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PubMed2000

Implications of human macrophage metalloelastase and vascular endothelial growth factor gene expression in angiogenesis of hepatocellular carcinoma.

OBJECTIVE: To determine molecular mechanisms involved in angiogenesis of hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: Tumor angiogenesis is believed to derive from the balance between angiogenic stimulators and inhibitors. It has been suggested that the switch to the angiogenic phenotype requires both upregulation of the first and downregulation of the second. However, its molecular basis in vivo remains obscure. In this study the authors analyze the participation of two factors in angiogenesis of HCC- human macrophage metalloelastase (HME), a matrix metalloproteinase responsible for the generation of angiostatin, a potent angiogenesis inhibitor, and vascular endothelial growth factor (VEGF), the most potent endogenous angiogenic factor. METHODS: Tumorous and contiguous nontumorous tissues from 25 patients with HCC who underwent curative partial hepatectomy were subjected to Northern blot analysis to detect HME and VEGF messenger RNA (mRNA) expression. Western blot analysis was used to detected angiostatin. Tumor vascularity was evaluated using hepatic angiography. RESULTS: Eleven of the 15 cases expressing the HME gene showed hypovascular tumors, whereas hypervascular tumors were seen in 9 of the 10 HME-negative cases. The median of HME mRNA expression (tumorous/nontumorous ratio) was 6.5 (range 0-264.5) in the hypovascular group and 0 (range 0-3.2) in the hypervascular group. A stepwise logistic analysis revealed that HME and VEGF mRNA expression were two independent variables significantly affecting the vascularity of HCC tumors. CONCLUSION: HME gene expression is significantly associated with hypovascular tumors; moreover, angiogenesis in HCC is not determined by a single factor, but depends on the net balance between HME and VEGF gene expressions.

Adult↗

PubMed1998

Angiogenesis in corneal diseases: histopathologic evaluation of 254 human corneal buttons with neovascularization.

PURPOSE: Angiogenesis in corneal diseases can necessitate corneal transplantation and induce graft rejection. The aim of this study was to find out the histopathologic prevalence of angiogenesis in human corneas removed during keratoplasty, to establish the histopathologic diagnoses most commonly associated with angiogenesis, and to evaluate the anatomic location of new corneal vessels. METHODS: Corneal buttons (2,557) after keratoplasty were sent to and analyzed in our ophthalmopathology laboratory between 1992 and 1996. Of these, 1,278 full-thickness and lamellar corneal buttons were randomly retrieved and evaluated in this study. RESULTS: Of 1,278 human corneal buttons obtained by keratoplasty, 254 (19.9%) showed angiogenesis. Associated histopathologic diagnoses were (a) scarring after keratitis (109, 45.4%); (b) graft rejection and insufficiency (73, 30.4%); (c) acute necrotizing ulcerative keratitis (30, 12.5%); and (d) scarring after mechanical or chemical injuries (28, 11.7%). Histopathologically, new vessels were usually associated with corneal edema or inflammatory cells or both (76%). The most common locations of new vessels were the upper and middle third of the corneal stroma. Only 11% of new vessels were located solely in the deep stromal layers. CONCLUSION: Angiogenesis is a common histopathologic feature of corneal diseases leading to corneal transplantation and was found in 19.9% of excised human corneal buttons. Systemic or topical antiangiogenic therapy could reduce the need for corneal transplantation and retransplantation.

Adolescent↗

PubMed2000

Altered central nervous system cytokine-growth factor expression profiles and angiogenesis in metallothionein-I+II deficient mice.

