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PubMed2003

Angiogenesis and the expression of vascular endothelial growth factors A and C in squamous cell carcinoma of the piriform fossa.

BACKGROUND: Angiogenesis is essential for tumor growth and invasion. Vascular endothelial growth factor A (VEGF-A) is a prime mediator of tumor angiogenesis; VEGF-C, another member of the closely related VEGF family of proteins, has major effects on lymphatic endothelial cells and may be important in the process of lymphatic metastasis. OBJECTIVES: To evaluate the expression of these cytokines in hypopharyngeal squamous cell carcinoma and to ascertain the effects of these proteins on lymphatic metastasis and vascular angiogenesis. DESIGN: Retrospective analysis of microvessel density and the expression of VEGF-A and VEGF-C. SETTING: An academic referral center. Subjects Thirty-four patients with stage T2 to T4 squamous cell carcinoma of the piriform fossa. INTERVENTIONS: Expression of VEGF-A and VEGF-C was determined by immunohistochemistry on formalin-fixed, paraffin-embedded biopsy specimens. Angiogenesis was measured as microvessel density by staining endothelial cells for platelet-endothelial cell adhesion molecule 1/CD31. RESULTS: Of the 34 tumors, 21 had clinicoradiologic evidence of lymphatic metastasis. Expression of VEGF-C was associated with lymphatic metastasis (P<.001), but not with microvessel density. The VEGF-A expression correlated with microvessel density (P<.001), but neither VEGF-A expression nor microvessel density was associated with lymphatic metastasis. CONCLUSIONS: The expression of VEGF-C is associated with lymphatic metastasis in squamous cell carcinoma of the piriform fossa. This is not secondary to effects on vascular angiogenesis and is hypothesized to be due to effects on lymphatic endothelial cells.

Aged↗
PubMed1996

The role of vascular endothelial growth factor in a murine chronic granulomatous tissue air pouch model of angiogenesis.

Chronic granulomatous inflammation may be considered an angiogenic-dependent process. Recently it has been demonstrated that vascular endothelial growth factor (VEGF) or vascular permeability factor is essential for tumour angiogenesis. Its role in inflammation-mediated angiogenesis has yet to be determined. In this study, the murine chronic granulomatous air pouch model was used to investigate the role of VEGF in angiogenesis. Animals were treated twice weekly with 10 micrograms per animal of neutralizing antibody to rh VEGF and the vascularity and granuloma dry weight were assessed after 7 days. This resulted in significant suppression of both angiogenesis and granuloma dry weight. Western blot analysis demonstrated the presence of VEGF; the levels of protein paralleled the angiogenic response. These results demonstrate for the first time that VEGF may be an important regulator of angiogenesis in inflammation.

Air↗
PubMed1999

Thrombospondin-1 inhibits Kaposi's sarcoma (KS) cell and HIV-1 Tat-induced angiogenesis and is poorly expressed in KS lesions.

Kaposi's sarcoma (KS), a neoplasm often associated with iatrogenic and acquired immunosuppression, is characterized by prominent angiogenesis. Angiogenic factors released by both KS and host cells, as well as HHV-8 and HIV viral products, have been implicated in the pathogenesis of this lesion. Angiogenesis is the result of imbalance among angiogenesis promoters and inhibitors, which disrupts homeostasis. The aim of this study was to investigate the expression and mechanism of KS control of thrombospondin-1 (TSP), a physiological inhibitor of angiogenesis. Immunohistochemical analysis of four KS lesions showed only spotty reactivity for TSP in the stroma and in less than 10 per cent of lesional blood vessels. In addition, the typical KS spindle cells were not stained. In agreement with these findings, decreased levels of TSP were measured with an ELISA assay in the supernatants of cultured KS cells, compared with endothelial cells. In vitro, TSP inhibited the endothelial cell proliferation and motility induced by KS cell supernatants. TSP also prevented endothelial cell motility induced by Tat, a product of HIV-1 endowed with angiogenic potential and implicated in the pathogenesis of AIDS-KS. In vivo, TSP inhibited the angiogenic activity exerted by Tat in the Matrigel sponge model. These results suggest that TSP down-regulation might be permissive for the development of KS-associated angiogenesis.

