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Tumor Vessels (tumor + vessel)
Selected AbstractsPharmaceutical and Biomedical Differences between Micellar Doxorubicin (NK911) and Liposomal Doxorubicin (Doxil)CANCER SCIENCE, Issue 10 2002Yoshihisa Tsukioka The stability and biological behavior of an in vitro system of doxorubicin (DXR) entrapped in NK911, polymer micelles, was examined and compared with those of DXR entrapped in Doxil, polyethylene-glycol-conjugated liposomes. The fluorescence of DXR inside micelles or liposomes in an aqueous solution is known to be strongly quenched by the outer shells of the micellar or liposomal formation. Thus, by measuring the fluorescence intensity of DXR released from NK911 or Doxil, we could determine the stability of the micellar or liposomal DXR formation. Furthermore, NK911 was found to be less stable than Doxil in saline solution. In drug distribution experiments using an in vitro solid tumor model, when spheroids formed from two human colonic cancer lines, HT-29 and WiDr, and a human stomach cancer line, MKN28, were exposed to NK911, DXR was distributed throughout the spheroids, including their center. On the other hand, when the spheroids were exposed to Doxil, DXR was distributed only to the surface of the spheroids. It has been suggested that Doxil can deliver DXR to a solid tumor more efficiently than NK911 via the EPR (enhanced permeability and retention) effect, because Doxil may be more stable in plasma than NK911. On the other hand, DXR packed in NK911 may be distributed by diffusion to cancer cells distant from the tumor vessel, because NK911 can leak out of the tumor vessel and may be able to release free DXR more easily than Doxil. It has been suggested that drug carrier systems such as liposomes and micelles should be selected appropriately bearing in mind the characteristics of the tumor vasculature and the tumor interstitium. [source] Therapy-induced antitumor vaccination by targeting tumor necrosis factor-, to tumor vessels in combination with melphalanEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2007Lorenzo Mortara Abstract Treatment of tumor-bearing mice with mouse (m)TNF-,, targeted to tumor vasculature by the anti-ED-B fibronectin domain antibody L19(scFv) and combined with melphalan, induces a therapeutic immune response. Upon treatment, a highly efficient priming of CD4+ T cells and consequent activation and maturation of CD8+ CTL effectors is generated, as demonstrated by in vivo depletion and adoptive cell transfer experiments. Immunohistochemical analysis of the tumor tissue demonstrated massive infiltration of CD4+ and CD8+ T cells 6,days after treatment and much earlier in the anamnestic response to tumor challenge in cured mice. In fact, the curative treatment with L19mTNF-, and melphalan resulted in long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2-type response and significant in vitro tumor-specific cytolytic activity. Finally, the combined treatment reduced the percentage and absolute number of CD4+CD25+ regulatory T cells in the tumor-draining lymph nodes of mice responding to therapy, and this was associated with the establishment of protective immunity. These findings pave the way for alternative therapeutic strategies based on the targeted delivery of biological and pharmacological cytotoxic compounds that not only kill most of the tumor cells but, more importantly, trigger an effective and long-lasting antitumor adaptive immune response. [source] Detection of different tumor growth kinetics in single transgenic mice with oncogene-induced mammary carcinomas by flat-panel volume computed tomographyINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Katharina Jannasch Abstract Transgenic mouse models offer an excellent opportunity for studying the molecular basis of cancer development and progression. Here we applied flat-panel volume computed tomography (fpVCT) to monitor tumor progression as well as the development of tumor vasculature in vivo in a transgenic mouse model for oncogene-induced mammary carcinogenesis (WAP-T mice). WAP-T mice develop multiple mammary carcinomas on oncogene induction within 3 to 