or Cr-1 and Cav-1 (EpH4 Cr-1/Cav-1), we demonstrate that Cav-1 expression markedly reduced the ability of Cr-1 to enhance migration, invasion, and formation of branching structures in EpH4 Cr-1/Cav-1 cells as compared to EpH4 Cr-1 cells. Furthermore, coexpression of Cav-1 together with Cr-1 in EpH4 Cr-1/Cav-1 cells inhibited Cr-1-mediated activation of c-src and mitogen-activated protein kinase signaling pathways. Conversely, primary mammary epithelial cells isolated from Cav-1 null(-/-)/mouse mammary tumor virus-CR-1 transgenic animals showed enhanced motility and activation of mitogen-activated protein kinase and c-src as compared to Cav-1(+/-)/CR-1 mammary cells. Finally, mammary tumors derived from mouse mammary tumor virus-CR-1 mice showed a dramatic reduction of Cav-1 expression as compared to mammary tissue from normal FVB/N mice, suggesting that in vivo Cav-1 is down-regulated during the process of CR-1-mediated mammary tumorigenesis.

Tumor microvascular permeability is a key determinant for antivascular effects of doxorubicin encapsulated in a temperature sensitive liposome

Previous data have demonstrated that doxorubicin (DOX) released from a lysolecithin-containing thermosensitive liposome (LTSL) can shut down blood flow in a human tumor xenograft (FaDu) in mice when the treatment is combined with hyperthermia (HT), suggesting that LTSL-DOX is a potential antivascular agent. To further understand mechanisms of the treatment, we investigated effects of LTSL-DOX (5 mg/kg body weight) plus HT (42°C, 1 h) on microcirculation in another tumor (a murine mammary carcinoma, 4T07) implanted in mouse dorsal skin-fold chambers and dose responses of tumor (FaDu and 4T07) and endothelial cells to LTSL-DOX or free DOX with or without HT. We observed that LTSL-DOX-HT could significantly reduce blood flow and microvascular density in 4T07 tumors. The antivascular efficacy of LTSL-DOX-HT could be enhanced through increasing tumor microvascular permeability of liposomes by using platelet activating factor (PAF). We also observed that the dose responses of FaDu and 4T07 to DOX in vitro were similar to each other and could be enhanced by HT. Taken together, these data suggested that tumor microvascular permeability was more critical than the sensitivity of tumor cells to DOX in determining the antivascular efficacy of LTSL-DOX-HT treatment.

MRI Assessment of Peritumoral Brain Edema in Human Astrocytomas: Correlation with Angiogenesis Biomarkers

Mass effect due to peritumoral brain edema (PTBE) is one of the most common imaging characteristics encountered in glial tumors. The severity and variety of the PTBE may increase the difficulties of cancer treatment. However, its pathogenesis is not well documented. Recently, more attention has been paid to vascular endothelial growth factor (VEGF), the polypeptides mediating tumor angiogenesis and microvascular permeability. The purpose of this study was to investigate PTBE index in astrocytomas obtained from MRI and its correlation with angiogenesis biomarkers, VEGF and microvessel density. Our results demonstrated that PTBE in human astrocytomas correlated with both VEGF expression and vessel density. The relationship of PTBE with angiogenesis biomarkers allows a better understanding its molecular mechanisms, and may have implications for clinical management of brain edema associated with human astrocytomas.

Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice

Tumor vasculature is hyperpermeable to macromolecules compared to normal vasculature; however, the relationship between tumor hyperpermeability and tumor progression is poorly understood. Here we show that a cell-permeable peptide derived from caveolin-1, termed cavtratin, reduces microvascular hyperpermeability and delays tumor progression in mice. These antipermeability and antitumor actions of cavtratin occur in the absence of direct cytostatic or antiangiogenic effects. Cavtratin blocks microvascular permeability by inhibiting endothelial nitric oxide synthase (eNOS), as the antipermeability and antitumor actions of cavtratin are markedly diminished in eNOS knockout mice. Our results support the concepts that hyperpermeability of tumor blood vessels contributes to tumor progression and that blockade of eNOS may be exploited as a novel target for antitumor therapy.