Tumor growth and metastasis are angiogenesis-dependent. The possibility of inhibiting tumor growth by interfering with the formation of new vessels has recently raised considerable interest. We previously reported that it is possible to inhibit primary tumor growth and metastasis in a transgenic model of spontaneous breast tumor, which shows many similarities to its human counterpart (including ability to metastasize) by intratumoral administration of a DNA conKeywords: gene therapy; breast adenocarcinoma; metastasis; transgenic mice; anti-angiogenesis; liposomesIt is now widely recognized that the development of new blood vessels (angiogenesis) is necessary to sustain tumor growth, invasion and metastasis. At some point during tumor growth, cancer cells acquire the ability to activate the quiescent vasculature to produce new blood vessels via a so-called 'angiogenic switch '. 1,2 Although the need for recruiting new blood vessels to the tumor has been know for more than two decades, the possibility of treating malignancies by acting on their vasculature has become popular only since the isolation of endogenous angiogenesis inhibitors, which dramatically affect cancer growth in experimental murine systems. Highly promising results on experimental tumors in rodents using these inhibitors as purified proteins as well as transduced genes, alone or in combination with traditional therapies have been reported. [3][4][5][6][7] The establishment of a dormancy status, which in some cases persists even after the suspension of therapy, has been obtained with these gene products, 5 and this, together with the absence of drug resistance, 8 raised the possibility that the anti-angiogenic effects could be useful in the treatment of human tumors.The achievement of the inhibition of local tumor growth is the usual end-point of these therapeutical attempts, but in humans it is the metastatic spread that is responsible for the majority of cancer-related deaths. Therefore, to be really useful in the human context, any new approach must be evaluated in its ability to interfere Correspondence: MG Sacco, ITBA CNR, Via F lli Cervi, 93, 20090 Segrate (MI), Italy Received 17 August 2000; accepted 11 October 2000 struct carrying the murine angiostatin cDNA driven by liposomes. Here we report that it is also possible to achieve this goal by a systemic (intraperitoneal) delivery of therapeutic DNA constructs carrying genes coding for mouse and human anti-angiogenic factors which include angiostatin, endostatin and TIMP-2. These findings may be relevant to the design of therapeutic interventions in humans. Gene Therapy (2001) 8, 67-70. with tumor cell invasion and metastasis, a therapeutical target which is rarely, if ever, investigated at the experimental level. Unfortunately, most of the results in experimental oncology have been obtained on transplantable tumors which are usually generated by inoculating highly malignant cultured cells, which rapidly grow in the site of injection and become the target for therapeutic intervention. ...

The early consequences of Helicobacter pylori infection and the role of bacterial virulence determinants in disease outcome remain to be established. The present study sought to measure the development of host inflammatory and immune responses and their relationship to the putative bacterial virulence factors cag pathogenicity island (cagPAI), vacA allele, and oipA in combination with bacterial colonization density in a feline model of the early stages of H. pylori infection. Gastric tissues obtained from infected and uninfected cats were evaluated for H. pylori ureB, cagPAI, vacA allele, and oipA and colonization density (urease, histology, and real-time PCR). Inflammation was assessed by measuring mRNA upregulation of gamma interferon (IFN-␥), interleukin (IL)-1␣, IL-1␤, IL-4, IL-6, IL-8, IL-10, and IL-12 p40 and histopathology. The mucosal immune response was characterized by morphometric analysis of lymphoid follicles and by differentiating lymphocyte populations with antibodies against surface markers. Infecting H. pylori strains were positive for vacAs1 but lacked cagPAI and an active oipA gene. Colonization density was uniform throughout the stomach. Upregulation of IFN-␥, IL-1␣, IL-1␤, and IL-8 and increased severity of inflammatory infiltrates and fibrosis were observed in infected cats. The median number and total area of lymphoid aggregates were 5 and 10 times greater, respectively, in the stomachs of infected than uninfected cats. Secondary lymphoid follicles in uninfected cats were rare and positive for BLA.36 and B220 but negative for CD3 and CD79␣, whereas in infected cats they were frequent and positive for BLA.36, CD79␣, and CD3 but negative for B220. Upregulation of IFN-␥, IL-1␣, IL-1␤, and IL-8 and marked hyperplasia of secondary lymphoid follicles are early consequences of H. pylori infection in cats. The response appears to be similar to that of infected people, particularly children, can develop independently of the pathogenicity factors cagPAI and oipA, and is not correlated with the degree of colonization density or urease activity.Helicobacter pylori is a gram-negative bacterium that chronically infects more than half of all people worldwide (6,66,69,75). Infection tends to begin in infancy (new infections are uncommon in adults) and is likely to last for decades (16).Over a span of 20 to 30 years, about one in six H. pyloriinfected adults in the West develops duodenal ulcers that are associated with antral predominant gastritis and increased acid secretion (18). Another smaller subset of people develop atrophy and intestinal metaplasia of the body of the stomach and go on to develop gastric carcinoma over a period of 30 to 40 years (55). While the factors determining this variable outcome are not well understood, the development of a sustained gastric inflammatory and immune response to infection appears to be pivotal for the development of disease (12,49,55,56). Chronic infection of adults with H. pylori is characterized by the infiltration of polymorphonuclear and mononuclear cells an...