5 months. Following induction, 3-dimensional fpVCT data sets were obtained by serial single scans of entire mice in combination with iodine containing contrast agents and served as basis for precise measurements of tumor volumes. Thereby, we were able to depict tumors within the mammary glands at a very early stage of the development. Tumors of small sizes (0.001 cm3) were detected by fpVCT before being palpable or visible by inspection. The capability to determine early tumor onset combined with longitudinal noninvasive imaging identified diverse time points of tumor onset for each mammary carcinoma and different tumor growth kinetics for multiple breast carcinomas that developed in single mice. Furthermore, blood supply to the breast tumors, as well as blood vessels around and within the tumors, were clearly visible over time by fpVCT. Three-dimensional visualization of tumor vessels in high resolution was enhanced by the use of a novel blood pool contrast agent. Here, we demonstrate by longitudinal fpVCT imaging that mammary carcinomas develop at different time points in each WAP-T mouse, and thereafter show divergent growth rates and distinct vascularization patterns. © 2009 UICC [source] Disparity between prostate tumor interior versus peripheral vasculature in response to verteporfin-mediated vascular-targeting therapyINTERNATIONAL JOURNAL OF CANCER, Issue 3 2008Bin Chen Abstract Photodynamic therapy (PDT) is a light-based cancer treatment modality. Here we employed both in vivo and ex vivo fluorescence imaging to visualize vascular response and tumor cell survival after verteporfin-mediated PDT designed to target tumor vasculature. EGFP-MatLyLu prostate tumor cells, transduced with EGFP using lentivirus vectors, were implanted in athymic nude mice. Immediately after PDT with different doses of verteporfin, tumor-bearing animals were injected with a fluorochrome-labeled albumin. The extravasation of fluorescent albumin along with tumor EGFP fluorescence was monitored noninvasively with a whole-body fluorescence imaging system. Ex vivo fluorescence microscopy was performed on frozen sections of tumor tissues taken at different times after treatment. Both in vivo and ex vivo imaging demonstrated that vascular-targeting PDT with verteporfin significantly increased the extravasation of fluorochrome-labeled albumin in the tumor tissue, especially in the tumor periphery. Although PDT induced substantial vascular shutdown in interior blood vessels, some peripheral tumor vessels were able to maintain perfusion function up to 24 hr after treatment. As a result, viable tumor cells were typically detected in the tumor periphery in spite of extensive tumor cell death. Our results demonstrate that vascular-targeting PDT with verteporfin causes a dose- and time-dependent increase in vascular permeability and decrease in blood perfusion. However, compared to the interior blood vessels, peripheral tumor blood vessels were found less sensitive to PDT-induced vascular shutdown, which was associated with subsequent tumor recurrence in the tumor periphery. © 2008 Wiley-Liss, Inc. [source] Loss of claudin-1 expression in tumor-associated vessels correlates with acquisition of metastatic phenotype in melanocytic neoplasmsJOURNAL OF CUTANEOUS PATHOLOGY, Issue 8 2005Michael L. Cohn Recent studies have suggested that some metastatic solid tumors lack claudin expression. It is unknown whether claudins play a role in cutaneous melanoma. Immunohistochemical studies were performed on tissue microarrays containing 19 benign melanocytic nevi (BN), 21 dysplastic nevi (DN), 23 primary malignant melanomas (MMs), and 31 metastatic melanomas (MMMs) using a polyclonal anti-claudin-1 antibody. Immunoreactivity in tumor cells and associated vessels was graded by intensity and by percentage of reactive cells. Normal epidermis served as internal control (3+ labeling). Cases with at least 2+ labeling in more than 25% of the cells were considered positive. Claudin-1 expression was present in 37% of BN, 24% of DN, 26% of MM, and 3.2% of MMM. Tumor-associated vessels showed the following results: 11 of 19 (58%) in BN, 14 of 21 (67%) in DN, 17 of 23 (74%) in MM, and 6 of 31 (19%) in MMM. A significant loss of expression was noted between MMM and all other lesions in tumor cells and associated vessels. There was no significant difference between BN, DN, and MM. Within primary melanomas, there was a significant correlation between expression of claudin in tumor cells and Clark level/Breslow thickness. Also significant was a decreased expression of claudin in tumor vessels of lesions with higher Breslow thickness or Clark level. These data suggest that loss of claudin-1 may play a significant role in the acquisition of metastatic phenotype in cutaneous melanoma. [source] Epithelioid cell histiocytoma , histogenetic and kinetics analysis of dermal microvascular unit dendritic cell subpopulationsJOURNAL OF CUTANEOUS PATHOLOGY, Issue 7 2003Jeffrey S. Silverman Background:, Epithelioid cell histiocytoma (ECH), also known as epithelioid fibrous histiocytoma, is a peculiar dermal tumor, which can mimic melanocytic, vascular, epithelial, or other histiocytic lesions. Thought to arise from dermal dendrocytes, most ECH contain approximately 50% FXIIIa+ histiocytic dendrocytes, but not all lesional cells express FXIIIa. A putative fibroblastic component has not been characterized. Methods:, We analyzed the differentiation and cell kinetics of dermal microvascular unit cells in 12 previously reported ECH using antibodies to FXIIIa, CD68 (KP1), CD34, CD117, CD31, smooth muscle actin, collagen type 1 aminopropeptide, and MIB-1, using single and double immunostains. Results:, In ECH, many variably sized CD34/CD31+ tumor vessels with actin+ myopericytes were surrounded by epithelioid-to-dendritic cells of three types. About 5,80% were dendritic histiocytes that expressed FXIIIa but not CD31 or KP1. Fibroblasts, in some cases showing mild nuclear pleomorphism, were usually collagen type 1+, but CD34 and actin, in 11/12 cases. One ,early' ECH had 40% CD34+ epithelioid cells, admixed with 50% FXIIIa+ histiocytes. Most ECH had about 2,20% KP1+, CD117+ mast cells. Mast cell numbers increased with FXIIIa+ histiocyte numbers and the intensity of FXIIIa expression. MIB-1/FXIIIa double-labeling showed only rare cycling histiocytes, with numerous cycling fibroblasts and endothelial cells. Conclusions:, Our findings support the impression that ECH is a vascular fibrous histiocytoma. The constituent cells appear to arise from the activation of resident microvascular CD34+ dermal fibroblasts and the accumulation of FXIIIa+ dendritic stromal assembly histiocytes. The CD34+ cells appear to differentiate toward collagenous fibrocytes in association with histiocytes and mast cells in forming collagenous stroma and vessels. ECH is a tumor composed of all requisite cell types consistent with the origin from the dermal microvascular unit. [source] Blood oxygenation level-dependent MRI of cerebral gliomas during breath holdingJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 2 2004Yuan-Yu Hsu MD Abstract Purpose To assess the cerebrovascular responses to short breath holding of cerebral gliomas using blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI). Materials and Methods Six patients with a low-grade glioma and one patient with a high-grade glioma were studied using T2*-weighted echo planar imaging (EPI) during repeated periods of 15-second or 20-second breath-holding. Tumor vascularity was evaluated using dynamic susceptibility contrast perfusion MRI. Results Increases in BOLD signal intensity during repeated breath-holding were consistently identified in patients' normal appearing gray matter, comparable with those in healthy adults. Absence of significant BOLD signal enhancement was noted both in low-grade and high-grade gliomas, which is either due to overwhelming hypoxia in a tumor, inadequacy or absence of hypercapnia-induced vasodilatation of tumor vessels, or both. Breath-hold regulated decreases in BOLD signals occurred only in the high-grade glioma, which is most likely due to the hypercapnia-induced steal effect that redistributes blood flow from tumor regions with unresponsive neovasculature to surrounding normal tissue. Conclusion BOLD MRI during short breath holding can