Animals↗
PubMed2000

Tumor angiogenesis is associated with progression after radical prostatectomy in pT2/pT3 prostate cancer.

BACKGROUND: The clinical relevance of tumor angiogenesis has been investigated in several human tumor types. Angiogenesis (measured as microvessel density; MVD) was recently correlated with tumor stage, grade, and clinical course in prostate cancer (PC). However, considerable controversy remains concerning the prognostic value of angiogenesis in PC. METHODS: We examined MVD in primary PCs to further establish the prognostic relevance of angiogenesis in this tumor entity. In 98 paraffin-embedded PCs of various stages, 5 prostate adenomas, and 20 normal prostate tissues, MVD was determined immunohistochemically using a polyclonal antibody against factor VIII. The findings were correlated with the clinical data of the patients. RESULTS: Normal prostate tissue and prostate adenomas had a low MVD. In PC, MVD increased significantly with tumor stage and grade (P < 0.001). The Wilcoxon rank statistics showed significant differences for MVD (P < 0.0001), tumor stage (P < 0. 0027), and grade (P < 0.0001), but not for preoperative prostate-specific antigen values in PC patients with and without tumor progression subsequent to treatment, respectively. Importantly, multivariate survival analysis revealed that MVD and tumor grade were the only independent markers for progression in prostate carcinoma. CONCLUSIONS: In this study, tumor angiogenesis measured by MVD was associated with a dismal pathologic appearance and a negative clinical prognosis in PC after radical prostatectomy.

Blood Vessels↗
PubMed1998

Tumor angiogenesis, hepatocyte growth factor, and c-Met expression in endometrial carcinoma.

BACKGROUND: This study was designed to evaluate the significance of tumor angiogenesis and angiogenic factors such as hepatocyte growth factor (HGF) and c-Met in determining the prognoses of 93 patients with endometrial carcinoma. METHODS: By immunohistochemical staining, this retrospective study investigated tumor angiogenesis, HGF expression, and c-Met expression, using one tissue slide that was representative of the invasive edge of the tumor. To evaluate tumor angiogenesis, the microvessels within the primary endometrial carcinoma were highlighted by staining their endothelial cells immunohistochemically for von Willebrand factor (VWF). The microvessels were then counted in the most intense areas of neovascularization. HGF and c-Met were identified with specific antibodies. Tumor angiogenesis, HGF expression, and c-Met expression were correlated with both the prognostic variables for and the survival of endometrial carcinoma. RESULTS: A high microvessel count (> or = 110 in a 0.90 mm2 area) was significantly correlated with surgical Stage III and IV, histologic Grade 3, positive lymph node involvement, and shorter patient survival. Expression of c-Met was significantly correlated with surgical Stage III and IV, histologic Grade 3, and shorter survival. HGF expression was significantly correlated with surgical Stage III and IV by semiquantitative analysis. Multivariate analysis showed that surgical Stage III and IV, histologic Grade 3, the score for myometrial invasion > 1/2, and a high microvessel count were independent indicators of the prognoses of patients with endometrial carcinoma. CONCLUSIONS: Both tumor angiogenesis, measured by the microvessel count, and c-Met expression were significant prognostic indicators for patients with endometrial carcinoma.

Adenocarcinoma↗
PubMed1999

Vascularity index as a novel parameter for the in vivo assessment of angiogenesis in patients with cervical carcinoma.