To study the importance of metallothionein-I and -II (MT-I+II) for brain inflammation and regeneration, the authors examined normal and MT-I+II knock-out (MT-KO) mice subjected to a cortical freeze injury. Normal mice showed profound neurodegeneration, inflammation, and gliosis around the injury, which was repaired by 20 days postlesion (dpl). However, in MT-KO mice the lesion-associated inflammation was still present as late as 90 dpl. Scanning electron microscopy demonstrated that the number of capillaries was lower, and ultrastructural preservation of the lesioned parenchyma was poorer in MT-KO mice, suggesting an altered angiogenesis. To gain insight into the mechanisms involved, a number of cytokines and growth factors were evaluated. The number of cells expressing the proinflammatory cytokines IL-1beta, IL-6, and TNF-alpha was higher in MT-KO mice than in normal mice, which was confirmed by RNase protection analysis, whereas the number of cells expressing the growth factors bFGF, TGFbeta1, VEGF, and NT-3 was lower. Increased expression of proinflammatory cytokines could be involved in the sustained recruitment of CD-14+ and CD-34+ inflammatory cells and their altered functions observed in MT-KO mice. Decreases in trophic factors bFGF, TGFbeta1, and VEGF could mediate the decreased angiogenesis and regeneration observed in MT-KO mice after the freeze lesion. A role for MT-I+II in angiogenesis was also observed in transgenic mice expressing IL-6 under the control of the promoter of glial fibrillary acidic protein gene (GFAP-IL6 mice) because MT-I+II deficiency dramatically decreased the IL-6-induced angiogenesis of the GFAP-IL6 mice. In situ hybridization analysis indicated that the MT-III expression was not altered by MT-I+II deficiency. These results suggest that the MT-I+II isoforms have major regulatory functions in the brain inflammatory response to injury, especially in the angiogenesis process.

Animals↗

PubMed2003

Cyclooxygenase-2 overexpression correlates with vascular endothelial growth factor expression and tumor angiogenesis in gastric cancer.

Angiogenesis is a key prerequisite for the successful establishment, growth, and dissemination of tumors. Vascular endothelial growth factor (VEGF) has a potent angiogenic activity and cyclooxygenase-2 (COX-2) promotes angiogenesis by modulated production of angiogenic factors including VEGF. The current study was designed to investigate the possible roles of COX-2 and VEGF in gastric cancer angiogenesis. In this study, we conducted an immunohistochemical investigation of COX-2 and VEGF expression in 97 patients with gastric cancer. To assess tumor angiogenesis, microvessel density (MVD) was determined by CD34 immunohistochemical staining. Expression of COX-2 and VEGF in gastric cancer tissues, was demonstrated in 63.9% and 75.3% of cases, respectively. The expression of COX-2 correlated significantly with VEGF expression. High MVD was significantly associated with depth of tumor invasion and poor survival. The mean MVD value of VEGF positive tumors was 79.8 +/- 32.0 and significantly higher than that of VEGF negative tumors. The mean MVD value of COX-2 positive tumors was 77.9 +/- 29.9 and not significantly higher than that of COX-2 negative tumor. The mean value of MVD in tumors positive for both COX-2 and VEGF was significantly higher than that in tumors negative for both. However, there was no correlation between COX-2 or VEGF expression and various clinicopathological features including patient survival. These results suggest that COX-2 may play an important role in carcinogenesis by stimulating tumor angiogenesis in concert with VEGF in human gastric cancer.

Adult↗

PubMed2005

Staurosporine promotes endothelial cell assembly and FAK phosphorylation during in vitro angiogenesis.

In the present study, we report that staurosporine, a known PKC inhibitor, enhanced in vitro angiogenesis. Endothelial cells plated in a three-dimensional matrix formed cords and enclosed structures within 4-6 hours. The cells in cord structures became elongated during the subsequent incubation. Tube formation was confirmed by confocal microscopy. Addition of VEGF enhanced the early responses of endothelial cells, leading to enhanced formation of cords. Staurosporine unexpectedly also enhanced the early endothelial responses, leading to faster alignment of cells and assembly into tube-like structures. At concentrations inhibitory to endothelial cell PKC activity, staurosporine produced 91% and 203% increases in the number of cords and the enclosed structures, respectively, as compared to the controls. Other selective inhibitors of PKC did not stimulate in vitro angiogenesis in the absence or presence of VEGF. Further investigation showed that inhibition of PI-3 kinase and Raf-1 significantly reduced the effects of staurosporine. Staurosporine-induced in vitro angiogenesis required integrins alpha2 and alphavbeta3 and was associated with significantly enhanced FAK phosphorylation. These data indicate that staurosporine enhances in vitro angiogenesis by a means unrelated to its PKC inhibition. The data suggest that enhancement of in vitro angiogenesis by staurosporine involves integrin-mediated signaling, including the stimulation of FAK phosphorylation.

Cells, Cultured↗

PubMed2001

The role of hypoxia and p53 in the regulation of angiogenesis in bladder cancer.

