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PubMed2004

Therapeutic potential of hammerhead ribozymes in the treatment of hyper-proliferative diseases.

The limited efficacy of current therapeutic approaches for a number of socially relevant human diseases such as cancer and cardiovascular pathologies, has required the exploration of alternative and more effective therapeutic strategies. In the last two decades, nucleic acid based drugs have emerged as an attractive and novel alternative with great therapeutic potential. Among these molecules, hammerhead ribozymes were the first to be extensively studied and predicted to be of potential practical utility. Hammerhead ribozymes are catalytic RNA molecules capable of inducing the site-specific cleavage of a phosphodiester bond within an RNA molecule. Thus, they can be used to reduce the intracellular level of a specific mRNA coding for a protein which affects cellular metabolism or environment, causing disease. As hammerhead ribozymes can be engineered to reduce the level of virtually any mRNA, they have a very broad applicability. Among the several pathological conditions amenable for a hammerhead ribozyme based therapeutic approach, we focused our attention on pathologies sustained by a dis-regulated and excessive cellular proliferation, being sure to properly demonstrate their usefulness. Trying to be as objective as possible in regard to the feasibility of hammerhead ribozyme employment as therapeutics, a technical section, describing some of the unresolved problems in this field, has been also included. Although some aspects of hammerhead ribozymes as therapeutics can and should be optimized, the encouraging results displayed so far fully justifies further efforts, economic and scientific, to bring them closer to the clinical practice.

Animals↗

PubMed1985

Tumor angiogenesis.

The hypothesis that tumors are angiogenesis dependent has, in the past decade, generated new investigations designed to elucidate the mechanism of angiogenesis itself. Many laboratories are now engaged in this pursuit. Some are studying angiogenesis that occurs in physiological situations, whereas others are interested in angiogenesis that dominates pathological conditions. These efforts have led to (1) the development of bioassays for angiogenesis; (2) the partial purification and, in one case, the complete purification of angiogenic factors from neoplastic and non-neoplastic cells; (3) the development of new polymer technology for the sustained release of these factors and other macromolecules in vivo; (4) the cloning and long-term culture of capillary endothelial cells; (5) the demonstration of the role of nonendothelial cells, such as mast cells in modulating angiogenesis; (6) the discovery of angiogenesis inhibitors; and (7) the demonstration that certain animal tumors will regress when angiogenesis is inhibited. The effects of angiogenesis inhibitors provide perhaps the most compelling evidence for the role of angiogenesis in tumor growth. It is conceivable that the original effort to understand the role of angiogenesis in tumor growth will also lead to the use of angiogenesis inhibitors as a new class of pharmacologic agents in a variety of non-neoplastic diseases such as arthritis, psoriasis, and ocular neovascularization. However, much work remains to be done before it will be possible to understand (1) the regulatory systems that govern capillary density in normal tissues; (2) the factors that maintain the viability of microvascular endothelium; (3) the development of the vascular system itself; and (4) the mechanism by which vascular regression occurs, both in the embryo and in the postnatal organism. A knowledge of the mechanisms which underlie these normal processes may help to enlarge our comprehension of tumor angiogenesis.

Angiogenesis Inducing Agents↗

PubMed2005

Lower expression of cyclooxygenase-2: is it associated with the development of borderline ovarian tumors?

Epithelial ovarian neoplasms can be divided into two major categories on the basis of their pathological and clinical behaviors: invasive ovarian tumors and borderline ovarian tumors. However, neither the etiology nor the pathogenesis of the borderline and invasive epithelial ovarian carcinomas has been understood completely. Borderline tumors are clearly more favaroble in terms of survival. The same pathological types can be seen both in borderline and invasive tumors. However; it is not clear if both diseases is a continuum of the same entity or are independent clinical entities. On the other hand, several in vivo and in vitro studies have demonstrated that overexpression of the cyclooxygenase-2 (COX-2) may have an important role in the development and the aggressive clinical behaviors of different malignancies. Furthermore, some recent studies have also revealed the overexpression of COX-2 in invasive epithelial ovarian carcinomas. In this manuscript, we propose that lower expressions of COX-2 may have a role in the development of borderline ovarian neoplasias, whereas higher levels have a role in the invasive epithelial ovarian cancers and this may be the basis for the clinical difference of both entities. To test this hypothesis; genetic, pathologic and epidemiologic studies may be performed. Patients with borderline tumors should be compared with the invasive counterparts in terms of COX mutations and expressions. Also, epidemiologic studies may reveal the role of COX inhibitors in the ovarian carcinogenesis. If this hypothesis is proven to be true, this may direct the clinicians to use prophylactic NSAIDs with or without combined oral contraceptives especially in high risk patients. Also, this hypothesis may enlight a new gene therapy targeting COX-2 gene in high risk patients for the development of EOC.

