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PubMed2001

Angiogenesis in acute promyelocytic leukemia: induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid.

Recent studies indicate that angiogenesis is important in the pathogenesis of leukemias, apart from its well-established role in solid tumors. In this study, the possible role of angiogenesis in acute promyelocytic leukemia (APL) was explored. Bone marrow trephine biopsies from patients with APL showed significantly increased microvessel density and hot spot density compared with normal control bone marrow biopsies. To identify the mediators of angiogenesis in APL, quantitative and functional assays were performed using the NB4 APL cell line as a model system. Conditioned media (CM) from the NB4 cells strongly stimulated endothelial cell migration. CM from the NB4 cells contained high levels of vascular endothelial growth factor (VEGF) but not basic fibroblast growth factor (bFGF). Most important, the addition of neutralizing VEGF antibodies completely inhibited the ability of NB4 CM to stimulate endothelial cell migration, suggesting that APL angiogenesis is mediated by VEGF. The effect of all-trans retinoic acid (ATRA) on APL angiogenesis was then studied. ATRA therapy resulted in a decrease in bone marrow microvessel density and hot spot density. CM from ATRA-treated APL cells did not stimulate endothelial cell migration. Finally, quantitative assays showed that ATRA treatment resulted in the abrogation of VEGF production by the NB4 cells. These results show that there is increased angiogenesis and VEGF production in APL and that ATRA therapy inhibits VEGF production and suppresses angiogenesis. The addition of specific antiangiogenic agents to differentiation therapy or chemotherapy should be explored. (Blood. 2001;97:3919-3924)

Bone Marrow↗
PubMed2005

Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis.

The multifunctional growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its receptor tyrosine kinase c-Met have emerged as key determinants of brain tumor growth and angiogenesis. SF/HGF and c-Met are expressed in brain tumors, the expression levels frequently correlating with tumor grade, tumor blood vessel density, and poor prognosis. Overexpression of SF/HGF and/or c-Met in brain tumor cells enhances their tumorigenicity, tumor growth, and tumor-associated angiogenesis. Conversely, inhibition of SF/HGF and c-Met in experimental tumor xenografts leads to inhibition of tumor growth and tumor angiogenesis. SF/HGF is expressed and secreted mainly by tumor cells and acts on c-Met receptors that are expressed in tumor cells and vascular endothelial cells. Activation of c-Met leads to induction of proliferation, migration, and invasion and to inhibition of apoptosis in tumor cells as well as in tumor vascular endothelial cells. Activation of tumor endothelial c-Met also induces extracellular matrix degradation, tubule formation, and angiogenesis in vivo. SF/HGF induces brain tumor angiogenesis directly through only partly known mechanisms and indirectly by regulating other angiogenic pathways such as VEGF. Different approaches to inhibiting SF/HGF and c-Met have been recently developed. These include receptor antagonism with SF/HGF fragments such as NK4, SF/HGF, and c-Met expression inhibition with U1snRNA/ribozymes; competitive ligand binding with soluble Met receptors; neutralizing antibodies to SF/HGF; and small molecular tyrosine kinase inhibitors. Use of these inhibitors in experimental tumor models leads to inhibition of tumor growth and angiogenesis. In this review, we summarize current knowledge of how the SF/HGF:c-Met pathway contributes to brain tumor malignancy with a focus on glioma angiogenesis.

Animals↗
PubMed1999

Inhibitory effects of tetrandrine and related synthetic compounds on angiogenesis in streptozotocin-diabetic rodents.

Structure-activity relationships of tetrandrine, isolated from a Kampo medicine, Stephania tetrandrae S. MOORE (root), and related synthetic compounds, were investigated in in vitro fetal bovine serum (FBS)-stimulated angiogenesis of cultured choroids in streptozotocin-diabetic Wistar rats, and air-pouch granuloma angiogenesis in vivo in diabetic mice. Tetrandrine, KS-1-1 (6,7-dimethoxy-1-[[4-[5-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroiso quinolinyl)methyl-2-methoxy]phenoxy]benzyl]-2-methyl-1,2,3,4-tetrahyd roisoquinoline), and KS-1-4 (6,7-dimethoxy-1-[[4-[4-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroiso quinolinyl)methyl]phenoxy]benzyl]-2-methyl-1,2,3,4-tetrahydroisoquino line), potently inhibited choroidal angiogenesis and air-pouch granuloma angiogenesis in the diabetic state. Their inhibitory effects on diabetic choroids were greater than those on normal choroids. Among these compounds, KS-1-4 inhibited only diabetic angiogenesis. These compounds significantly inhibited FBS-stimulated tube formation in vascular endothelial cells from normal rats. Tetrandrine and KS-1-4, but not KS-1-1, inhibited vascular endothelial growth factor- and platelet-derived growth factor-BB-stimulated angiogenesis in normal choroids. The bis[tetrahydroisoquinoline] moiety, connected by oxy-bis[phenylenemethylene] and 2,2'-dimethyl groups in tetrandrine, contributes to the inhibition of diabetic choroidal angiogenesis. KS-1-4 may be a candidate for anti-choroidopathy and retinopathy drugs in the diabetic state.

