Effects Of Antiangiogenic Drugs Research Articles

Classical VEGF, Notch and Ang signalling in cancer angiogenesis, alternative approaches and future directions (Review).

Angiogenesis is the formation of new vessels starting from pre-existing vasculature. Tumour environment is characterized by ‘aberrant angiogenesis’, whose main features are tortuous and permeable blood vessels, heterogeneous both in their structure and in efficiency of perfusion and very different from normal vessels. Therapeutic strategies targeting the three pathways chiefly involved in tumour angiogenesis, VEGF, Notch and Ang signalling, have been identified to block the vascular supply to the tumour. However, phenomena of toxicity, development of primary and secondary resistance and hypoxia significantly blunted the effects of anti-angiogenic drugs in several tumour types. Thus, different strategies aimed to overcome these problems are imperative. The focus of the present review was some principal ‘alternative’ approaches to classic antiangiogenic therapies, including the cyclooxygenase-2 (COX-2) blockade, the use of oligonucleotide complementary to the miRNA to compete with the mRNA target (antimiRs) and the inhibition of matrix metalloproteinases (MMPs). The role of blood soluble VEGFA as a predictive biomarker during antiangiogenic therapy in gastric, ovarian and colorectal cancer was also examined.

Development of a 3D angiogenesis model to study tumour \u2013 endothelial cell interactions and the effects of anti-angiogenic drugs

The tumour microenvironment and tumour angiogenesis play a critical role in the development and therapy of many cancers, but in vitro models reflecting these circumstances are rare. In this study, we describe the development of a novel tri-culture model, using non-small cell lung cancer (NSCLC) cell lines (A549 and Colo699) in combination with a fibroblast cell line (SV 80) and two different endothelial cell lines in a hanging drop technology. Endothelial cells aggregated either in small colonies in Colo699 containing microtissues or in tube like structures mainly in the stromal compartment of microtissues containing A549. An up-regulation of hypoxia and vimentin, ASMA and a downregulation of E-cadherin were observed in co- and tri-cultures compared to monocultures. Furthermore, a morphological alteration of A549 tumour cells resembling “signet ring cells” was observed in tri-cultures. The secretion of proangiogenic growth factors like vascular endothelial growth factor (VEGF) was measured in supernatants. Inhibition of these proangiogenic factors by using antiangiogenic drugs (bevacizumab and nindetanib) led to a significant decrease in migration of endothelial cells into microtissues. We demonstrate that our method is a promising tool for the generation of multicellular tumour microtissues and reflects in vivo conditions closer than 2D cell culture.

Targeting neurokinin-3 receptor: a novel anti-angiogenesis strategy for cancer treatment.

Angiogenesis is essential for tumor growth and metastasis, controlling angiogenesis is a promising strategy in cancer treatment. However, thus farther severe side effects of anti-angiogenic drugs have been rather demonstrated, stimulating interest in seeking novel targets of anti-angiogenesis. Neurokinin receptors, also known as tachykinin receptors, are usually considered as drug targets due to diverse physiological functions and their tractability. Although Neurokinin B, the selective natural agonist of neurokinin-3 receptor, have been shown to exhibit anti-angiogenesis activity, the effect and mechanism of neurokinin-3 receptor-mediated angiogenesis still remains unclear. In the present study, we demonstrated that [Mephe7]NKB, an analogue of NKB, possess significant anti-angiogenic effect on CAM. Furthermore, by introducing the tumor angiogenesis homing sequence (NGR), we designed and synthesized two novel agonist analogues of NK3R, NK3R-A1 and NK3R-A2. Both of the two analogues exhibit more efficient anti-migration effect on HUVECs by activating NK3R in vitro, and showed potent antitumor activities with no significant side effects in vivo. Taken together, our results illuminated that NK3R might be a potential novel target for the anti-angiogenesis therapy. Notably, NK3R-A1 might be used as a template for the development of the anti-tumor drugs on the basis of the anti-angiogenesis strategy.