Apoptosis↗

PubMed2005

TIMP-2: an endogenous inhibitor of angiogenesis.

Remodeling of the extracellular matrix--regulated by the matrix metalloproteinases (MMPs) and their endogenous inhibitors--is an important component of disease progression in many chronic disease states. Unchecked MMP activity can result in significant tissue damage, facilitate disease progression and is associated with host responses to pathologic injury, such as angiogenesis. The tissue inhibitors of metalloproteinases (TIMPs) have been shown to regulate MMP activity. However, recent findings demonstrate that an MMP-independent effect of TIMP-2 inhibits the mitogenic response of human microvascular endothelial cells to growth factors. This is the first demonstration of a cell-surface signaling receptor for a member of the TIMP family and suggests that TIMP-2 functions to regulate cellular responses to growth factors. These new findings are integrated in a comprehensive model of TIMP-2 function in tissue homeostasis.

Endothelial Cells↗

PubMed2000

Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation.

Angiogenesis, or the formation of new blood vessels out of pre-existing capillaries, is a sequence of events that is fundamental to many physiologic and pathologic processes such as cancer, ischemic diseases, and chronic inflammation. With the identification of several proangiogenic molecules such as the vascular endothelial cell growth factor, the fibroblast growth factors (like in FGFs), and the angiopoietins, and the recent description of specific inhibitors of angiogenesis such as platelet factor-4, angiostatin, endostatin, and vasostatin, it is recognized that therapeutic interference with vasculature formation offers a tool for clinical applications in various pathologies. Whereas inhibition of angiogenesis can prevent diseases with excessive vessel growth such as cancer, diabetes retinopathy, and arthritis, stimulation of angiogenesis would be beneficial in the treatment of diseases such as coronary artery disease and critical limb ischemia in diabetes. In this review we highlight the current knowledge on angiogenesis regulation and report on the recent findings in angiogenesis research and clinical studies. We also discuss the potentials, limitations, and challenges within this field of research, in light of the development of new therapeutic strategies for diseases in which angiogenesis plays an important role.

Angiogenesis Inhibitors↗

PubMed1999

Expression pattern of vascular endothelial growth factor isoform is closely correlated with tumour stage and vascularisation in renal cell carcinoma.

Vascular endothelial growth factor (VEGF) has five isoforms (VEGF206, 189, 165, 145 and 121). Increased VEGF expression in renal cell carcinoma (RCC) is associated with angiogenesis, but, it is not apparent which isoform is involved in this effect. We examined the isoform patterns of VEGF by reverse transcription-polymerase chain reaction (RT-PCR) in 47 RCCs. All showed increased VEGF expression as compared with extraneoplastic renal tissue. Four of the 47 RCCs showed VEGF121 alone, 10 showed VEGF121 + 165, and 33 showed the VEGF121 + 165 + 189 pattern. Patients with pathological stage pT3-4 RCC showed the VEGF121 + 165 + 189 isoform pattern at a significantly higher incidence (10/10, 100%) than those with pT0-2 (23/37, 62%) (P < 0.022). The VEGF121 + 165 + 189 isoform pattern was also significantly associated with high vessel counts and density (P = 0.0002, Mann-Whitney U test). These observations suggested that the VEGF189 mRNA isoform is closely associated with angiogenesis and results in the growth of RCC.

Blotting, Northern↗

PubMed2005

Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure.