BACKGROUND: The importance of angiogenesis now is well recognized. Conventionally, tumor angiogenesis is assessed by determination of microvessel density (MVD) in the surgical specimen. This study examines tumor angiogenesis using power Doppler ultrasound and a quantitative image processing system. The authors hope to develop an in vivo and noninvasive method for quantitating tumor angiogenesis. METHODS: Thirty-five patients with FIGO Stage IB-IIA cervical carcinoma exhibiting visible cervical tumors by transvaginal ultrasound were included in this study. All patients underwent radical abdominal hysterectomy and pelvic lymph node dissection. Transvaginal power Doppler ultrasound was performed before surgery to search for blood flow signals from the tumor. The intratumoral vascularity index (VI) and resistance index (RI) were calculated. The VI was defined as the number of colored pixels divided by the number of total pixels in the defined tumor section. Maximal VI and minimal RI of a certain tumor were used for analysis. Clinical and pathologic data also were recorded. The MVD of the excised tumor was assessed immunohistochemically using a monoclonal antibody against CD34. RESULTS: Significantly higher VI values were noted in Stage II tumors compared with Stage 1 tumors (19.01+/-10.90% vs. 9.09+/-6.59%; P = 0.008), tumors invad-ing+/-50% of the cervical stroma compared with tumors invading < 50% of the cervical stroma (13.20+/-8.20% vs. 5.72+/-5.00%; P = 0.003), tumors with lymphovascular emboli compared with tumors without lymphovascular emboli (17.28+/-8.26% vs. 6.98 +/- 5.09%; P = 0.001), and tumors with pelvic lymph node metastases compared with tumors without pelvic lymph node metastases (26.16+/-7.88% vs. 8.00+/-4.95%; P = 0.021). None of the variables mentioned earlier showed a significant difference in terms of the RI values. No correlation was noted between intratumoral RI and VI in respective tumors (P = 0.53). Analysis of VI revealed linear regression with regard to tumor size (P < 0.001, correlation coefficient [r] = 0.586) and depth of stromal invasion (P = 0.002, r = 0.497). In addition, the MVD exhibited a linear relation with VI (P = 0.006, r = 0.454), tumor size (P = 0.005, r = 0.465), and depth of stromal invasion (P = 0.009, r = 0.436) using simple regression analysis. No correlation could be found between MVD and RI. CONCLUSIONS: In cervical carcinoma, intratumoral VI assessment by power Doppler ultrasound and quantitative image processing system showed better correlation with tumor stage, tumor size, and pathologic findings including depth of stromal invasion, lymphovascular emboli, and pelvic lymph node metastases than intratumoral RI. The in vivo indicator of angiogenic activity (VI) is well correlated with the conventional indicator of tumor angiogenic activity (MVD). Thus, VI could be a useful parameter for the in vivo assessment of global tumor angiogenesis.

Adenocarcinoma↗
PubMed1996

Evidence of involvement of CD44 in endothelial cell proliferation, migration and angiogenesis in vitro.

Angiogenesis is essential for tumor growth and metastasis. In the process of angiogenesis, the interaction between adhesive proteins of endothelial cells and extracellular matrix components plays an important role by mediating cell attachment, which is indispensable for their motility, and by transmitting the regulatory signals for cell locomotion and proliferation. In this study, we examined the hypothesis that CD44 expressed on the endothelial cell surface is involved in the angiogenesis process. The experiments using calf pulmonary artery endothelial cells (CPAE) and a human microvascular endothelial cell line (HMEC-1) show that a monoclonal antibody against CD44 (clone J 173) inhibits endothelial cell proliferation by about 30% and migration by 25-50%, and abolishes the stimulating effect of hyaluronan polysaccharides on endothelial cell migration and proliferation. This antibody also suppresses the capillary formation of CPAE in an in vitro model of angiogenesis using fibrin matrix. These results provide evidence of the involvement of endothelial-cell-associated CD44 in angiogenesis.

Animals↗
PubMed1999

Angiogenesis inhibitors overcome tumor induced endothelial cell anergy.