Abstract. Detailed histopathological evaluation of the gastric mucosa of Helicobacter-infected cats is complicated by the difficulty of recognizing Helicobacter organisms on hematoxylin and eosin (HE)-stained sections and the ability of multiple Helicobacter species to infect cats. In this study, the presence and localization of different species of Helicobacter in the stomachs of cats was investigated using silver staining and immunohistochemistry. Five groups containing 5 cats each were established (group 1: urease negative and Helicobacter free; groups 2, 3, 4, and 5: urease positive and infected with Helicobacter heilmannii, unclassified Helicobacter spp., Helicobacter felis, and Helicobacter pylori, respectively). Gastric samples were evaluated by HE and silver staining and by immunohistochemistry with 3 different anti-Helicobacter primary antibodies. Helicobacter were detected by Steiner stain in all infected cats at the mucosal surface, in the lumen of gastric glands, and in the cytoplasm of parietal cells. In silver-stained sections, H. pylori was easily differentiated from H. felis, H. heilmannii, and unclassified Helicobacter spp., which were larger and more tightly coiled. No organisms were seen in uninfected cats. Helicobacter antigen paralleled the distribution of organisms observed in Steinerstained sections for 2 of the 3 primary antibodies tested. The antisera were not able to discriminate between the different Helicobacter species examined. A small amount of Helicobacter antigen was present in the lamina propria of 3 H. pylori-, 3 H. felis-, and 1 H. heilmannii-infected cat. Minimal mononuclear inflammation was present in uninfected cats and in those infected with unclassified Helicobacter spp. and H. heilmannii cats. In H. felis-infected cats, lymphoid follicular hyperplasia with mild pangastric mononuclear inflammation and eosinophilic infiltrates were present. The H. pylori-infected cats had severe lymphoid follicular hyperplasia and mild to moderate mononuclear inflammation accompanied by the presence of neutrophils and eosinophils. These findings indicate that Steiner staining and immunohistochemistry are useful for detecting Helicobacter infections, particularly when different Helicobacter species can be present. Monoclonal antibodies specific for the different Helicobacter species could be important diagnostic aids. There appear to be differences in the severity of gastritis in cats infected with different Helicobacter species.Gastric spiral-shaped bacteria of the genus Helicobacter have been described in many animal species as well as in humans. 24,81 Although their presence has been documented since the end of the 19th century, it is only since the discovery of Helicobacter pylori in humans by Warren and Marshall in 1983 that much interest has been expressed in gastric Helicobacter in animals. 5,74,77,87 Helicobacter pylori infection in humans has been associated with chronic active gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue lymphoma, and adenocarcinoma. 10,20,30...

Background and Purpose: Fenretinide, a synthetic retinoid derivative first investigated for cancer prevention and treatment, has been shown to ameliorate glucose tolerance, improve plasma lipid profile and reduce body fat mass. These effects, together with its ability to inhibit ceramide synthesis, suggest that fenretinide may have an anti-atherosclerotic action.Experimental Approach: To this aim, nine-week-old apoE-knockout (EKO) female mice were fed for twelve weeks a Western diet, without (control) or with (0.1% w/ w) fenretinide. As a reference, wild-type (WT) mice were treated similarly. Growth and metabolic parameters were monitored throughout the study. Atherosclerosis development was evaluated in the aorta and at the aortic sinus. Blood and lymphoid organs were further characterized with thorough cytological/histological and immunocytofluorimetric analyses.Key Results: Fenretinide treatment significantly lowered body weight, glucose levels and plasma levels of total cholesterol, triglycerides, and phospholipids. In the liver, fenretinide remarkably reduced hepatic glycogenosis and steatosis driven by the Western diet. Treated spleens were abnormally enlarged, with severe follicular atrophy and massive extramedullary haematopoiesis. Severe renal hemosiderin deposition was observed in treated EKO mice. Treatment resulted in a threefold increase of total leukocytes (WT and EKO) and raised the activated/resting monocyte ratio in EKO mice. Finally, atherosclerosis development was markedly increased at the aortic arch, thoracic and abdominal aorta of fenretinide-treated mice. Conclusions and Implications:We provide the first evidence that, despite beneficial metabolic effects, fenretinide treatment may enhance the development of atherosclerosis.

Breast cancer in women is a major health problem, causing a great deal of suffering and a high number of deaths. So far, early diagnosis followed by surgery is the only way to cure the disease, while therapeutic protocols for women at an advanced stage of the disease are still unsatisfactory and, in the long term, metastatic breast cancer is still associated with high treatment failure. 1 In humans, both chemotherapy and hormonal approaches for the management of the advanced disease are of great clinical relevance. Various drugs, including taxol, are active against disseminated breast cancer. 2 In addition, in patients with estrogen receptor positive tumors, antiestrogens, and tamoxifen in particular, have been widely used. 3 Many randomized trials have shown that postsurgical tamoxifen (TAM) treatment significantly reduces the growth of hormone receptor-positive breast cancer. Recently, the efficacy of TAM for chemoprevention of breast tumors has been evaluated, and the data from the Breast Cancer Prevention Trial have demonstrated that TAM administration reduces the incidence of estrogen receptor-positive, but not receptor-negative tumors. 4,5 More recently, inhibition of tumor angiogenesis was investigated as a therapeutic strategy that can inhibit Correspondence: MG Sacco, CNR-ITB, Via Fratelli Cervi, 93, 20090 Segrate (MI)