Alkaloids↗
PubMed2001

[Endogenous prostaglandins and angiogenesis].

Angiogenesis is a process involved in several physiological events including embryonic development, female reproductive cycle placentation and wound repair. It also plays a part in various pathological conditions such as tumor growth, diabetic retinopathy and rheumatoid arthritis. Angiogenesis is a very complex multistep process involving a variety of biologically active substances, among which are the prostaglandins (PGs), which can induce several growth factors and proliferation of endothelial cells in vitro and in vivo. Angiogenesis is reportedly enhanced by prostaglandins (PGs). We investigated whether or not COX-2 mediated angiogenesis in chronic and proliferate granuloma. In rat sponge implants, angiogenesis was gradually developed over a 14-day experimental period as granuloma formed. In sponge granuloma, mRNA of COX-1 was constitutively expressed, whereas that of COX-2 was increased with neovascularization in parallel with the increased expression of vascular endothelial growth factor (VEGF). bFGF-stimulated angiogenesis was inhibited by indomethacin or a selective COX-2 inhibitor, NS-398. These results suggested that endogenous PGs generated through COX-2 may enhance the neovascularization in sponge granuloma by increased expression of VEGF and that a COX-2 inhibitor would facilitate the management of conditions involving angiogenesis.

Animals↗
PubMed2001

A potential role of bradykinin in angiogenesis and growth of S-180 mouse tumors.

Angiogenesis is an important event in tumor growth. We evaluated the contribution of endogenous bradykinin to tumor-associated angiogenesis and tumor growth using pharmacological approaches in mice bearing sarcoma 180 cells. The weight of implanted tumors increased in parallel with increased hemoglobin contents (a parameter to evaluate angiogenesis) over a 20-day experimental period. Daily administration of bradykinin B2-receptor antagonists, Hoe140 (0.1 and 1 mg/kg per day, local injection) or FR173657 (30 mg/kg per day, p.o.), significantly suppressed the increment in angiogenesis and tumor weight, but a B1-receptor antagonist, desArg10-Hoe140 (1 mg/kgperday), did not. Administration of a plasma kallikrein inhibitor, soybean trypsin inhibitor (3 mg/site per day), significantly suppressed angiogenesis and tumor growth. In contrast, bradykinin-degrading enzyme inhibitors, captopril and phosphoramidon (500 microg/site per day), enhanced angiogenesis and increased tumor weight. Our results suggest that bradykinin, produced by plasma kallikrein or plasma kallikrein-like enzymes, promote tumor-associated angiogenesis and tumor growth in vivo.

Adrenergic beta-2 Receptor Antagonists↗
PubMed2001

Human endometrial angiogenesis.

Angiogenesis is the development of new microvessels from existing vessels, a process that involves microvascular endothelial cells. Physiological angiogenesis rarely occurs in adults except in the ovary and endometrium during the reproductive life of females. Angiogenesis occurs by sprouting and non-sprouting mechanisms. Since endothelial sprouts are not observed in human endometrium, we hypothesized that non-sprouting mechanisms such as intussusception and elongation are involved in endometrial angiogenesis. The demand for angiogenesis differs spatially and temporally in the endometrium: angiogenesis occurs in the basalis layer during menstruation and in the functionalis and subepithelial capillary plexus during the proliferative and early secretory stages. Most studies have failed to demonstrate a link between expression of endometrial angiogenic factors and new vessel growth. However, we demonstrated recently a strong relationship between vascular endothelial growth factor (VEGF) immunolocalized in in-travascular neutrophils and endothelial cell proliferation in each of the subepithelial capillary plexus, functionalis and basalis regions of the human endometrium. Our data also indicate that focal neutrophil VEGF has a role in the development of the subepithelial capillary plexus and functionalis microvessels during the proliferative phase of the menstrual cycle. We propose that neutrophils are an intravascular source of VEGF for vessels that undergo angiogenesis by intussusception and elongation.