P09.27 Effectiveness of antiangiogenic drugs (ADs) in glioblastoma (GBM) patients (PTS): a metanalysis of randomized clinical trials (RCTs)

Background: GBMs are highly vascularized tumors and various ADs have been investigated in clinical trials showing unclear results. We performed this metanalysis to evaluate the effectiveness of ADs, in terms of progression-free survival (PFS) and overall survival (OS), as first or second-line therapy and their association with chemotherapy in GBM PTS. Methods: the authors searched relevant published and unpublished RCTs analyzing ADs versus chemotherapy in GBM PTS from 2000 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases. Results: sixteen RCTs (9 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) were identified including 4566 PTS. All trials showed no improvement in OS with a pooled HR of 1.02 (95% CI 0.93-1.1; p = 0.7). The use of bevacizumab (BEV) did not improve OS; indeed, the pooled HR for OS for BEV studies (9 studies, 2752 PTS) was 0.98 (95% CI 0.89-1.08; p = 0.7); 6 RCTs (2084 PTS) analyzed BEV as first-line and the pooled HR for OS was 1.02 (95% CI 0.88-1.19; p = 0.8); 3 RCTs studied BEV as second-line therapy and the pooled HR for OS was 0.95 (95% CI 0.77-1.17; p = 0.6). No improvement of OS was shown when BEV was associated with chemotherapy (2588 PTS) with a pooled HR of 0.99 (95% CI 0.88-1.11; p = 0.8). Seven RCTs with a different AD demonstrating no improvement of OS versus standard treatment with a pooled HR of 1.05 (95% CI 0.89-1.23; p = 0.5). 14 RCTs (4349 PTS) were analyzed for PFS and the use of ADs showed a statistically longer PFS with a pooled HR of 0.73 (95% CI 0.62-0.86;p < 0.01); However, among ADs, only bevacizumab (2752 PTS) demonstrated an improvement of PFS; indeed, the pooled HR for PFS for BEV studies was significant at HR = 0.6 (95% CI 0.5-0.7; p < 0.01), both alone (HR = 0.6; CI 95% 0.44-0.82; p < 0.01) or in combination to CT (HR = 0.6; 95% CI 0.4-0.7;p < 0.01), both as first-line treatment (HR = 0.65; 95% CI 0.52-0.83; p < 0.01) or in recurrent disease (HR = 0.51; 95% CI 0.43-0.61; p < 0.01). Conclusions: ADs did not improve OS in GBM PTS, both as first or second-line treatment. Among ADs, only BEV demonstrated a PFS benefit both as single agent or in combination with chemotherapy, both as first or second-line treatment.

Protracted Inhibition of Vascular Endothelial Growth Factor Signaling Improves Survival in Metastatic Colorectal Cancer: A Systematic Review.

Clinical data suggest that beyond-progression, the blockade of angiogenesis is associated with improved survivals in colorectal cancer. We conducted a systematic review to investigate the therapeutic effects of antiangiogenic drugs administered as later lines of treatment in patients already progressed to a previous anti-VEGF based treatment. An extensive literature search was conducted. Hazard ratios (HR) for progression (PFS) and death (OS) were extracted. An inverse-variance meta-analysis model was implemented. 6 randomized controlled trials were retrieved, including 3407 patients, treated with different antiangiogenic drugs. All of them had progressed during or after a previous line of treatment with bevacizumab. Overall, both PFS (HR=0.63, P <0.001) and OS (HR=0.81, P < 0.001) were significantly increased with the use of antiangiogenic drug. No heterogeneity was observed despite different drugs. Protracted inhibition of the VEGF pathway is associated with a significant improvement of both PFS and OS, independently from the antiangiogenic agent used.

Expression profiles of angiogenesis in two high grade chondrosarcomas: A xenotransplant experience in nude mice.