disclose differential cerebrovascular response between normal tissue and cerebral glioma. J. Magn. Reson. Imaging 2004;19:160,167. © 2004 Wiley-Liss, Inc. [source] Morphometric analysis of CD34-positive vessels in salivary gland adenoid cystic and mucoepidermoid carcinomasJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 9 2009H. Luukkaa Background:, Carcinomas of the salivary glands are uncommon and morphologically a diverse group of malignancies. To evaluate the prognostic value of CD34 immunostaining of the vessels in adenoid cystic carcinoma (AdCC) and mucoepidermoid carcinoma (MEC), an automated image analysis method was used. Method:, In a nationwide study, covering salivary gland cancer (SGC) patients in Finland 1991,1996, 37 AdCC and 18 MEC patients (M 25, F 30, age 25,90, mean 63) were included. In addition to clinical characteristics the size, shape, staining intensity and vessel density in CD34 immunostained histologic samples were measured. Results:, Altogether 4433 vessels were measured from AdCC and 2615 from MEC tumor. Of the total tumor vessels measured, 2651 were from patients who deceased with disease (Group I) and 4397 were from specimens derived from those who did not die of disease (Group II) during the 10-year follow-up. The staining intensity was significantly higher in MEC than in AdCC tumor (P = 0.0005). In MEC, the Group I patients had a higher staining intensity among high-grade patients compared with patients with low grade disease, whereas the tumors in Group II had a lower staining intensity among the high-grade compared with the low grade tumors (P = 0.018). A higher vessel density was found in patients with MEC in group II compared with group I (P = 0.017). Conclusions:, The staining intensity of CD34 positive vessels in MEC was higher than in AdCC. In MEC, higher staining intensity of vessels in high-grade tumors and lower vessel density in all MEC patients, predicted poor survival. [source] Tumor cell-associated neuropilin-1 and vascular endothelial growth factor expression as determinants of tumor growth in neuroblastomaNEUROPATHOLOGY, Issue 3 2005Karen Marcus We sought to characterize the expression of vascular endothelial growth factor (VEGF) and its receptors in neuroblastoma (NBL) and to correlate the results with N-myc (MYCN) expression and in vivo growth of these tumors. Two representative human-derived NBL cell lines, SK-N-AS (AS) with low and SK-N-DZ (DZ) with a high MYCN copy number, were used for the study. We examined their proliferation, VEGF and VEGF receptor expression in vitro and xenograft tumor growth in vivo. In parallel, human NBL specimens were analyzed for expression of VEGF and neuropilin-1 (NRP-1). DZ cells exhibited a 4-fold higher proliferation rate than AS. In contrast, VEGF protein expression was significantly higher in AS cells. NRP-1 was the only VEGF receptor produced in AS and DZ cells in vitro and in vivo. Both AS and DZ cells formed tumors in athymic mice but AS tumors grew 3.5 times larger than DZ tumors and had larger diameter tumor vessels. VEGF and NRP-1 expression was also demonstrated in human NBL specimens. Our studies indicate that VEGF and VEGF receptor expression in NBL tumor cells are associated with tumor growth and that angiogenic factors may serve as a biological marker together with already established MYCN amplification. [source] Characterization of endoglin and Ki-67 expression in endothelial cells from benign and malignant lesions of the uterine cervixPATHOLOGY INTERNATIONAL, Issue 10 2009Anca M. Cimpean Activation of endothelial cells is often associated with the cellular proliferation in vitro. CD105 is a more specific marker of activated endothelial cells from tumor vessels and Ki-67 is used to assess the proliferation status of both tumor and endothelial cells. The aim of the present study was to evaluate the status of endothelial cells using CD105 and Ki-67 immunohistochemistry in benign and malignant lesions of the uterine cervix. Double stain for CD105/Ki-67 in benign and malignant lesions of the uterine cervix showed that these two markers had divergent expression on endothelial cells from associated tumor blood vessels