Endometrium↗
PubMed2005

Photoperiod-induced differential expression of angiogenesis genes in testes of adult Peromyscus leucopus.

Non-pathological angiogenesis in adults is rare and is largely thought to be restricted to wound healing and female reproductive cycles. Adult male rodents, however, display seasonal angiogenesis to support seasonal changes in reproductive tissue morphology. Non-tropical rodents use photoperiod (day length) to determine the time of year. During short days, the reproductive system undergoes involution and mating behaviours stop, adaptations which presumably allow energy resources to be shifted to processes necessary for winter survival. We compared the patterns of gene expression involved in angiogenesis in testes of white-footed mice (Peromyscus leucopus) following 7, 14, 21 or 34 weeks of long or short day lengths. Short days decreased body mass, reproductive tract mass and seminiferous tubule diameter. Potential genes involved in seasonal angiogenesis were screened by hybridizing testicular RNA from each group to angiogenesis-specific microarrays. Genes that were > or =6-fold different between long- and short-day testes (i.e. hypoxia-inducible factor 1alpha(Hif1alpha), plasminogen activator inhibitor 1 (Serpine1), transforming growth factor beta receptor 3 (Tgfbetar3) and tumour necrosis factor (Tnf )) were sequenced and expression differences were compared throughout gonadal regression and recrudescence using quantitative RT-PCR. Our results suggest that short days trigger expression of Hif1alpha, Serpine1, and Tgfbetar3 to inhibit angiogenesis or promote apoptosis during testicular regression, and also trigger expression of Tnf to promote angiogenesis during testicular recrudescence.

Animals↗
PubMed1992

Adenosine 3':5'-cyclic monophosphate inhibits in vitro angiogenesis induced by endothelial cell growth factor.

The formation of new blood capillaries (angiogenesis) occurs in response to angiogenic factors released by either normal or tumoral cells. In the present study, we cultured human umbilical vein endothelial cells (HUVEC) on collagen gels and aimed to clarify the effects of cyclic nucleotides on angiogenesis induced by endothelial cell growth factor (ECGF). HUVEC invaded the underlying collagen matrix and formed tube-like structures when ECGF was added. ECGF (9.4 to 75 micrograms/ml) induced angiogenesis in a concentration-dependent manner; the effect reached a plateau at 75 micrograms/ml. Cyclic AMP (10(-3) M), dibutyryl cyclic AMP (10(-3) M), 8-bromo cyclic AMP (10(-5) M) and Sp-cAMPS (10(-3) M), a stimulator of cyclic AMP-dependent protein kinase, each significantly inhibited ECGF-induced angiogenesis by 64.2, 86.1, 46.5, 74.7%, respectively. Forskolin and cholera toxin, which are activators of adenylate cyclase, did not inhibit ECGF-induced angiogenesis. Dibutyryl cyclic GMP (10(-4), 10(-3) M) also did not affect the formation of capillary-like tubes induced by ECGF. In conclusion, cyclic AMP, but not cyclic GMP, inhibits angiogenesis in vitro. This antiangiogenic activity may be applicable to the treatment of such conditions as solid tumors, diabetic retinopathy and rheumatoid arthritis in which the suppression of angiogenesis is important.

Capillaries↗
PubMed1999

The rationale and future potential of angiogenesis inhibitors in neoplasia.