Chondrosarcomas (Chs) are malignant cartilage-forming tumors that represent the third most common malignant solid tumor of bone in adults. Angiogenesis is a major factor for tumor growth and metastasis. Our aim was to make a histological, immunohistochemical, ultrastructural and molecular characterization of the neovascularization established between xenotransplanted Chs and the host during the initial phases of growth in nude transfer, in order to find potential markers for distinguishing between high grades II and III Chs. two xenotransplanted high grade human Chs were evaluated. Tumor pieces were implanted subcutaneously on the backs of 14 athymic Balb-c nude mice. The animals were sacrificed 24, 48, and 96 hours; and 7, 14, 21 and 28 days after implantation. Two grade I Chs were also transferred in nude but did not grow. Morphological differences were apparent between these two Chs during the early stages of neoplastic growth. Immunohistochemistry demonstrated overexpression of pro-angiogenic factors 24h-48h after tumor implantation. Additionally, neoplastic cells co-expressed chemokines (CXCL9, CXCL10 and GRO) and their receptors. Molecular studies showed two expression profiles, revealing an early and a late phase in the angiogenic process. High grade Chs demonstrated two different stages of induced angiogenesis, with an intimate association between structural and molecular events that might explain the different aggressive biological behavior of grade II and III Chs. The present model may be useful for testing the effect of anti-angiogenic drugs.

Effectiveness of antiangiogenic drugs in glioblastoma patients: A systematic review and meta-analysis of randomized clinical trials.

glioblastomas are highly vascularized tumors and various antiangiogenic drugs have been investigated in clinical trials showing unclear results. We performed a systematic review and a meta-analysis to clarify and evaluate their effectiveness in glioblastoma patients. we searched relevant published and unpublished randomized clinical trials analyzing antiangiogenic drugs versus chemotherapy in glioblastoma patients from January 2006 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases. fourteen randomized clinical trials were identified (7 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) including 4330 patients. Antiangiogenic drugs showed no improvement in overall survival with a pooled HR of 1.00, a trend for an inferior outcome, in terms of overall survival, was observed in the group of patients receiving antiangiogenic drug alone compared to cytotoxic drug alone (HR=1.24, p=0.056). Bevacizumab did not improve overall survival. Twelve trials (4113 patients) were analyzed for progression-free survival. Among antiangiogenic drugs, only bevacizumab demonstrated an improvement of progression-free survival (HR=0.63, p<0.001), both alone (HR=0.60, p=0.003) or in combination to chemotherapy (HR=0.63; p<0.001), both as first-line treatment (HR=0.70, p<0.001) or in recurrent disease (HR=0.52, p<0.001). antiangiogenic drugs did not improve overall survival in glioblastoma patients, either as first or second-line treatment, and either as single agent or in combination with chemotherapy. Among antiangiogenic drugs, only bevacizumab improved progression-free survival regardless of treatment line, both as single agent or in combination with chemotherapy.

The effect of anti-angiogenic drugs on regulatory T cells in the tumor microenvironment.

A benefit of anti-angiogenic drugs is improved tumor immune tolerance. Regulatory T cells (Tregs) in the tumor microenvironment mediate tumor immune tolerance and anti-angiogenic drugs not only indirectly affect Tregs via dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) but they can also act directly on Tregs causing immunosuppression. Specifically, these drugs may induce differentiation and chemotaxis and reduce the number and function of Tregs by targeting vascular endothelial growth factor receptor 2 (VEGFR-2) and neuropilin-1 (NRP-1) on the cell surface. Recently, anti-angiogenic drugs have been documented to promote a new way of thinking about tumor immunotherapy: clinical application of Tregs and related immunosuppressive molecules may be promising targets for synergistic tumor immunotherapy.

328PD - Effectiveness of antiangiogenic drugs (ADs) in glioblastoma (GBM) patients (PTS): a metanalysis of randomized clinical trials (RCTs)

