Current Angiogenesis (Discontinued) - Volume 2, Issue 2, 2013

The progression of multiple myeloma depends on bone marrow microenvironment that can offer favorable conditions for its growth. Among the most important features of the disease is the alteration of bone marrow microenvironment, including dysregulation of various molecules with consequent increased angiogenic potential, extended bone disease, resistance to any likely therapy and furthermore direct growth of myeloma clone. Angiogenesis, as can be estimated by immunohistochemical staining of blood vessels, i.e. microvascular density, is a hallmark in the progress of many malignancies, including multiple myeloma. Many pro-angiogenic molecules participate in the process, being aberrantly or over-expressed by myeloma and other cells of bone marrow. Those molecules, possessing multiple properties, may circulate in peripheral blood and therefore could be measured. Here we present an overview of the most important molecules that participate, directly and indirectly, in the angiogenic process of multiple myeloma and try to evaluate their role, as factors of disease activity and moreover of prognosis. Furthermore, many of circulating angiogenic molecules have been constituted possible targets for therapeutic interventions. All this provided information contributes to a better comprehension of the complex pathophysiology of multiple myeloma.

Data concerning angiogenesis in chronic lymphocytic leukaemia (CLL) indicate that CLL patients are characterized by various abnormalities in the angiogenic profile including increased microvessel density in lymph nodes and in bone marrow and increased levels of certain pro-angiogenic vascular growth factors. Vascular endothelial growth factor (VEGF) and its receptors, basic fibrobast growth factor (bFGF) and matrix metalloproteinases(MMPs) were found to be highly expressed in CLL patients while there was no difference in angiogenin expression between CLL patients and healthy individuals. VEGF is implicated in CLL pathogenesis through various mechanisms. Enhanced angiogenesis in CLL has been associated in several reports with disease characteristics and patients’ survival. Various anti-angiogenic agents targeting angiogenesis related pathways such as immunomodulatory drugs and receptor tyrosine kinase inhibitors have already been entered in clinical trials. Among them lenalidomide is the most promising antiangiogenic drug showing a significant efficacy in relapsed/refractory CLL patients.

Angiogenesis is involved in several diseases, including hematological malignancies and solid tumors as an essential step of disease progression. In Waldenstrom’s macroglobulinemia (WM) the bone marrow microvessel density is increased in 30%-40% of patients with symptomatic disease, but not in patients with monoclonal gammopathy of undetermined significance of IgM type (IgM-MGUS) and in patients with asymptomatic WM. The serum levels of angiogenic cytokines such as vascular endothelial growth factor (VEGF), VEGF-A, basic fibroblast growth factor, angiogenin and angiopoietin-2 (Ang-2) are markedly elevated in WM patients, while Ang-1 levels and the corresponding Ang-1 to Ang-2 ratio are significantly decreased, indicating an angiogenic shift. Circulating angiogenin and angiopoietin-1/angiopoietin-2 ratio correlate with disease activity and clinical features of WM. Ang-2 may also have a prognostic significance for WM patients as high levels of Ang-2 were found to be associated with significantly shorter progression-free survival. The chemokine C-C motif ligand 3 (CCL3) is a chemo-attractant for macrophages and mast-cells and was found to be elevated in the serum of patients with WM. CCL3 is produced by WM cells and correlates with inferior overall survival. In turn, activated inflammatory cells synthesize angiogenic regulators and modulate angiogenesis. This paper summarizes all available data for the role of angiogenic cytokines and supporting cells in the biology of WM and their correlation with clinical and laboratory features of the disease.

Neovascularisation is a vital process underlying the development and progression of malignant neoplasms. Limited information on the subject is available regarding Waldenstrom’s macroglobulinemia/Lymphoplasmacytic lymphoma (WM/LPL), a rare and usually indolent B-cell lymphoma. We therefore studied by immunohistochemistry microvessel characteristics and IL-6, IL-8, CXCR2 and VEGF expression in the bone marrow of WM/LPL patients and investigated any possible correlation with disease characteristics and outcome. Sixty-three patients were studied (47 WM and 16 LPL) of whom 32, 25 and 6 were low, intermediate and high risk respectively, according to the IPSSWM staging system. Seventy-six percent of the patients required treatment while 24% were asymptomatic and were regularly followed- up. Microvascular characteristics, i.e microvessel density (MVD), total vascular area (TVA) and several other sizeand shape-related parameters, were evaluated in CD34-stained bone marrow slides using computerized image analysis. A Histo-score (H-score) was calculated for IL-6, IL-8, CXCR2 and VEGF expression. IL-6, IL-8, IL-8 receptor CXCR2 and VEGF expression was observed in 84%, 43%, 89% and 90% respectively. A positive correlation between IL-6 and CXCR2 H-scores was observed; IL-6 and VEGF H-scores correlated with hypoalbulinemia and increased serum β2- microglobulin respectively and both with bone marrow lymphoplasmacytic infiltration and MVD. The degree of angiogenesis, microvessel shape, VEGF expression and CXCR2 expression correlated with a shorter time to first treatment in multivariate analysis. In conclusion, in WM/LPL, increased expression of Th-2 cytokines, CXCR2 and VEGF is implicated in neovascularization. CXCR2 and VEGF expression along with the extent and the architecture of the microvessels are brought forward as contributors to biologic aggressiveness reflected by a need for earlier treatment.