PURPOSE: Our previous studies defined thrombospondin-1 (TSP-1) and vascular endothelial growth factor (VEGF) as the primary mediators of angiogenesis in the bladder and the loss of inhibitory TSP-1 as a key event in the transition to an angiogenic phenotype during bladder cancer development. We evaluated the role of p53, which is commonly inactivated in bladder cancer, and hypoxia in the regulation of angiogenesis in the bladder. MATERIALS AND METHODS: The p53 status was modulated in normal urothelial and bladder cancer cells, and conditioned media was collected under normal oxygen or hypoxic (0.5% O2) conditions. Angiogenic activity was evaluated with the endothelial cell migration assay, and the levels of secreted TSP-1 and VEGF were determined by Western blot analysis and enzyme-linked immunosorbent assay, respectively. RESULTS: Retroviral mediated expression of the E6 oncoprotein reduced wild-type p53 levels in normal urothelial cells by greater than 90% but did not significantly alter TSP-1 or VEGF levels, while total inductive and inhibitory activities remained unchanged. Adenoviral mediated expression of wild-type p53 was confirmed in 4 bladder cancer cell lines by Western blot analysis for p53 and its downstream effector protein p21 (2.5 to 5.0-fold increase). TSP-1 levels remained unchanged but the levels of secreted VEGF in the high grade UMUC-3 and 253J cell lines were significantly decreased 5 to 50-fold and a corresponding decrease in net angiogenic activity was observed. However, (increased expression) of p53 had no effect on the angiogenic activity of the low grade RT4 or high grade HT1376 bladder cancer cells. Hypoxia converted normal urothelial cell derived conditioned media from anti-angiogenic to angiogenic and increased the angiogenic activity of bladder cancer cell derived conditioned media. This change was due to 2.5 to 6-fold hypoxic up-regulation of VEGF because the expression of inhibitory TSP-1 was not significantly altered. CONCLUSIONS: Our results suggest that p53 does not regulate angiogenesis in the bladder in the setting of an otherwise normal genome and gene therapy with wild-type p53, which is currently being studied for this cancer, may have only limited effects on angiogenesis. In contrast, hypoxia regulates angiogenesis in this system, primarily through its effects on VEGF.

Blotting, Western↗

PubMed1999

Association of vascular endothelial growth factor expression with angiogenesis and lymph node metastasis in nasopharyngeal carcinoma.

OBJECTIVE: Recent experimental evidence indicates that angiogenesis affects tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is considered to be an important regulator of tumor angiogenesis. The present study was designed to examine the role of VEGF on angiogenesis and lymph node metastasis in primary nasopharyngeal carcinomas (NPCs). STUDY DESIGN: Formalin-fixed paraffin-embedded biopsy specimens were obtained from 29 primary NPCs that consisted of 22 differentiated nonkeratinizing carcinomas and seven undifferentiated carcinomas. METHODS: Microvessels were highlighted by staining endothelial cells with von Willebrand factor (VWF) using immunohistochemical techniques, and were counted (per x 400 field) in the most active area of angiogenesis on light microscopy. The expression of VEGF was also studied with immunohistochemistry. Positive ratio for VEGF was graded on a scale of 1 and 2. Scale 1 represents patients with less than the mean value of the positive ratio, and scale 2 represents patients with more than the corresponding value. RESULTS: There was a significant correlation between increased microvessel count and the progression of regional lymph node involvement. The microvessel counts and the progression of N factor were significantly higher in scale 2 patients than in scale 1 patients. CONCLUSION: These results suggest that VEGF plays an important role in lymph node metastasis through induction of angiogenesis in NPCs.

Carcinoma, Squamous Cell↗

PubMed2002

Comparative evaluation of angiogenesis in gastric adenocarcinoma by nestin and CD34.