GBMs are highly vascularized tumors and various ADs have been investigated in clinical trials showing unclear results. We performed this metanalysis to evaluate the effectiveness of ADs, in terms of progression-free survival (PFS) and overall survival (OS), as first or second-line therapy and their association with chemotherapy in GBM PTS. The authors searched relevant published and unpublished RCTs analyzing ADs versus chemotherapy in GBM PTS from 2000 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases. Sixteen RCTs (9 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) were identified including 4566 PTS. All trials showed no improvement in OS with a pooled HR of 1.02 (95% CI 0.93-1.1; p = 0.7). The use of bevacizumab (BEV) did not improve OS; indeed, the pooled HR for OS for BEV studies (9 studies, 2752 PTS) was 0.98 (95% CI 0.89-1.08; p = 0.7); 6 RCTs (2084 PTS) analyzed BEV as first-line and the pooled HR for OS was 1.02 (95% CI 0.88-1.19; p = 0.8); 3 RCTs studied BEV as second-line therapy and the pooled HR for OS was 0.95 (95% CI 0.77-1.17; p = 0.6). No improvement of OS was shown when BEV was associated with chemotherapy (2588 PTS) with a pooled HR of 0.99 (95% CI 0.88-1.11; p = 0.8). Seven RCTs with a different AD demonstrating no improvement of OS versus standard treatment with a pooled HR of 1.05 (95% CI 0.89-1.23; p = 0.5). 14 RCTs (4349 PTS) were analyzed for PFS and the use of ADs showed a statistically longer PFS with a pooled HR of 0.73 (95% CI 0.62-0.86;p < 0.01); However, among ADs, only bevacizumab (2752 PTS) demonstrated an improvement of PFS; indeed, the pooled HR for PFS for BEV studies was significant at HR = 0.6 (95% CI 0.5-0.7; p < 0.01), both alone (HR = 0.6; CI 95% 0.44-0.82; p < 0.01) or in combination to CT (HR = 0.6; 95% CI 0.4-0.7;p < 0.01), both as first-line treatment (HR = 0.65; 95% CI 0.52-0.83; p < 0.01) or in recurrent disease (HR = 0.51; 95% CI 0.43-0.61; p < 0.01). ADs did not improve OS in GBM PTS, both as first or second-line treatment. Among ADs, only BEV demonstrated a PFS benefit both as single agent or in combination with chemotherapy, both as first or second-line treatment.

S01 - Effectiveness of antiangiogenic drugs (ADs) in glioblastoma (GBM) patients (PTS): a metanalysis of randomized clinical trials (RCTs)

Background: GBMs are highly vascularized tumors and various ADs have been investigated in clinical trials showing unclear results. We performed this metanalysis to evaluate the effectiveness of ADs, in terms of progression-free survival (PFS) and overall survival (OS), as first or second-line therapy and their association with chemotherapy in GBM PTS. Methods: the authors searched relevant published and unpublished RCTs analyzing ADs versus chemotherapy in GBM PTS from 2000 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases. Results: sixteen RCTs (9 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) were identified including 4566 PTS. All trials showed no improvement in OS with a pooled HR of 1.02 (95% CI 0.93-1.1; p = 0.7). The use of bevacizumab (BEV) did not improve OS; indeed, the pooled HR for OS for BEV studies (9 studies, 2752 PTS) was 0.98 (95% CI 0.89-1.08; p = 0.7); 6 RCTs (2084 PTS) analyzed BEV as first-line and the pooled HR for OS was 1.02 (95% CI 0.88-1.19; p = 0.8); 3 RCTs studied BEV as second-line therapy and the pooled HR for OS was 0.95 (95% CI 0.77-1.17; p = 0.6). No improvement of OS was shown when BEV was associated with chemotherapy (2588 PTS) with a pooled HR of 0.99 (95% CI 0.88-1.11; p = 0.8). Seven RCTs with a different AD demonstrating no improvement of OS versus standard treatment with a pooled HR of 1.05 (95% CI 0.89-1.23; p = 0.5). 14 RCTs (4349 PTS) were analyzed for PFS and the use of ADs showed a statistically longer PFS with a pooled HR of 0.73 (95% CI 0.62-0.86;p < 0.01); However, among ADs, only bevacizumab (2752 PTS) demonstrated an improvement of PFS; indeed, the pooled HR for PFS for BEV studies was significant at HR = 0.6 (95% CI 0.5-0.7; p < 0.01), both alone (HR = 0.6; CI 95% 0.44-0.82; p < 0.01) or in combination to CT (HR = 0.6; 95% CI 0.4-0.7;p < 0.01), both as first-line treatment (HR = 0.65; 95% CI 0.52-0.83; p < 0.01) or in recurrent disease (HR = 0.51; 95% CI 0.43-0.61; p < 0.01). Conclusions: ADs did not improve OS in GBM PTS, both as first or second-line treatment. Among ADs, only BEV demonstrated a PFS benefit both as single agent or in combination with chemotherapy, both as first or second-line treatment.