Although increased external load initially induces cardiac hypertrophy with preserved contractility, sustained overload eventually leads to heart failure through poorly understood mechanisms. Here we describe a conditional transgenic system in mice characterized by the sequential development of adaptive cardiac hypertrophy with preserved contractility in the acute phase and dilated cardiomyopathy in the chronic phase following the induction of an activated Akt1 gene in the heart. Coronary angiogenesis was enhanced during the acute phase of adaptive cardiac growth but reduced as hearts underwent pathological remodeling. Enhanced angiogenesis in the acute phase was associated with mammalian target of rapamycin-dependent induction of myocardial VEGF and angiopoietin-2 expression. Inhibition of angiogenesis by a decoy VEGF receptor in the acute phase led to decreased capillary density, contractile dysfunction, and impaired cardiac growth. Thus, both heart size and cardiac function are angiogenesis dependent, and disruption of coordinated tissue growth and angiogenesis in the heart contributes to the progression from adaptive cardiac hypertrophy to heart failure.

Angiopoietin-2↗

PubMed2001

[p53 and vascular endothelial growth factor expression in astrocytoma and their relation to angiogenesis].

OBJECTIVE: This investigation was done to show the pathological importance of p53 protein detection, vascular endothelial growth factor expression (VEGF) and intratumoral microvessel density (IMVD) in astrocytoma. METHODS: The surgical specimens from 60 brain astrocytoma patients were stained immunohistochemically for p53 and IMVD expressions. IMVD was calculated by labeling the endothelial cells of the blood vessels within the tumor. RESULTS: p53, VEGF expression were closely correlated with histopathological grade of astrocytoma. Positive p53 protein accumulation and VEGF expression were found in 45.0% (27/60) and 65.0% (39/60) of tumors. The conformation rate of p53 and VEGF was 70.0% (42/60). IMVD was significantly higher in the p53-positive or VEGF-positive tumors than in the negative ones (P < 0.05). Comparing the IMVD in p53+/VEGF+ group, p53-/VEGF+ group and p53+/VEGF- group, p53-/VEGF- group, its difference was also highly significant (P < 0.05). CONCLUSION: (1) p53 protein detection, VEGF expression and IMVD can be considered as a biological indicator of malignant potential in brain astrocytoma patients and (2) p53 and VEGF expressions, both contributing to the tumor neovascularization, may be helpful in the understanding of intra-tumoral angiogenetic mechanism in the future.

Adolescent↗

PubMed2003

A randomised clinical trial of high-intensity focused ultrasound ablation for the treatment of patients with localised breast cancer.

High-intensity focused ultrasound (HIFU) is a noninvasive treatment that induces complete coagulative necrosis of a tumour at depth through the intact skin. This study was to explore the possibility of using HIFU for the treatment of patients with localised breast cancer in a controlled clinical trial. A total of 48 women with biopsy-proven breast cancer (T(1-2), N(0-2), M0) were randomised to the control group in which modified radical mastectomy was performed, and the HIFU group in which an extracorporeal HIFU ablation of breast cancer was followed by modified radical mastectomy. Short-term follow-up, pathologic and immunohistochemical stains were performed to assess the therapeutic effects on tumour and complications of HIFU. The results showed that no severe side effect was observed in the HIFU-treated patients. Pathologic findings revealed that HIFU-treated tumour cells underwent complete coagulative necrosis, and tumour vascular vessels were severely damaged. Immunohistochemical staining showed that no expression of PCNA, MMP-9, and CD44v6 was detected within the treated tumour cells in the HIFU group, indicating that the treated tumour cells lost the abilities of proliferation, invasion, and metastasis. It is concluded that, as a noninvasive therapy, HIFU could be effective, safe, and feasible in the extracorporeal treatment of localised breast cancer.

Adult↗

PubMed1999

Diverse roles of macrophage matrix metalloproteinases in tissue destruction and tumor growth.

In the mouse, macrophage elastase is critical to macrophage proteolysis. The use of gene-targeting has uncovered both pathological roles, including destructive effects in aneurysm formation and emphysema, and physiological roles, such as tumor growth inhibition and regulation of inflammation. Translation of findings from mouse to human biology depends upon how well the disease models replicate the human conditions and the similarity of enzyme profile between species. We know that human MMP-12 is associated with these diseases, but as opposed to the mouse, other MMPs may also be of importance (MMP-9, and perhaps MMP-7, in particular). Our interpretation is that findings in mice reflect the critical role of macrophage proteolysis in these disease processes.

Aneurysm↗

PubMed2005

[Correlation of bone marrow stromal cells to leukemia and its research advancement in gene therapy for leukemia].