We report here that tumor angiogenesis-mediated endothelial cell (EC) anergy can be overcome by inhibitors of angiogenesis. We found previously that tumor growth, known to be dependent on angiogenesis, results in down-regulation of endothelial adhesion molecules and tumor EC anergy to inflammatory signals. We hypothesized that counteracting angiogenesis induces re-expression of adhesion molecules and normalizes responses to inflammatory cytokines. Here, we present data to show that the angiogenesis inhibitor platelet factor-4 (PF4) is able to prevent basic fibroblast growth factor (bFGF)-induced down-regulation of intercellular adhesion molecule-1 (ICAM-1). Furthermore, PF4 restores ICAM-1 expression following bFGF-induced down-regulation of ICAM-1. This PF4 effect occurs at the protein level and the RNA level and it has functional impact on leukocyte adhesion. In addition, PF4 overcomes the tumor-induced EC anergy to inflammatory signals such as tumor necrosis factor alpha (TNF alpha). Our findings may be the basis of new cancer therapies by combining anti-angiogenic therapy and immunotherapy to decrease blood vessel formation and to increase the effectiveness of inflammatory reactions against tumors.

Animals↗
PubMedDate not supplied

Tumor angiogenesis in T1 oral cavity squamous cell carcinoma: role in predicting tumor aggressiveness.

BACKGROUND: Angiogenesis is necessary for tumor growth and metastasis. In breast and other cancers angiogenesis has been shown to correlate with tumor size, metastatic potential, and prognosis. Some studies of head and neck cancer have shown a similar correlation, although results are inconclusive. This study was performed to determine whether tumor angiogenesis can be used as a prognostic indicator for early oral cancers. METHODS: CD-31 immunostaining, the technique of choice for determining microvessel density, was utilized to investigate T1 squamous cell carcinomas of the ventral tongue and floor of the mouth. RESULTS: Adequate staining was achieved in 19 tumors. Seven tumors were deemed aggressive due to either the development of metastases or recurrence. The mean microvessel density in the aggressive patients was 43.1/hpf (range 15--79) and in the nonaggressive patients was 38.6/hpf (range 17--78). Statistical analysis failed to reveal any correlation between tumor aggressiveness and tumor angiogenesis in these early tumors. CONCLUSIONS: Tumor angiogenesis failed to predict tumor aggressiveness in T1 oral cavity carcinoma; however, low levels of neoangiogenesis were seen in all cases. For this reason this technique may prove more valuable in more advanced cancers.

Adult↗
PubMed1997

Tumor angiogenesis as a prognostic indicator in T2-T4 oral cavity squamous cell carcinoma: a clinical-pathologic correlation.

BACKGROUND: Tumor angiogenesis has been shown to correlate with tumor size, metastatic potential, and prognosis in breast and other cancers. Studies in head and neck cancer have suggested a similar correlation, but results have been inconclusive. This study was performed to determine the correlation between angiogenesis and oral tumor behavior. METHODS: Tumor angiogenesis was evaluated in 31 T2-T4 primary oral cavity squamous cell carcinomas by quantitating the microvessel density with two different anti-endothelial cell antigens, factor VIII antigen (FVIIIAg) and CD-31. The stains were compared to assess whether these antigens yielded complimentary results. The microvessel densities were correlated with T stage and N stage and patient survival. RESULTS: FVIIIAg and CD-31 staining yielded consistent microvessel densities, but FVIIIAg was generally more uniform and easier to interpret. Increasing microvessel density was seen with increasing T stage and N stage; however, there was considerable overlap and no correlation with survival. CONCLUSIONS: These results suggest that oral tumors are less angiogenesis dependent than tumors in other sites. Tumor angiogenesis, as currently measured, is not of value in predicting tumor aggressiveness in patients with oral cavity carcinoma.

Biomarkers, Tumor↗
PubMed1996

Ets-1 regulates angiogenesis by inducing the expression of urokinase-type plasminogen activator and matrix metalloproteinase-1 and the migration of vascular endothelial cells.