Tumor angiogenesis has been shown to be important for growth and metastasis in human neoplasms. Angiogenesis is usually determined by immunohistochemical staining of tumor tissue using various antibodies specific for endothelial cells. CD34 has been the one most commonly used in studies of tumor angiogenesis. Nestin, a class VI intermediate filament protein, was reported to be a good angiogenic marker in animal models. The aim of the current study was to compare the predictive value of angiogenesis as determined by CD34 and nestin on the same group of patients with advanced gastric carcinomas and to evaluate the possibility of nestin being a newer, better angiogenesis marker. Immunohistochemical staining using antinestin polyclonal antibody and anti-CD34 monoclonal antibody was carried out on surgical specimens from 61 patients with advanced gastric adenocarcinomas. The sensitivity of each of the two antibodies was evaluated by microvessel density (MVD) measurement by counting vessels in three 200x fields of intense neovascularization ("hot spots") of invasive tumors using a digital image analyzer. Immunoreactivity for nestin and CD34 was seen in the endothelial cells, and no stain was noted in the negative controls. MVD determined by nestin [87.74 +/- 29.30 (mean +/- standard deviation)] staining was significantly greater than that obtained by CD34 (82.48 +/- 32.27), and the difference was statistically significant. There was no correlation between MVD and patient clinical outcome with either antibody. Interestingly, in patients with larger carcinomas, MVD determined by nestin correlated better with longer survival than CD34. The difference was statistically significant. These results indicate that nestin is the better marker to evaluate neovascularity in endothelial cells. Evaluation of MVD determined by immunohistochemistry has limited value in patients with gastric carcinomas.

Adenocarcinoma↗

PubMed2003

Dynamic assessment of angiogenesis in renal cell carcinoma spheroids by intravital microscopy.

PURPOSE: Renal cell cancer represents a suitable tumor model for in vivo observation of neo-angiogenesis. We used intravital microscopy and the well established dorsal skin fold chamber model to characterize neo-angiogenesis in freely implanted renal cell cancer spheroids. MATERIAL AND METHODS: Tumor spheroids were implanted into dorsal skin fold chambers of 8 nude mice. At days 3, 6, 10 and 14 after implantation the newly vascularized spheroid area, density of perfused microvessels in the spheroid versus the periphery, capillary center erythrocyte velocity and capillary diameter were recorded by intravital microscopy. Video images were analyzed by a computer assisted image analysis device. After the experiments the chambers were analyzed morphologically. RESULTS: The model enabled quantitative analysis of microcirculation and angiogenesis in the renal cell cancer spheroids during 14 days of observation. Mean spheroid center perfused microvessel density +/- SEM increased from 3 +/- 2 to 269 +/- 21 cm.-1 on days 3 to 10 and subsequently decreased to 189 +/- 38 cm.-1 on day 14. Spheroid periphery perfused microvessel density was significantly higher throughout the experiments, attaining a mean maximum of 522 +/- 34 cm. on day 14. Mean capillary diameter decreased continuously from 14.2 +/- 0.9 to 8.4 +/- 0.4 microm. on days 3 to 14. In contrast, mean capillary center erythrocyte velocity significantly increased during 14 days of observation from 0.09 + 0.02 mm. per second on day 3 to 0.24 +/- 0.08 mm. per second on day 14. Histological analysis after 14 days revealed the spheroids as cell clusters in the upper layers of the dorsal skin fold chamber. CONCLUSIONS: The model is suitable for the analysis of renal cell cancer angiogenesis. Although it is heterotopic, angiogenesis in renal cell cancer spheroids mimics important characteristics of human renal cell cancer.

Animals↗

PubMed2003

Inhibition of tumor-induced angiogenesis and matrix-metalloproteinase expression in confrontation cultures of embryoid bodies and tumor spheroids by plant ingredients used in traditional chinese medicine.

Tumor-induced angiogenesis is a prerequisite for excessive tumor growth. Blood vessels invade the tumor tissue after degradation of the extracellular matrix scaffold by matrix metalloproteinases (MMPs). Inhibition of MMPs has been therefore suggested to be a useful tool to abolish neoangiogenesis of solid tumors. In the present study, antioxidative plant ingredients used in traditional Chinese medicine were investigated for their capacity to down-regulate MMP expression and to inhibit angiogenesis in embryonic stem cell-derived embryoid bodies and tumor-induced angiogenesis in confrontation cultures consisting of embryoid bodies and multicellular DU-145 prostate tumor spheroids. Embryoid bodies transiently expressed MMP-1, MMP-2, and MMP-9 during the time of differentiation of capillary-like structures. In confrontation cultures, MMP expression was increased compared with control tumor spheroids and embryoid bodies cultivated separately. The increased expression of MMPs in confrontation cultures was a result of elevated levels of reactive oxygen species (ROS) upon confrontation culture and was totally abolished in the presence of the free radical scavenger vitamin E. Incubation of embryoid bodies with baicalein, epicatechin, berberine, and acteoside, which are herbal ingredients used in traditional Chinese medicine, significantly inhibited angiogenesis in embryoid bodies and decreased intracellular ROS levels. Tumor-induced angiogenesis in confrontation cultures was totally abolished in the presence of the free radical scavenger vitamin E. Because herbal ingredients down-regulated MMP expression, we conclude that ROS generated during confrontation culture induce the expression of MMPs that are necessary for endothelial cell invasion into the tumor tissue.