Bone marrow stromal cells (BMSCs) have a pluripotent characteristic, and can be readily isolated and expanded in vitro. After in vivo transplantation, BMSCs can home to blood marrow, and survive for a long time by self-renewing. They can influence the biological characteristics of leukemia cells from several aspects, and participate in the outbreak process and pathologic process of leukemia. BMSCs with normal functions have direct antitumur effects on leukemic cells. They can regulate the immunity remarkably. Genetically engineered BMSCs can deliver target therapeutic proteins over sufficient time after in vivo transplantation. Thus, BMSCs are considered to be an ideal therapeutic cell vehicle and target cells in the gene therapy for leukemia. Interferons, a cytokines family, are capable of producing multiplex biological effects, and have remarkable curative effects on hair cell leukemia and chronic myelogenous leukemia. Here we reviewed the possibility and perspective of molecular target therapy for leukemia by interferons-modified BMSCs.

Animals↗

PubMed1997

Pathology of lung cancer.

In this review, we focus on a number of developments pertaining to lung cancer diagnosis, entirely restricted to those parameters assessable by light microscopy. A number of discrete areas of interest stand out in 1996 related to the pathology of lung cancer. Aberrant p53 expression continues to be debated as an independent prognostic factor in nonsmall cell carcinoma. Neuroendocrine differentiation may be an independent prognostic factor in nonsmall cell carcinoma and new associations with the protein product of the bcl-2 oncogene have been described. Angiogenesis continues to arise as a predictor of metastatic potential in lung cancer. Finally, we review conceptual aspects of carcinogenesis from atypical adenomatous hyperplasia to bronchioloalveolar carcinoma, in addition to a variety of individual tumor-related issues associated with progression, response to chemotherapy, and survival.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed1995

[Angiogenesis is induced by growth factors. The molecular mechanisms are not yet known].

Angiogenesis, the formation of new vessels from the vessel bed, is crucially involved in physiological and pathological processes. Angiogenesis may be regarded as a series of cellular events--e g, basement membrane degradation, and the migration, proliferation and differentiation of endothelial cells. Several different growth factors trigger one or more of these events both in vivo and in vitro, though the underlying mechanisms are still largely unknown. Elucidation of the function of growth factor receptors in angiogenesis, and their propagation of intracellular signals eventually resulting in angiogenesis is an important task for research. In all likelihood, such studies will give rise to clinically useful tools for the regulation of angiogenesis, which might be of importance in such disease as diabetes and cancer.

Collateral Circulation↗

PubMed2003

Vascular endothelial growth factor (VEGF) expression in operable gallbladder carcinomas.

AIM: To investigate the angiogenic and prognostic role of vascular endothelial growth factor (VEGF) in operable gallbladder carcinomas. METHODS: Sixty patients with early gallbladder carcinomas, treated with surgery alone, were investigated immunohistochemically for the expression of VEGF, thymidine phosphorylase (TP) and new blood vessel formation. The results were correlated with clinico-pathological features and prognosis. RESULTS: An increased VEGF secretion in gallbladder carcinomas was significantly associated with increased angiogenesis but not with patients survival, although high angiogenesis did relate with poor prognosis. TP was also associated with angiogenesis, but only the combined VEGF/TP expression was associated with unfavourable survival. Histological grade was another independent factor of prognosis. CONCLUSION: Both VEGF and TP expression are associated with high rate of angiogenesis, a factor directly associated with prognosis. The combined expression of these angiogenic factors confer a particularly poor post-operative outcome, speculature.

Adult↗

PubMed2005

Pancreatic cancer pain and its correlation with changes in tumor vasculature, macrophage infiltration, neuronal innervation, body weight and disease progression.

To begin to understand the relationship between disease progression and pain in pancreatic cancer, transgenic mice that develop pancreatic cancer due to the expression of the simian virus 40 large T antigen under control of the rat elastase-1 promoter were examined. In these mice precancerous cellular changes were evident at 6 weeks and these included an increase in: microvascular density, macrophages that express nerve growth factor and the density of sensory and sympathetic fibers that innervate the pancreas, with all of these changes increasing with tumor growth. In somatic tissue such as skin, the above changes would be accompanied by significant pain; however, in mice with pancreatic cancer, changes in pain-related behaviors, such as morphine-reversible severe hunching and vocalization only became evident at 16 weeks of age, by which time the pancreatic cancer was highly advanced. These data suggest that in mice as well as humans, there is a stereotypic set of pathological changes that occur as pancreatic cancer develops, and while weight loss generally tracks disease progression, there is a significant lag between disease progression and behaviors indicative of pancreatic cancer pain. Defining the mechanisms that mask this pain in early and mid-stage disease and drive the pain in late-stage disease may aid in earlier diagnosis, survival, and increased quality of life of patients with pancreatic cancer.