The coordinate induction of protease activities and cell migration is a principal feature of endothelial cells (ECs) invading the interstitial space in the initial step of angiogenesis. However, the molecular mechanisms of these events are not fully characterized. Ets-1 is a member of the ets gene family of transcription factors, which binds to the Ets binding motif in the cis-acting elements and regulates the expression of certain genes. Four typical angiogenic growth factors, aFGF, bFGF, VEGF, and EGF, induced the expression of ets-1 mRNA in either human umbilical vein endothelial cells (HUVECs), ECV-304 cells (immortalized HUVECs), or human omental microvascular endothelial cells (HOMECs). The expression of ets-1 reached its maximum at 2 hr after factor addition and then decreased to the basal level by 12 hr. For characterization of the role of Ets-1 in angiogenesis, ets-1 antisense and sense oligodeoxynucleotides (ODNs) were constructed. The ets-1 antisense ODN but not sense ODN efficiently blocked the synthesis of Ets-1 protein by human ECs in response to angiogenic growth factors. Moreover, the ets-1 antisense ODN but not sense ODN almost completely abolished the binding of endothelial cell extract to DNA containing the Ets binding motif. The expression of urokinase-type plasminogen activator and matrix metalloproteinase-1 and the migration of ECs in response to growth factors were significantly inhibited by ets-1 antisense ODN but not by sense ODN. Tube formation by HOMECs in type 1 collagen gel stimulated with EGF was abrogated by ets-1 antisense ODN. Finally, the expression of Ets-1 protein in ECs during angiogenesis in vivo was confirmed by an immunohistochemical analysis using a murine angiogenesis model. These results indicate that the induction of ets-1 mRNA is a mutual phenomenon in ECs stimulated with angiogenic growth factors. Ets-1 appears to play an important role in angiogenesis, regulating the expression of proteases and the migration of ECs.

Animals↗
PubMed2003

Inflammation and angiogenesis in osteoarthritis.

OBJECTIVE: To quantify the relationship between inflammation and angiogenesis in synovial tissue from patients with osteoarthritis (OA). METHODS: Hematoxylin and eosin staining and histologic grading for inflammation were performed for 104 patients who met the American College of Rheumatology criteria for OA and had undergone total joint replacement or arthroscopy. A purposive sample of synovial specimens obtained from 70 patients was used for further analysis. Vascular endothelium, endothelial cell (EC) proliferating nuclei, macrophages, and vascular endothelial growth factor (VEGF) were detected by immunohistochemical analysis. Angiogenesis (EC proliferation, EC fractional area), macrophage fractional area, and VEGF immunoreactivity were measured using computer-assisted image analysis. Double immunofluorescence histochemical analysis was used to determine the cellular localization of VEGF. Radiographic scores for joint space narrowing and osteophyte formation in the knee were also assessed. RESULTS: Synovial tissue samples from 32 (31%) of 104 patients with OA showed severe inflammation; thickened intimal lining and associated lymphoid aggregates were often observed. The EC fractional area, EC proliferation, and VEGF immunoreactivity all increased with increasing histologic inflammation grade and increasing macrophage fractional area. In the synovial intimal lining, VEGF immunoreactivity was localized to macrophages and increased with increasing EC fractional area and angiogenesis. No inflammation or angiogenic indices were significantly correlated with radiographic scores. CONCLUSION: Inflammation and angiogenesis in the synovium are associated with OA. The angiogenic growth factor VEGF generated by the inflamed synovium may promote angiogenesis, thereby contributing to inflammation in OA.

Aged↗
PubMed2002

Osteopontin induces angiogenesis of murine neuroblastoma cells in mice.