dependent on lesion type and proliferation status of tumor cells. Absence of CD105/Ki-67 coexpression in endothelial cells was correlated with histopathology of the uterine cervix lesions and tumor proliferative status. The present findings suggest that CD105 expression is an early event, specific for premalignant lesions of the uterine cervix, while endothelial proliferation assessed on Ki-67 combined with the lack of CD105 expression is often associated with invasive cervical carcinoma. [source] Liposomal gemcitabine (GemLip),efficient drug against hormone-refractory Du145 and PC-3 prostate cancer xenograftsTHE PROSTATE, Issue 11 2009Peter Jantscheff Abstract BACKGROUND Gemcitabine (Gemc) is an efficient chemotherapeutic drug in various cancer types (e.g., pancreas) but has only limited effects on hormone-refractory prostate cancer (HRPCa). Since HRPCa cells are highly sensitive to even low doses of Gemc in vitro, the lack of clinical effects might be due to rapid degradation of Gemc by deaminases combined with impaired accumulation in tumor tissue and PCa cells. Liposomal formulation (GemLip) is expected to protect the entrapped cytotoxic substance from enzymatic degradation and furthermore augment its accumulation within tumor tissues due to an enhanced permeability of the tumor vessels. METHODS Anti-tumoral and anti-metastatic activity of GemLip and Gemc were investigated in two luciferase-expressing, human hormone-refractory PC-3 and Du145 HRPCa xenograft models in immunodeficient mice. Tumor growth was monitored by in vivo luminescence imaging (orthotopic) or callipering (subcutaneous). Anti-metastatic effects of treatment were determined by in vitro luciferase assay of the tissues. RESULTS Tumor growth of subcutaneous Du145 xenografts was significantly inhibited only by GemLip (8 mg/kg: P,=,0.014 and 6 mg/kg: P,=,0.011) but not by conventional Gemc (360 mg/kg). In contrast, growth of orthotopic PC-3 xenografts was significantly inhibited by both, GemLip (P,=,0.041) and Gemc (P,=,0.002). The drugs furthermore strongly reduced spleen and liver metastases in this model. CONCLUSIONS As shown by the very low efficient concentration of GemLip, liposomal entrapment of Gemc greatly enhances its activity. GemLip has, even at very low doses, a significant anti-tumoral and anti-metastatic therapeutic effect in HRPCa xenografts in vivo and was beneficial even when the conventional Gemc failed. Prostate 69:1151,1163, 2009. © 2009 Wiley-Liss, Inc. [source] Tumor blood flow interruption after radiotherapy strongly inhibits tumor regrowthCANCER SCIENCE, Issue 7 2008Katsuyoshi Hori To clarify the therapeutic significance of interrupting tumor blood flow after irradiation, we investigated X-irradiation-induced changes in hemodynamic parameters (blood flow, extravasation and washout of fluorescein isothiocyanate-dextran, and interstitial fluid pressure) in a variant of Yoshida sarcoma, LY80. Tumors in anesthetized male Donryu rats received local irradiation (10 Gy). At 48 h after irradiation, tumor blood flow increased significantly; at 72,96 h after irradiation, a 2,2.5-fold increase was observed. All parameters then consistently showed improved tumor microcirculation, which probably contributed to regrowth of cancer because certain cells survived irradiation. Rats received an intravenous dose (10 mg/kg) of a combretastatin derivative, AC7700 (AVE8062), which interrupts tumor blood flow and disrupts tumor vessels. At all times evaluated after irradiation, AC7700 completely stopped tumor blood flow. Radiotherapy efficacy was significantly enhanced when combined with AC7700: AC7700 given 48 h after irradiation, when tumor blood flow increased significantly, remarkably suppressed tumor regrowth compared with AC7700 given 48 h before irradiation. Also, postirradiation AC7700 completely inhibited not only primary tumor regrowth but also regional lymph node metastases in half of tumor-bearing rats and led to a significant improvement in survival. These results strongly suggest that the combination effect was enhanced via interruption of increased tumor blood flow after irradiation. This therapeutic combination and timing may