Murine fundus fluorescein angiography: An alternative approach using a handheld camera

In today’s modern pharmacologic approach to treating sight-threatening retinal vascular disorders, there is an increasing demand for a compact, mobile, lightweight and cost-effective fluorescein fundus camera to document the effects of antiangiogenic drugs on laser-induced choroidal neovascularization (CNV) in mice and other experimental animals. We have adapted the use of the Kowa Genesis Df Camera to perform Fundus Fluorescein Angiography (FFA) in mice. The 1 kg, 28 cm high camera has built-in barrier and exciter filters to allow digital FFA recording to a Compact Flash memory card. Furthermore, this handheld unit has a steady Indirect Lens Holder that firmly attaches to the main unit, that securely holds a 90 diopter lens in position, in order to facilitate appropriate focus and stability, for photographing the delicate central murine fundus. This easily portable fundus fluorescein camera can effectively record exceptional central retinal vascular detail in murine laser-induced CNV, while readily allowing the investigator to adjust the camera’s position according to the variable head and eye movements that can randomly occur while the mouse is optimally anesthetized. This movable image recording device, with efficiencies of space, time, cost, energy and personnel, has enabled us to accurately document the alterations in the central choroidal and retinal vasculature following induction of CNV, implemented by argon-green laser photocoagulation and disruption of Bruch’s Membrane, in the experimental murine model of exudative macular degeneration.

Effectiveness of antiangiogenic drugs (ADs) in glioblastoma (GBM) patients (PTS): A metanalysis of randomized clinical trials (RCTs).

e13501Background: GBMs are highly vascularized tumors and various ADs have been investigated in clinical trials showing unclear results. We performed this metanalysis to evaluate the effectiveness ...

Large artery stiffness and hypertension after antiangiogenic drugs: influence on cancer progression.

Systemic hypertension is a frequent side effect of antiangiogenic drugs (AADs) and may represent a marker of efficacy on cancer. We hypothesized that large artery properties are affected by AADs, and contribute to the rise of blood pressure and may be better related to cancer progression and mortality than hypertension. Participants were studied before AADs (V0), 10 days later (V1) and then every 2 weeks for 6 weeks (V1-V4). We included 57 consecutive patients in whom treatment with sorafenib (400 mg twice daily) or sunitinib (37.5-50 mg once daily) was indicated. The target dose could be adjusted according to tolerance and response. Aortic and carotid stiffness, brachial and central blood pressure and augmentation index were measured noninvasively at each visit. Data regarding cancer progression and mortality were collected at 6 months. Twenty-eight patients (49%) developed hypertension. Brachial SBP significantly increased during follow-up (V0-V1: +9.6 ± 15.2 mmHg, P < 0.001; V0-V4: +6.0 ± 17.8 mmHg, P = 0.04). Central BP, and aortic and carotid stiffness increased independently of brachial BP changes. Aortic and carotid stiffening were associated with cancer progression independently of BP changes [hazard risk 1.24 (1.01-1.51) and 1.34 (1.03-1.73), respectively; P < 0.05], but not with cancer mortality. Brachial SBP had no predictive value. Large arteries stiffen during AAD treatment partly independently of BP changes. Arterial mechanical properties are associated with BP rise. Arterial stiffening is related with the effects of AAD on cancer progression independently of BP changes. Large artery properties might help monitor AAD therapy in cancer patients.

Enhanced Anti-Angiogenic Effect of Low Molecular Weight Heparin-Bile Acid Conjugates by Co-Administration of a Selective COX-2 Inhibitor.

To overcome definite limitations of angiogenesis inhibitors such as insufficient therapeutic efficacy as a single drug and resisting or conflicting effect under chronic treatment, it is required to develop a new regimen to improve the therapeutic effect. The combination effect of a multi-targeting angiogenesis inhibitor (LHT7) and a selective cyclooxygenase-2 inhibitor (celecoxib) on neovascularization in tumor growth was studied both in vitro and vivo experiments. While hypoxia-mediated COX-2 overexpression and macrophage recruitment were observed at LHT7-treated tumor tissues, it was well-controlled by the combination of celecoxib and LHT7. On the other hand, the in vitro tube formation and the in vivo tumor vessel formation and structure were inhibited by either LHT7 or celecoxib, but the inhibition effect was further enhanced by using them together. However, the combination therapy did not further enhance the inhibitory effect on tumor growth in terms of volume compared to single drug uses, which attributed not to increased cellular apoptosis but to decreased cell proliferation. COX-2 inhibition could enhance the therapeutic effect of anti-angiogenic drugs both by inhibiting the inflammatory reactions induced by hypoxia and by altering the vascular stabilization that is mediated by an assembly with mural cells.