Cells, Cultured↗

PubMed2005

Quantification of angiogenesis in otosclerosis.

OBJECTIVES/HYPOTHESIS: The determinants of clinical versus histologic otosclerosis are unknown, but angiogenesis is associated with active disease. We hypothesized that quantification of angiogenesis in otosclerotic human temporal bones could reveal significant differences between clinical and histologic cases. STUDY DESIGN: We reviewed all otosclerosis specimens meeting criteria from the temporal bone collection of the Massachusetts Eye and Ear Infirmary and 10 normal controls. METHODS: Digital images were taken at predilection sites, followed by computer-assisted analysis. Canalicular area (CA), the aggregate of vascular spaces within bone, microvessel density (MVD), area, and depth were the main measures. Evidence of a direct connection between local vessels and the vasculature of the otosclerotic focus was also recorded for each specimen. RESULTS: The average area (mm) and depth (number of sections containing otosclerosis) of clinical lesions was significantly greater than histologic lesions. Total microvessel counts were significantly greater in clinical versus histologic lesions, and both clinical and histologic lesions contained significantly greater numbers of microvessels than the normal otic capsule. CA was also significantly higher in clinical lesions. MVD was slightly but not significantly higher in clinical lesions. Importantly, a direct connection between named vessels and the otosclerotic vasculature was significantly more frequent in clinical lesions. CONCLUSIONS: Computer-assisted quantification revealed significantly greater measures of angiogenesis in clinical versus histologic otosclerosis. Direct connection to adjacent vessels may support angiogenesis in this disease. Sustained angiogenesis may be an important determinant of clinical otosclerosis.

Aged↗

PubMed2003

Can angiogenesis induced by chronic electrical stimulation enhance latissimus dorsi muscle flap survival for application in cardiomyoplasty?

In cardiomyoplasty, the latissimus dorsi muscle is lifted on its primary neurovascular pedicle and wrapped around a failing heart. After 2 weeks, it is trained for 6 weeks using chronic electrical stimulation, which transforms the latissimus dorsi muscle into a fatigue-resistant muscle that can contract in synchrony with the beating heart without tiring. In over 600 cardiomyoplasty procedures performed clinically to date, the outcomes have varied. Given the data obtained in animal experiments, the authors believe these variable outcomes are attributable to distal latissimus dorsi muscle flap necrosis. The aim of the present study was to investigate whether the chronic electrical stimulation training used to transform the latissimus dorsi muscle into fatigue-resistant muscle could also be used to induce angiogenesis, increase perfusion, and thus protect the latissimus dorsi muscle flap from distal necrosis. After 14 days of chronic electrical stimulation (10 Hz, 330 microsec, 4 to 6 V continuous, 8 hours/day) of the right or left latissimus dorsi muscle (randomly selected) in 11 rats, both latissimus dorsi muscles were lifted on their thoracodorsal pedicles and returned to their anatomical beds. Four days later, the resulting amount of distal flap necrosis was measured. Also, at predetermined time intervals throughout the experiment, muscle surface blood perfusion was measured using scanning laser Doppler flowmetry. Finally, latissimus dorsi muscles were excised in four additional stimulated rats, to measure angiogenesis (capillary-to-fiber ratio), fiber type (oxidative or glycolytic), and fiber size using histologic specimens. The authors found that chronic electrical stimulation (1) significantly (p < 0.05) increased angiogenesis (mean capillary-to-fiber ratio) by 82 percent and blood perfusion by 36 percent; (2) did not reduce the amount of distal flap necrosis compared with nonchronic electrical stimulation controls (29 +/- 5.3 percent versus 26.6 +/- 5.1 percent); (3) completely transformed the normally mixed (oxidative and glycolytic) fiber type distribution into all oxidative fibers; and (4) reduced fiber size in the proximal and middle but not in the distal segments of the flap. Despite the significant increase in angiogenesis and blood perfusion, distal latissimus dorsi muscle flap necrosis did not decrease. This might be because of three reasons: first, the change in muscle metabolism from anaerobic to aerobic may have rendered the muscle fibers more susceptible to ischemia. Second, because of the larger diameter of the distal fibers in normal and stimulated latissimus dorsi muscle, the diffusion distance for oxygen to the center of the distal fibers is increased, making fiber survival more difficult. Third, even though angiogenesis was significantly increased in the flap, cutting all but the single vascular pedicle resulted in the newly formed capillaries not receiving enough blood to provide nourishment to the distal latissimus dorsi muscle. The authors' findings indicate that chronic electrical stimulation as tested in these experiments could not be used to prevent distal latissimus dorsi muscle flap ischemia and necrosis in cardiomyoplasty.