Angiogenesis is an essential process for tumor growth and is regulated by tumor-derived angiogenic cytokines. Osteopontin (OPN) is one of the cytokines produced by various tumor cells and is suggested to be involved in angiogenesis by upregulating endothelial cell migration in cooperation with vascular endothelial cell growth factor (VEGF). To provide evidence of OPN involvement in a causal role in tumor angiogenesis, we generated a stable transfectant from murine neuroblastoma C1300 cells to constitutively secrete high levels of murine OPN. The OPN mRNA expression and protein secretion were confirmed by RT-PCR and ELISA, respectively. The biological activity of secreted OPN was determined with migration assay by using human umbilical vein endothelial cells (HUVEC). Transfection with OPN gene did not increase VEGF production and did not affect gene expression of other angiogenic factors confirmed by complementary DNA macroarray system. To demonstrate the effect of OPN on tumor-induced angiogenesis in vivo, millipore chambers containing OPN-transfected or control cells were implanted to the dorsal air sac of mice. The OPN-transfected cells significantly induced neovascularization in comparison to the control cells in mice. Conclusively, these results provide direct evidence of OPN involvement in the role of tumor angiogenesis.

Animals↗
PubMed2001

The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells.

Angiogenesis is now recognized as a crucial process in tumor development, including hepatocellular carcinoma (HCC). Since HCC is known as a hypervascular tumor, anti-angiogenesis is a promising approach to inhibit the HCC development. Trientine dihydrochloride (trientine) is used in clinical practice as an alternative copper (Cu)-chelating agent for patients with Wilson's disease of penicillamine intolerance. In our study, we examined the effect of Cu-chelating agents on tumor development and angiogenesis in the murine HCC xenograft model. Although both trientine and penicillamine in the drinking water suppressed the tumor development, trientine exerted a more potent inhibitory effect than penicillamine. In combination with a Cu-deficient diet, both trientine and penicillamine almost abolished the HCC development. Trientine treatment resulted in a marked suppression of neovascularization and increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. In vitro studies also exhibited that trientine is not cytotoxic for the tumor cells. On the other hand, it significantly suppressed the endothelial cell proliferation. These results suggested that Cu plays a pivotal role in tumor development and angiogenesis in the murine HCC cells, and Cu-chelators, especially trientine, could inhibit angiogenesis and enhance apoptosis in the tumor with consequent suppression of the tumor growth in vivo. Since trientine is already used in clinical practice without any serious side effects as compared to penicillamine, it may be an effective new strategy for future HCC therapy.

Animals↗
PubMed2004

Irradiated C6 glioma cells induce angiogenesis in vivo and activate endothelial cells in vitro.

Malignant gliomas are angiogenesis dependent and present a remarkable degree of resistance to radiotherapy. In the present work, we studied the effect of irradiation of C6 glioma cells on their proliferation and activation in vitro and on glioma cell-induced angiogenesis in vivo and in vitro. Irradiation of C6 glioma cells decreased cell proliferation in a dose-dependent manner. Interestingly, metalloproteinase-2 and -9 expression and secretion, as well as integrin alpha(v) expression, increased with elevated doses of X rays 48 hr after irradiation and was mostly evident at the higher doses used. When pre-irradiated C6 cells were implanted on nonirradiated chicken embryo chorioallantoic membranes (CAMs), there was a significant dose-dependent increase in tumor induced angiogenesis, compared to angiogenesis induced by nonirradiated cells. Similar results were obtained when C6 cells were irradiated 48 hr after their inoculation onto nonirradiated CAMs. In the same line, conditioned medium from irradiated C6 cells significantly increased endothelial cell proliferation and migration in vitro, in a manner dependent on the dose of X rays. These results explain at least in part the low effectiveness of radiation therapy of malignant gliomas and support the notion that inhibition of angiogenesis in parallel with radiotherapy may represent a new therapeutic approach.

Allantois↗
PubMed2006

Tumor shedding of laminin binding protein modulates angiostatin production in vitro and interferes with plasmin-derived inhibition of angiogenesis in aortic ring cultures.