Anti-Angiogenic Drugs and Biomarkers in Non-Small-Cell Lung Cancer: A ‘Hard Days Night'

The discovery of specific molecular alterations (i.e. EGFR activating mutations, EML4/ALK translocation, ROS1 rearrangements) in a selected population of patients affected by non small cell lung cancer (NSCLC) translated into effective treatments for this small but well defined fraction of patients, driven by the use of predictive biomarkers of efficacy for targeted agents. Unfortunately, the same reliable predictive biomarkers are lacking for anti-angiogenic drugs. Angiogenesis plays a major role in the progression of NSCLC, however, anti-angiogenic agents provided a minimal, although significant, clinical benefit in unselected populations, burdened by a not negligible toxicities. In this context, no validated angiogenic factor or other molecular biomarker of angiogenesis can reliably predict clinical outcome, sensitivity, early response or resistance to any of the investigated anti-angiogenic therapies currently used. Moreover, the available clinical data are prevalently retrospective, underpowered, and, in many cases, contradictory, thus underscoring that the understanding of the complex architecture of angiogenic signaling is still incomplete. We here review the currently available studies on the effect of anti-angiogenic drugs in NSCLC, with a particular focus on bio-molecular factors that are regarded as potential predictors of treatment efficacy.

0247: Changes in blood pressure and arterial mechanical properties after antiangiogenic drugs: association with cancer progression and mortality

Hypertension is a frequent side effect of antiangiogenic drugs (AAD). Targeting VEGF pathway may also affect large and small artery properties, along with or independently of blood pressure changes. We hypothesized that large and small artery property changes in response to AAD reflect their effect on the microcirculation at the site of the tumor, and thus may be related to cancer progression and mortality. We included 60 patients [age 58 (15) years, mean SBP 127(21) mmHg] in whom treatment with AAD was indicated for various metastatic solid tumors. Noninvasive arterial investigation was performed before AAD (V0), 1 week later (V1) and then every two weeks for two months (V1 to V4): carotid-femoral pulse wave velocity (cfPWV), central SBP and augmentation index (cAIx) by applanation tonometry (SphygmoCor®), and carotid stiffness (CStiff) and internal diameter (CiD) by high resolution echotracking (Artlab®). Cancer progression and mortality were assessed at 6 months. 28(47%) patients developed hypertension during follow-up. bSBP significantly increased during follow-up (V0-V1: +9.3± 15.2mmHg, P<0.001; V0-V4: +6.0±17.8mmHg, P=0.03), as well as PWV, CStiff, and CiD. Baseline cAIx predicted cancer progression (RR=0.73 per 10%) and mortality (RR=0.73 per 10%, P<0.001) while SBP did not. The V0-V1 increase in CStiff predicted cancer progression (RR=1.37 per 1 m/s, P=0.02), independently of age and MBP. In conclusion, increased AIx and arterial stiffness, but not brachial or central SBP, were related with the effects of AAD on cancer progression and mortality.

Metabolic effects of antiangiogenic drugs in tumors: Therapeutic implications

Antiangiogenic therapy has become a mainstay of cancer therapeutics, but clinical responses are generally short-term owing to the development of secondary resistance. Tumor starvation by antiangiogenic drugs is largely attributed to increased hypoxia and impaired nutrients supply, suggesting that angiogenesis inhibition causes remarkable metabolic perturbations in the tumor microenvironment. We review here recent acquisitions concerning metabolic effects of angiogenesis blockade in tumors and discuss the possibility that some metabolic features of tumor cells – i.e. their dependency from glucose as primary energy substrate – might affect tumor responses to anti-vascular endothelial growth factor treatment. Moreover, we discuss the hypothesis that anti-angiogenic therapy might foster metabolic evolution of tumors. The therapeutic implications of this hypothesis will be discussed further here.