have important benefits, even in tumors with low sensitivity to either treatment alone, because the effect was considerably greater than additive. Our data thus show that destruction of tumor microcirculation after irradiation is quite effective for preventing cancer recurrence. (Cancer Sci 2008; 99: 1485,1491) [source] Antivascular effects of TZT-1027 (Soblidotin) on murine Colon26 adenocarcinomaCANCER SCIENCE, Issue 12 2006Junichi Watanabe We investigated the ability of TZT-1027 (Soblidotin), a novel antimicrotubule agent, to induce antivascular effects, because most vascular targeting agents that selectively disrupt tumor vasculature also inhibit tubulin polymerization. Treatment with 10,7 g/mL TZT-1027 rapidly disrupted the microtubule cytoskeleton in human umbilical vascular endothelial cells (HUVEC), and significantly enhanced vascular permeability in HUVEC monolayers. In addition, single intravenous administration of 2 mg/kg TZT-1027 to mice bearing Colon26 tumors significantly reduced tumor perfusion and caused extravascular leakage of erythrocytes 1 h after administration. Subsequently, thrombus formation with deposition of fibrin and tumor necrosis was observed 3 and 24 h after administration, respectively. These results strongly suggest that TZT-1027 possesses antivascular effects. TZT-1027 induced apoptosis not only in HUVEC but also in C26 cancer cells (cell line of Colon26 solid tumor) in vitro, suggesting it exerts direct cytotoxicity against tumor cells in addition to its antivascular effects. A single intravenous administration of 1, 2 and 4 mg/kg TZT-1027 significantly prolonged the survival of mice with advanced-stage Colon26 tumors in a dose-dependent manner. Furthermore, TZT-1027 itself less markedly enhanced the permeability of normal vessels, but was additive with vascular endothelial growth factor, indicating the possibility that TZT-1027 selectively exerts its activity on tumor vessels. In summary, these results suggest that TZT-1027 exerts both an indirect antivascular effect and a direct cytotoxic effect, resulting in strong antitumor activity against advanced-stage tumors, and that TZT-1027 may be useful clinically for treating solid tumors. (Cancer Sci 2006; 97: 1410,1416) [source] Role of hematopoietic lineage cells as accessory components in blood vessel formationCANCER SCIENCE, Issue 7 2006Nobuyuki Takakura In adults, the vasculature is normally quiescent, due to the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli. However, blood vessels in adults retain the capacity for brisk initiation of angiogenesis, the growth of new vessels from pre-existing vessels, during tissue repair and in numerous diseases, including inflammation and cancer. Because of the role of angiogenesis in tumor growth, many new cancer therapies are being conducted against tumor angiogenesis. It is thought that these anti-angiogenic therapies destroy the tumor vessels, thereby depriving the tumor of oxygen and nutrients. Therefore, a better understanding of the molecular mechanisms in the process of sprouting angiogenesis may lead to more effective therapies not only for cancer but also for diseases involving abnormal vasculature. It is widely believed that after birth, endothelial cells (EC) in new blood vessels are derived from resident EC of pre-existing vessels. However, evidence is now emerging that cells derived from the bone marrow may also contribute to postnatal angiogenesis. Most studies have focused initially on the contribution of endothelial progenitor cells in this process. However, we have proposed a concept in which cells of the hematopoietic lineage are mobilized and then entrapped in peripheral tissues, where they function as accessory cells that promote the sprouting of resident EC by releasing angiogenic signals. Most recently we found that hematopoietic cells play major roles in tumor angiogenesis by initiating sprouting angiogenesis and also in maturation of blood vessels in the fibrous cap of tumors. Therefore, manipulating these entrapment signals may offer therapeutic opportunities to stimulate or inhibit angiogenesis. (Cancer Sci 2006; 97: 568,574) [source] | ||||||||||||||||||||||