Animals↗

PubMed2006

Changes in laminin isoforms associated with brain tumor invasion and angiogenesis.

Laminins are the major constituents of blood vessel basement membranes (BMs). Each laminin is a trimer consisting of three assembled polypeptide chains, alpha, beta and gamma. More than 15 laminin isoforms are known to date and the expression of specific isoforms may change in certain pathological conditions. Here we show that during progression of glial tumors laminin-9 (alpha4beta2gamma1) is switched to laminin-8 (alpha4beta1gamma1), which is dramatically increased in glial brain tumors. Laminin-8 overproduction by glial tumor cells facilitates spread of glioma. Brain tumors with laminin-8 overexpression recur faster after standard treatment and patients have shorter survival time. Laminin-8 may be thus used as a predictor of tumor recurrence, patient survival and as a potential molecular target for glioma therapy.

Animals↗

PubMed1995

Biological and clinical role of angiogenesis in breast cancer.

Angiogenesis, the process leading to the formation of new blood vessels, plays a central role in tumor progression of solid neoplasia. The switch from the avascular to the vascular phase is generally accompanied by rapid primary tumor growth and local invasiveness. Furthermore, angiogenesis is also necessary both at the beginning and at the end of the development of distant metastasis and is implicated in the phenomenon of dormant micrometastases. The angiogenic activity of both the primary tumor and its metastases is the result of the net balance between angiogenic peptides and natural inhibitors, and it is regulated by multiple biochemical and genetic mechanisms. In normal tissues of the adult, unlike invasive cancers, the angiogenic inhibitory pathway predominates. Several experimental and clinico-pathologic studies have confirmed that angiogenesis is specifically involved in transformation and progression of human breast cancer. In particular, clinicopathologic studies have found that the degree of vascularization of primary invasive human breast cancer is heterogeneous and correlates with the prognosis of patients. A number of antiangiogenic agents have been recently discovered, and some are under early clinical evaluation. Thus, angiogenic activity of the tumors represents a potentially novel anticancer therapeutic target. This issue of Breast Cancer Research and Treatment reports on the most relevant basic biological aspects of angiogenesis, on its clinical role in breast cancer prognosis, and on the implications of inhibition of angiogenesis for future novel anticancer therapeutic approaches.

Adult↗

PubMed2001

Expression of thrombospondin-1 in pancreatic carcinoma: correlation with microvessel density.

Thrombospondin-1 (TSP-1) is a multifunctional platelet and extracellular matrix protein that is involved in angiogenesis. Under certain pathological conditions, e.g., malignant tumors, high concentrations of TSP-1 work as an angiogenic agonist. Here we examined 98 pancreatic carcinomas with respect to TSP-1 immunoreactivity and its correlation to intratumoral microvessel density (MVD), a representation of the overall degree of angiogenesis in carcinomas. Northern blot analysis for TSP-1 mRNA was performed in seven additional cases. Eighty-seven tumors showed strong TSP-1 immunoreactivity, nine carcinomas were only weakly positive, and two lesions were negative for TSP-1. TSP-1 immunoreactivity was detected in the extracellular matrix, mostly at the invasion front of the tumor. Using Northern blot analysis, we observed high levels of TSP-1 mRNA in three out of seven pancreatic carcinomas. The mean MVD in pancreatic carcinoma was 38.8 vessels per mm2. Tumors with a high expression of TSP-1 showed a higher MVD and the correlation between TSP-1 immunoreactivity and microvessel density was highly significant (P=0.003). As a modulator of angiogenesis, TSP-1 is strongly expressed in most pancreatic adenocarcinomas and is likely to contribute to the extensive neovascularization and spread of this highly aggressive tumor.

Adenocarcinoma↗