Contrasting responses of non-small cell lung cancer to antiangiogenic therapies depend on histological subtype.

The vascular endothelial growth factor (VEGF) pathway is a clinically validated antiangiogenic target for non-small cell lung cancer (NSCLC). However, some contradictory results have been reported on the biological effects of antiangiogenic drugs. In order to evaluate the efficacy of these drugs in NSCLC histological subtypes, we analyzed the anticancer effect of two anti-VEGFR2 therapies (sunitinib and DC101) in chemically induced mouse models and tumorgrafts of lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Antiangiogenic treatments induced vascular trimming in both histological subtypes. In ADC tumors, vascular trimming was accompanied by tumor stabilization. In contrast, in SCC tumors, antiangiogenic therapy was associated with disease progression and induction of tumor proliferation. Moreover, in SCC, anti-VEGFR2 therapies increased the expression of stem cell markers such as aldehyde dehydrogenase 1A1, CD133, and CD15, independently of intratumoral hypoxia. In vitro studies with ADC cell lines revealed that antiangiogenic treatments reduced pAKT and pERK signaling and inhibited proliferation, while in SCC-derived cell lines the same treatments increased pAKT and pERK, and induced survival. In conclusion, this study evaluates for the first time the effect of antiangiogenic drugs in lung SCC murine models in vivo and sheds light on the contradictory results of antiangiogenic therapies in NSCLC.

A GFP endometriosis model reveals important morphological characteristics of the angiogenic process that govern benign and malignant diseases.

Endometriosis involves the growth of endometriotic tissue outside the uterine cavity, and is frequently associated with different malignancies. A well-reported alteration in the disease microenvironment is the proliferation of new blood vessels around the lesions, as part of a necessary repertory to contribute to the invasiveness and development of infiltrating endometriosis. Therefore, the establishment of a reliable experimental model is essential to elucidate the contribution of angiogenesis and to develop new therapeutic approaches to endometriosis treatment. For this purpose we transplanted endometrial fragments from green fluorescent protein (GFP)-mice (n=20) into the peritoneal cavity of wild-type mice (n=20), and then analyzed the morphological changes and the process of angiogenesis. The lesions were cystic and vascularized, and showed morphological hallmarks such as endometrial glands and stroma. An increase in endometriotic lesion vascular density was revealed by immunostaining and RNAm expression for Vegf and its receptor Flk-1, and the lesions were confirmed as a tissue-donor source by GFP fluorescent cells. The same pattern was observed through staining of activated macrophages and an increase of about 25% in the number of macrophage-positive cells was also demonstrated in endometriotic lesions by flow cytometry, which concords with previous data that correlate endometriosis, angiogenesis and inflammation. According to our understanding, this is the first demonstration that the pattern of the angiogenic process in the GFP endometriosis model is very similar to that of cancer. These observations will be useful for investigation of the process of angiogenesis involved in the attachment and invasion of endometrial cells, as well as an in vivo platform model to study the effects of antiangiogenic drugs.

The emerging issue of cardiac dysfunction induced by antineoplastic angiogenesis inhibitors

Left ventricular dysfunction from anticancer drugs has emerged as a relevant problem in the clinical and scientific communities. Anthracycline toxicity has always been the most relevant, but with the increasing use of biological targeted therapies in treatment protocols, with an increasing number of cancer survivors, new toxicities have been increasing in more recent years. Cardiomyopathy after ErbB2 inhibitors has been intensively studied. Another important class of biological anticancer drugs are vascular endothelial growth factor (VEGF) inhibitors. VEGF signalling is crucial for vascular growth, but it also has a major impact on myocardial function. Also, it is important to note that such angiogenesis inhibitors are multitargeted in most cases, and can produce a broad spectrum of cardiovascular side effects. Here we review the mechanisms and pathophysiology of the most significant cardiotoxic effects of antiangiogenic drugs, and particular attention is drawn to LV dysfunction, discussing the assessment and management on the basis of the most recent cardio-oncological findings and heart failure guidelines.