Introduction: Multi relapsed/refractory lymphoma (MRRL) represents a medical challenge in the field of clinical Hematology. All effective treatments have been used upfront and the low performance status that accompanies these patients adds to the toxicity of any subsequent treatment. Clearly a new concept for treatment is warranted aiming towards effectiveness with minimal toxicity. The concept of metronomic therapy (MT) depends on the dispensation of chemotherapy at lower dosages aiming at an antiangiogenic rather than a direct effect on the tumor. Patients and Methods: We performed a non-interventional retrospective review of MRRL patients treated in our institute with metronomic therapy (MT). Results: Between June 2004 and November 2012, nine (9) MRRL patients were treated with MT. Median age was 56 years (range 31-65), median number of prior treatment lines was 6 (range 4-9), 55% (5/9) patients had a previous autologous stem cell transplant, and all had progressive disease before receiving MT. Two (2) patients achieved complete remission (22%), one partial remission (11%), one stable disease (11%) and five (55%) had progressive disease. With a median follow up of 2.5 years, median overall survival and progression free survival were 12.7 and 3.3 months respectively. Hematological toxicity was the most frequentreported treatment related toxicity, nevertheless, no more than grade 3 of nonhematological toxicities were reported. Conclusion: Based on a limited number of patients MT achieved an overall response rate of thirty three percent combined with a favorable toxicity profile thus representing a potentially effective salvage treatment for MRRL.

Glioblastoma Multiforme (GBM) is recognised as one of the most hypervascular human tumors. Various drugs have been developed that target pro-angiogenic factors in an attempt to disrupt the blood supply and thus arrest tumor growth. Clinical studies have largely been in groups of unselected patients and have encompassed both primary and recurrent GBM. Despite initial promise, in both pre-clinical models and preliminary clinical trials, sustained therapeutic benefit in the clinic has yet to be demonstrated. In this review article we present the most up to date clinical trials and aim to elucidate the common mechanisms by which GBM may be escaping these therapies. We also discuss other potential mechanisms of action and possible future indications for anti-angiogenic medication.

Inflammation is implicated in the progression of multiple types of cancers including lung, colorectal, breast and hematological malignancies. Cyclooxygenases (Cox) -1 and -2 are important enzymes involved in the regulation of inflammation. Elevated Cox-2 expression is associated with a poor cancer prognosis. Hematological malignancies, which are among the top 10 most predominant cancers in the USA, express high levels of Cox-2. Current therapeutic approaches against hematological malignances are insufficient as many patients develop resistance or relapse. Therefore, targeting Cox-2 holds promise as a therapeutic approach to treat hematological malignancies. NSAIDs and Cox-2 selective inhibitors are anti-inflammatory drugs that decrease prostaglandin and thromboxane production while promoting the synthesis of specialized proresolving mediators. Here, we review the evidence regarding the applicability of NSAIDs, such as aspirin, as well as Cox-2 specific inhibitors, to treat hematological malignancies. Furthermore, we discuss how FDA-approved Cox inhibitors can be used as anti-cancer drugs alone or in combination with existing chemotherapeutic treatments.

Prostaglandins (PGs) are bioactive lipids involved in many physiological functions as well as in inflammation. The overexpression of PGs is a critical common point in the pathophysiology of cancer and depression: high plasmatic levels of these bioactive lipids have been reported in both disorders. In this review, the authors would like to deepen the role of PGs in cancer and depression, in order to make inquiries about a possible biological link (via the PGs pathway) between the two disorders, debating also over the implications of such a link in the therapeutic field.

Although cancers are derived from human body, their metabolic regulations are different from most normal tissues which mainly reflect on energy and biosynthesis metabolism. In energy metabolism, cancer cells take up glucose and glutamine at a high rate for aerobic glycolysis (Warburg effects). Although aerobic glycolysis does seem wasteful, it is essential for cancer growth in both energy supply and biosynthesis. In biosynthesis, nucleic acid, lipid and protein synthesis are more active in cancer cells than normal cells, but synthetic pathways in cancer cells are different from normal cells, cancer cells prefer to de novo synthesis even though it is not economic. Altered biosynthesis in cancer has challenges, but also opportunities. Understanding the process of cancer biosynthesis will help to develop new approaches in early diagnosis and target therapy of cancer.

Platelets play a potentially crucial role in (tumor) angiogenesis. Their high content of growth factors suggests that they are important players in cancer biology. Therefore, platelet characteristics and platelet-derived angiogenic and angiostatic growth factors are progressively being used in biomarker research. However, platelets are vulnerable to manipulations and can easily become activated during blood collection. Therefore, most researchers investigating basic platelet characteristics draw blood without tourniquet pressure and vacuum tubes. However, this method is less suitable for clinical studies, as it is not used in hospitals. Because the effect of the use of a combination of tourniquet pressure and vacuum tubes on platelet activation has not yet been investigated, we set out to do so. After different platelet retrieval procedures, whole blood flow cytometry was performed to quantify two indicators of activation: P-selectin expression and activation of the integrin αIIbβ3 on the platelet surface. Platelets were left untreated or were activated with two concentrations of a weak (ADP) and a strong (thrombin) platelet agonist to investigate platelet reactivity. The results showed no relevant effects of the use of tourniquet pressure and/or vacuum blood collection on the activation status of resting platelets or on platelet reactivity in vitro. Therefore, we conclude that in clinical trials aimed to measure the activation status of resting platelets or platelet reactivity in vitro, samples can be collected during regular blood drawings with tourniquet pressure and vacuum tubes.