Animals↗

PubMed1995

A quantative in vivo method of analyzing human tumor-induced angiogenesis in mice using agarose microencapsulation and hemoglobin enzyme-linked immunosorbent assay.

This study was conducted to develop a quantitative assay system for use in the in vivo evaluation in mice of angiogenesis induced by human tumor cells. The human epidermoid carcinoma cells, A431 cells, were cultured on microcarriers. Microcarrier-attached A431 cells (A431-MC) were microencapsulated with agarose hydrogel to isolate them from the immune system of the C57BL/6 mice after subcutaneous dorsal midline implantation. The agarose hydrogel-microencapsulated A431 cells (Aga-A431 cells; diameter=300 micron) survived for at least 10 days in vitro, and the proliferation profile of the Aga-A431 cells was indistinguishable from that of non-microencapsulated A431 cells. The Aga-A431 cells were subcutaneously injected into mice with an 18-gauge needle. Ten days later, few vessels had formed at the site implanted with cell-free agarose beads, whereas notable angiogenesis was observed at the site implanted with Aga-A431 cells. The degree of angiogenesis was evaluated by measurement of the hemoglobin content in the implanted site using a mouse hemoglobin (mHb) enzyme-linked immunosorbent assay (ELISA) system. This mHb-ELISA system has the advantages of great simplicity and reproducibility. The measured mHb-content of new blood vessels at the site implanted with agarose beads was in good agreement with the amount of angiogenesis observed under a stereoscopic microscope. This assay system enabled us to evaluate the angiogenesis induced by xenogeneic cells, such as human tumor cells. Thus, our novel method may be useful for the study of the angiogenic potential of various human tumor cells and in research on the anti-angiogenic properties of various agents.

Animals↗

PubMed1998

Clotrimazole, an imidazole antimycotic, is a potent inhibitor of angiogenesis.

Clotrimazole, an imidazole antimycotic, interferes with the rise in cytosolic Ca2+ and inhibits cell proliferation in a reversible manner. Here we describe the effect of clotrimazole on vascular endothelial cells (ECs). Clotrimazole inhibited the proliferation of ECs stimulated with typical angiogenic growth factors; vascular endothelial growth factor and basic fibroblast growth factor (bFGF). This inhibitory effect of clotrimazole was dose-dependent and the maximal inhibition was observed at a concentration of 10 mM. We did not observe any increase in 51Cr release from ECs during treatment with 10 microM clotrimazole. Moreover, clotrimazole inhibited the basal and bFGF-stimulated migration of ECs. As clotrimazole inhibited two principle components of angiogenesis; the proliferation and migration of ECs, we examined whether clotrimazole inhibited angiogenesis. Tube formation by ECs in type 1 collagen gel was investigated, and clotrimazole was found to be significantly inhibitory. The inhibitory effect of clotrimazole on angiogenesis was further confirmed in an in vivo angiogenesis model of murine Matrigel plug assay. These results demonstrate that clotrimazole is a potent inhibitor of angiogenesis.

Animals↗

PubMed2001

A potential use of a synthetic retinoid TAC-101 as an orally active agent that blocks angiogenesis in liver metastases of human stomach cancer cells.