Malignant tumours are angiogenesis-dependent diseases. Several experimental studies suggest that primary tumour growth, invasiveness and metastasis require neovascularisation. Tumour-associated angiogenesis is a complex multistep process under the control of positive and negative soluble factors. A mutual stimulation occurs between tumour and endothelial cells by paracrine mechanisms. Angiogenesis is necessary, but not sufficient, as the single event for tumour growth. There is, however, compelling evidence that acquisition of the angiogenic phenotype is a common pathway for tumour progression, and that active angiogenesis is associated with other molecular mechanisms leading to tumour progression. Experimental research suggests that it is possible to block angiogenesis by specific inhibitory agents, and that modulation of angiogenic activity is associated with tumour regression in animals with different types of neoplasia. The more promising angiosuppressive agents for clinical testing are: naturally occurring inhibitors of angiogenesis (angiostatin, endostatin, platelet factor-4 and others), specific inhibitors of endothelial cell growth (TNP-470, thalidomide, interleukin-12 and others), agents neutralising angiogenic peptides (antibodies to fibroblast growth factor or vascular endothelial growth factor, suramin and analogues, tecogalan and others) or their receptors, agents that interfere with vascular basement membrane and extracellular matrix [metalloprotease (MMP) inhibitors, angiostatic steroids and others], antiadhesion molecules antibodies such as antiintegrin alpha v beta 3, and miscellaneous drugs that modulate angiogenesis by diverse mechanisms of action. Antiangiogenic therapy is to be distinguished from vascular targeting. Gene therapy aimed to block neovascularisation is also a feasible anticancer strategy in animals bearing experimental tumours. Antiangiogenic therapy represents one of the more promising new approaches to anticancer therapy and it is already in early clinical trials. Because angiosuppressive therapy is aimed at blocking tumour growth indirectly, through modulation of neovascularisation, antiangiogenic agents need to be developed and evaluated as biological response modifiers. Therefore, adequate and well designed clinical trials should be performed for a proper evaluation of antiangiogenic agents, by determination and monitoring of surrogate markers of angiogenic activity.

Animals↗
PubMed2006

Regulation of angiogenesis by the kallikrein-kinin system.

High molecular weight kininogen (HK) is a plasma protein that is cleaved by plasma kallikrein in the clinical settings of sepsis and chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease. This proteolytic event results in a nonapeptide, bradykinin (BK), and a kinin-free derivative of HK, namely HKa. BK promotes angiogenesis by upregulation of bFGF through the B1 receptor or by stimulation of VEGF formation via the B2 receptor. Kininogen-deficient rats show diminished angiogenesis when neovascularization is stimulated. The formation of HKa results in exposure of domain 5 (D5). HKa or D5 inhibit endothelial cell migration and proliferation, both of which are needed for angiogenesis. In the chicken chorioallantoic membrane assay when neovascularization is stimulated by bFGF or VEGF, HKa or D5 inhibit angiogenesis. Monoclonal antibody C11C1, which prevents binding of HK to endothelial cells, also limits its conversion to BK thus downregulating angiogenesis. In vivo, mAb C11C1 inhibits tumor angiogenesis in mice as well as in experimental inflammatory arthritis and inflammatory bowel disease in Lewis rats. In vitro HKa or D5 inhibits endothelial cell adhesion to vitronectin and fibrinogen, resulting in anokis and apoptosis. The HKa receptor, uPAR, forms a signaling complex containing the integrin alphavbeta3 or alpha5beta1, caveolin, Src kinase Yes, focal adhesion kinase and paxcillin. HKa physically disrupts the complex by interfering with the binding of vitronectin to uPAR. Both mAb C11C1 and D5 have potential applications for controlling unwanted angiogenesis in inflammation and cancer.

Animals↗
PubMed2006

Cerebral ischemia and angiogenesis.

Angiogenesis occurs in a wide range of conditions. As ischemic tissue usually depends on collateral blood flow from newly produced vessels, acceleration of angiogenesis should be of therapeutic value to ischemic disorders. Indeed, therapeutic angiogenesis reduced tissue injury in myocardial or limb ischemia. In ischemic stroke, on the other hand, angiogenic factors often increase vascular permeability and thus may deteriorate tissue damage. In order to apply safely the therapeutic angiogenesis for ischemic stroke treatment, elucidating precise mechanism of brain angiogenesis is mandatory. In the present article, we review previous reports which investigated molecular mechanisms of angiogenesis. Endothelial cell mitogens, enzymes that degrade surrounding extracellular matrix, and molecules implicated in endothelial cells migration are induced rapidly in the ischemic brain. Their possible neuroprotective or injury exacerbating effects are discussed. Because therapeutic potential of angiogenic factors application had gained much attention, we here extensively reviewed relevant previous reports. In the future however, there is a need to consider angiogenesis in relation with regenerative medicine, as angiogenic factors sometimes possess neuron producing property.

Angiogenic Proteins↗
PubMed1999

Correlation between expression of matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) and angiogenesis in colorectal adenocarcinoma.