The growth of solid tumors is largely controlled by the process of angiogenesis. A 67 kDa protein, the laminin binding protein (LBP), is shed from malignant cells in significant amounts and binds to laminin-1 (Starkey et al., Cytometry 1999;35:37-47; Karpatová et al., J Cell Biochem 1996;60:226-34). However, the functions of shed LBP are not fully understood. We hypothesize that matrix-bound LBP could modulate local tumor angiogenesis. In support of this hypothesis, we demonstrate that shed LBP exhibits sulfhydryl oxidase-like activities, and modifies the production of angiostatins from plasmin in vitro. The molecular weights of the autocatalytic products of lys-plasmin incubated with LBP in vitro suggest that PMDs (plasmin A chains attached to degraded B chains) (Ohyama et al., Eur J Biochem 2004;271:809-20) are preferentially generated. Using rat aortic ring assays, we also show that shed LBP reverses plasmin-dependent inhibition of vascular outgrowth. To elucidate which LBP region(s) are active in modulating angiogenesis, limited proteolysis experiments were conducted to determine stable rLBP domains likely to fold correctly, and these were cloned, expressed and purified. The stable LBP fragments were tested for binding to laminin-1 and for competition with shed LBP activity in the aortic ring assay. Results of these studies suggest that the active LBP domains lie within the 137-230 amino acid sequence, a region known to contain 2 bioactive sequences. Since this fragment binds to laminin-1 and modulates angiogenesis, it appears likely that binding of shed LBP to matrix laminin-1 is related to its functions in tumor angiogenesis. The findings presented in this manuscript suggest that LBP shedding could provide a useful therapeutic target.

Animals↗
PubMed2007

The effects of aging on tumor growth and angiogenesis are tumor-cell dependent.

It is generally accepted that histologically similar tumors grow more slowly, with less angiogenesis, in aged mice relative to young mice. We subcutaneously implanted TRAMP-C2 tumor cells, a prostate cancer cell line not previously examined in aging, into syngeneic C57/Bl6 young (4 month) and aged (20 month) mice and compared tumor growth and angiogenesis. Unexpectedly, the prostate tumors grew as fast in aged as in young mice. Angiogenesis in TRAMP-C2 tumors was robust, with no differences between the young and aged mice in the number of vessels, distribution of vessel sizes or features of vessel maturation. Aged mice had lower levels of serum testosterone than the young mice. VEGF levels were similar in the tumors and sera of the young and aged mice. Comparison with B16/F10 melanoma, a cancer cell line that is representative of previous studies in aged mice, showed that B16/F10 tumors grew minimally in the aged mice. In contrast to the B16/F10, TRAMP-C2 tumors had an extracellular matrix with significantly higher levels of MMP2 and MMP9 expression and activity. These unique results demonstrate that tumor progression can be as robust in aged tissues as young tissues. The ability of aged mice to grow large, vascularized prostate tumors is associated with high levels of MMP2/9 activity that may produce a permissive environment for tumor growth and angiogenesis. These data demonstrate that tumor-cell specific features determine the effect of aging on tumor growth and angiogenesis.

Aging↗
PubMed1998

Regulating angiogenesis: a new therapeutic strategy.

Angiogenesis is the proliferation of endothelial and smooth muscle cells to form new blood vessels. Largely muted after adolescence, angiogenesis may be reignited by cancerous cells. Neoangiogenesis plays a primary role in tumor growth and metastases. Antiangiogenic therapy to limit and even reverse the growth of tumors are under investigation and showing promise. A derivative of fumagillin, TNP 470, is the first angiogenesis inhibitor to be given to humans. Surprisingly, several potent inhibitors are derived from tumors themselves. Researchers nowc recognize that stimulation of angiogenesis may have a place in the treatment of cardiovascular disease. Reestablishing blood flow to ischemic tissue through angiogenesis may provide a biologic "bypass" for patients with ischemic heart disease. The same applies to the treatment of peripheral vascular disease.

Angiostatins↗