TAC-101 (4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid) is a novel, synthetic retinoid that is effective against liver metastases of human gastrointestinal cancer cells such as the human stomach carcinoma line AZ-521 in animal models, and is currently in use in phase I cancer trials. However, the mechanism of its antimetastatic action is still poorly understood. Tumor metastasis depends on angiogenesis, and various retinoids have been found to exhibit antiangiogenic activity. Based on these findings we here examined the antiangiogenic effects of TAC-101. Oral administration of TAC-101 (2-8 mg/kg/day) resulted in a drastic suppression of the AZ-521 cell-induced angiogenesis in a mouse dorsal air sac assay system, compared to the vehicle alone. Immunohistochemical analysis with antibody against the endothelial marker CD31 revealed a significant reduction in microvessel density in liver metastases from animals treated with TAC-101 (8 mg/kg p.o.), compared to liver metastases from the untreated control animals. The ability of TAC-101 (8 mg/kg p.o.) to prevent experimental liver metastasis of AZ-521 cells in athymic nude mice was comparable with that of the known angiogenesis inhibitor TNP-470 (30 mg/kg s.c.). TAC-101 also affected angiogenesis in chorioallantoic membranes and some functions of endothelial cells associated with angiogenesis, whereas the retinoid failed to suppress AZ-521 cell proliferation directly. These data suggest that the TAC-101 is an orally active antiangiogenic agent and that this antiangiogenic property may contribute to its efficacy against liver metastasis of human stomach cancer cells.

Administration, Oral↗

PubMed1993

Short report: effect of sucralfate on angiogenesis in granulation tissue of acetic acid-induced gastric ulcers in rats.

We investigated the effect of sucralfate on angiogenesis in granulation tissue of gastric ulcers induced by acetic acid in rats using the carmine dye method. Intragastric administration of sucralfate at a dose of 500 mg/kg twice daily for 9 days significantly accelerated ulcer healing and significantly increased the extent of angiogenesis in the ulcer base on the tenth day after ulcer induction. As we reported previously, intragastric administration of cimetidine at a dose of 100 mg/kg once daily for 9 days decreased the extent of angiogenesis on the tenth day. However, combination treatment using sucralfate and cimetidine accelerated ulcer healing significantly, without altering the extent of angiogenesis. It is concluded, therefore, that the treatment with sucralfate may be effective in peptic ulcer disease from the standpoint of angiogenesis in the ulcer base.

Animals↗

PubMed1994

Bone marrow angiogenesis and progression in multiple myeloma.

Tumour growth is angiogenesis-dependent. We found a high correlation between the extent of bone marrow angiogenesis, evaluated as microvessel area, and the proliferating (S-phase) fraction of marrow plasma cells, evaluated as labelling index (LI), in patients with multiple myeloma (MM) and in those with monoclonal gammopathies of undetermined significance (MGUS). Angiogenesis itself was significantly associated with active as opposed to non-active MM and MGUS. The highest microvessel area accompanied rapidly progressive MM with the highest LI. When a cut-off value of 2% or greater of the microvessel area was used, most patients with active MM were classified correctly. The risk of active disease in patients with MM increased in parallel with the microvessel area. A causal relationship between plasma cell growth, activity phase in MM and marrow angiogenesis is suggested. Since angiogenesis proceeds in step with the enlargement of plasma cell tumours and the activity phase in MM, its measurement could be a useful prognostic marker in patients with plasma cell proliferative disorders.

Aged↗

PubMed2004

Enhanced angiogenesis following allogeneic blood transfusion.

Blood transfusions are associated with recurrence of solid cancers. Angiogenesis is essential for cancer growth. Our aim was to determine for the first time in a prospective cohort study the effect of prestorage allogeneic leucodepleted SAGM (saline, adenine, glucose, mannitol) red cell transfusion on angiogenic factor levels and in vitro angiogenesis. Forty pretransfusion adult hospital inpatients were selected consecutively. Serum vascular endothelial growth factor (VEGF) and endostatin were measured in each patient before and after prestorage allogeneic leucodepleted SAGM red cell transfusion. All samples were exposed to an in vitro endothelial cell proliferation assay and 10 sample groups were also exposed to an in vitro whole angiogenesis assay. The median number of units transfused was 2 (minimum-maximum, 2-4). Twenty-nine (73%) patients had a rise in VEGF, with an overall increase of 118 pg/ml (quartiles -5, 306; P < 0.01). Twenty-eight (70%) patients had a decrease in endostatin, with an overall reduction of 1.2 ng/ml (quartiles 4.0, 0.0; P = 0.017). There was an overall 33% increase in endothelial cell proliferation (P < 0.01) and a 9.4% increase in in vitro whole assay angiogenesis (P < 0.01). Prestorage allogeneic leucodepleted SAGM red cell transfusions are associated with a favourable angiogenic factor imbalance and an elevation in in vitro angiogenesis.

Adult↗