Matrix metalloproteinases-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), which degrade extracellular matrix, are believed to play a crucial role in tumor invasion and metastasis. Angiogenesis is also perceived as an important step in tumor growth and metastasis. To investigate the expression of MMPs and the correlation between the expression of MMPs and angiogenesis in colorectal adenocarcinoma, we studied 72 cases of colorectal adenocarcinoma in Inha University Hospital from 1996 to 1997. We evaluated the expression of MMPs by immunohistochemistry and angiogenesis by counting the microvessels. The expression of MMP-2 was increased according to the Astler-Coller stage (p< 0.05). Angiogenesis in the metastatic group was higher than that of the localized one (p<0.05). The expression of MMP-2 positively correlated with angiogenesis (p<0.05), and marked expression of MMP-9 positively correlated with angiogenesis (p<0.05). The present results suggest that the expression of MMP-2 provides clues for tumor progression and angiogenesis provides significant information to predict whether metastasis is present in colorectal adenocarcinoma.

Adenocarcinoma↗
PubMed2002

The role of vascular endothelial growth factor (VEGF) and p53 status for angiogenesis in gastric cancer.

BACKGROUND: Angiogenesis is of crucial importance for tumor growth and development of metastases. Vascular endothelial growth factor (VEGF) has a potent angiogenic activity and mutations of the p53 gene has been thought to upregulate VEGF. The purpose of our study was to evaluate the prognostic significance of these tumor biomarkers for angiogenesis relative to the information derived from established clinicopathological parameters in gastric cancer. METHODS: In this study, we conducted an immunohistochemical investigation of VEGF and p53 expression in 145 tissue samples obtained from gastric cancer patients undergoing curative surgical treatment. To evaluate angiogenesis, microvessel density (MVD) was counted by staining endothelial cells immunohistochemically using anti-CD34 monoclonal antibody. RESULTS: High MVD was significantly associated with depth of tumor invasion and distant metastasis (p = 0.004, 0.021, respectively). Moreover, overall survival for patients with high MVD were significantly lower than that of low MVD (p = 0.048). Positive expression of VEGF correlated significantly with lymph node and distant metastasis (p = 0.040, 0.048, respectively). However, no significant correlation was found between p53 expression and various clinicopathological parameters. VEGF positive tumors showed a higher MVD than VEGF negative tumors (p = 0.028). The expression of p53 did not correlate with VEGF expression. Also, the relationship between the status of p53 expression and MVD had not statistically significant differences. In the multivariate analysis, status of VEGF, p53 expression and MVD were not an independent prognostic factor. CONCLUSION: VEGF seems to be an important, clinically relevant inducer of angiogenesis and angiogenesis assessed by the MVD may be a useful marker for predicting metastasis in gastric cancer. However, further studies are warranted to clarify the impact of p53 on the angiogenesis and the prognostic significance of angiogenesis in gastric cancer.

Adult↗
PubMed1998

Relationship between vascular endothelial growth factor and angiogenesis in spontaneous and indomethacin-delayed healing of acetic acid-induced gastric ulcers in rats.

Angiogenesis is an important event for gastric ulcer healing. Vascular endothelial growth factor (VEGF) is known to be a potent stimulator of angiogenesis. This study consequently examined VEGF production, VEGF mRNA expression and angiogenesis during the spontaneous and indomethacin-delayed healing of acetic acid-induced ulcers in rats. The production of VEGF, taking place in the normal mucosa, was significantly elevated by ulceration. The mRNA expression of three isoforms of VEGF (VEGF188, VEGF164 and VEGF120) was also detected. Following the increase in VEGF production, angiogenesis was significantly promoted in the ulcer base. VEGF-immunoreactivity was observed in granulocytes, fibroblasts and regenerated epithelial cells. Indomethacin markedly inhibited prostaglandin E2 synthesis in the ulcer base, resulting in the prevention of ulcer healing. Angiogenesis was also significantly inhibited by indomethacin, but neither VEGF production nor VEGF mRNA expression was reduced. Such results suggest that VEGF might play a role in angiogenesis in the spontaneous healing of gastric ulcers in rats. However, the inhibition of angiogenesis in indomethacin-delayed ulcer healing is not explainable on VEGF expression.

Acetic Acid↗
PubMed1999

[Angiogenesis and neuropathology].

Angiogenesis is crucial for both tissue development and tissue function and is an integral part of central nervous system embryogenesis and tumor growth. Angiogenesis is extremely active during development, then remains stable during adulthood and decreases gradually during aging. Physiological processes and inflammation can transiently stimulate angiogenesis in adults. Angiogenesis is modulated by a host signaling pathways, growth factors, growth factor receptors, and membrane proteins associated with these receptors or transcription factors. In disorders affecting the central nervous systems, as in those arising elsewhere in the body, angiogenesis can become inadequate, excessive, or qualitatively abnormal (dysplasia). These abnormalities can result in cerebral trophic disorders and in secondary remodeling. A few examples are given to illustrate various types of primary angiogenesis disorders responsible for cerebral lesions and of secondary angiogenesis disorders caused by an underlying cerebral disorder.

Adult↗
PubMed1999

Cyclooxygenase inhibitors suppress angiogenesis and reduce tumor growth in vivo.

Angiogenesis plays a key role in the development of malignant tumors. To clarify the roles of cyclooxygenase (COX) in malignant tumor development and angiogenesis, we investigated the effects of COX inhibitors on two kinds of gastrointestinal cancer xenograft, one of which overexpresses COX-2 and the other expresses no COX, in nude mice in vivo. There was a positive correlation between tumor volume and angiogenesis within the xenograft. Oral administration with a specific COX-2 or a nonspecific COX inhibitors lowered the expression of potent angiogenic factors; vascular endothelial growth factor and basic fibroblast growth factor, reduced angiogenesis and growth, induced apoptosis, and suppressed cell replication of the COX-2 overexpressing cancer xenografts in a dose-dependent manner. A nonspecific COX inhibitor, not a specific COX-2 inhibitor, reduced growth and angiogenesis of non-COX expressing cancer xenograft by inhibition of COX-1 in vascular endothelial cells. These results demonstrate that COX inhibitors suppress angiogenesis and tumor growth by inhibiting expression of angiogenic factors and vascular endothelial cell growth. They support the hypothesis that COX plays an important role in cancer growth via angiogenesis. These findings offer a new strategy against cancer using COX inhibitors (nonsteroidal anti-inflammatory drugs).

Animals↗
PubMed2000

Irradiation of a primary tumor, unlike surgical removal, enhances angiogenesis suppression at a distal site: potential role of host-tumor interaction.

Changes in distal angiogenesis in response to irradiation of primary tumors are not known. To this end, PC-3, a human prostate carcinoma, and FSA-II, a murine fibrosarcoma, were grown in the gastrocnemius muscles of male nude mice. Distal angiogenesis was measured in gel containing human recombinant basic fibroblast growth factor placed in the cranial windows of these mice. PC-3-bearing mice showed inhibition of distal angiogenesis, as compared with non-tumor-bearing controls. Surgical removal of tumors tended to accelerate distal angiogenesis; in comparison, after irradiation of the PC-3 primary tumor, rates of angiogenesis in the cranial window were retarded. Irradiation of the non-tumor-bearing leg or of non-tumor-bearing animals showed no measurable effect on rate of growth of vessels in the cranial window. Similar results were found with the FSA-II tumors, with slowed distal angiogenesis in tumor-bearing animals and further suppression in animals with irradiated tumors. These results demonstrate that the effect of irradiation of a primary tumor on angiogenesis at a distal site may differ from the effect of surgical removal of the primary tumor. Unlike surgery, irradiation of a tumor may enhance angiogenic suppression at a distal site, and this difference may involve host-tumor interaction.

Analysis of Variance↗
PubMed2001

Independent association of angiogenesis index with outcome in prostate cancer.

New molecular factors have been characterized that are associated with the prognosis of prostate carcinoma patients, including p53 status and angiogenesis. We reported recently that mutant p53 (mp53) was associated with decreased expression of an endogenous inhibitor of angiogenesis, thrombospondin-1 (TSP-1), and increased microvessel density in melanoma and breast cancer. In this study, we performed a similar analysis on primary prostate carcinoma to determine whether these factors were associated with each other or patient outcomes. Paraffin-embedded specimens of 98 cases of primary prostate carcinoma were obtained and examined to confirm tissue diagnosis and Gleason scores. Carcinoma-specific levels of p53, TSP-1, and tumor angiogenesis were determined using semiquantitative immunohistochemistry (IHC) methods. Acquisition of mp53 was significantly associated with decreased TSP-1 (P = 0.002) and increased angiogenesis (P < 0.0001). An angiogenesis index integrating mp53, TSP-1, and angiogenesis (CD31) scores was found to be an independent predictor of survival in univariate and multivariate analyses that included Gleason score, clinical stage, and patient age. Further validation of the angiogenesis index in prostate carcinoma may provide a new tool to stratify patient risk.

Adenocarcinoma↗