Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors.

Tumor escape from immunity, as well as the failure of several anti-cancer vaccination and cellular immunotherapy approaches, is suggested to be due to the angiogenesis-mediated suppression of endothelial cell (EC) adhesion molecules involved in leukocyte-vessel wall interactions. We hypothesized that inhibition of angiogenesis would overcome this escape from immunity. We investigated this in vivo by means of intravital microscopy and ex vivo by immunohistochemistry in two mouse tumor models. Angiogenesis inhibitors anginex, endostatin, and angiostatin, and the chemotherapeutic agent paclitaxel were found to significantly stimulate leukocyte-vessel wall interactions by circumvention of EC anergy in vivo, i.e., by the up-regulation of endothelial adhesion molecules in tumor vessels. This was confirmed by in vitro studies of cultured EC at the protein and mRNA levels. The new angiostatic designer peptide anginex was most potent at overcoming EC anergy; the enhanced leukocyte-vessel interactions led to an increase in the numbers of tumor infiltrating leukocytes. While anginex inhibited tumor growth and microvessel density significantly, the amount of infiltrated leukocytes (CD45), as well as the number of CD8+ cytotoxic T lymphocytes, was enhanced markedly. The current results suggest that immunotherapy strategies can be improved by combination with anti-angiogenesis.

Monocyte/macrophage infiltration in tumors: modulators of angiogenesis.

The role of a tumor immune infiltrate in cancer progression and metastasis has been debated frequently. Although often considered to be associated with improved prognosis and leading to the enhanced survival of cancer patients, inflammatory cells have also been described to assist the tumor's capabilities to progress, proliferate, and metastasize. Tumor-associated macrophages (TAMs), for example, have been shown to be symbiotically related to tumor cells: Tumor cells recruit TAMs and provide them with survival factors, and TAMs in turn produce a variety of angiogenic factors in response to the tumor microenvironment. This review will describe the composition of an immune infiltrate in tumors and the angiogenic and angiostatic properties of the cells present. Special emphasis will be on the angiogenesis-associated activities of TAMs. The development of immunotherapy and gene therapy using TAMs to mediate tumor cytotoxicity or to deliver gene constructs will be discussed as well. As immunotherapy has so far not been as effective as anticipated, a combination therapy in which angiostatic agents are used as well is put forward as a novel strategy to treat cancer.

Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression.

The expression of endothelial cell (EC) adhesion molecules involved in leukocyte-vessel wall interactions is suppressed in malignancies. In the present study, we investigated in vivo the regulation of leukocyte-vessel wall interactions by the presence of a tumor. By means of intravital microscopy, tumor necrosis factor alpha-stimulated leukocyte-vessel wall interactions were studied in ear skin microvessels of nude mice bearing small human LS174T colon carcinomas and in C57Bl/6 mice bearing murine B16F10 melanomas. Leukocyte-vessel wall interactions were studied both within and outside small tumors growing in the ear, and in ear microvessels of mice with a large tumor growing on their flank. Tumor-free mice were used as controls. Compared with values measured at the edge of the ear and in the contralateral ear, leukocyte adhesion was found to be diminished significantly in vessels inside the ear tumor in both mouse models. This reduction disappeared with increasing distance from the tumor. Surprisingly, the level of leukocyte adhesion in ear venules of mice with a large flank tumor was also reduced significantly. Leukocyte rolling, i.e., the step preceding adhesion, was not influenced by the presence of a tumor in nude mice, but was down-regulated in immune-competent C57Bl/6 mice. Treatment of mice bearing a small ear tumor with a humanized antivascular endothelial growth factor antibody prevented the down-regulation of leukocyte-vessel wall interactions inside the tumor vessels compared with the nontreated group. Fluorescence-activated cell sorter analysis showed that isolated tumor ECs have suppressed levels of intercellular adhesion molecule 1 as compared with ECs from normal mouse tissues. In cultured b.END5 cells the tumor necrosis factor alpha-induced up-regulation of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 was reduced in ECs that were preincubated with basic fibroblast growth factor or vascular endothelial growth factor. The current results may have an impact on the effectiveness of clinical immunotherapeutic treatment protocols, because immune effector cells may not be able to enter tumor tissue.

[Treatment of spasticity in nursing homes: botulinum toxin type A as part of therapy]. / Behandeling van spasticiteit in verpleeghuizen: botulinetoxine A als onderdeel van de therapie.

Complications of spasticity can severely limit daily activities and care-giving. For those who treat or provide care to patients with spasticity in nursing homes, it is important to recognise complaints in order to prevent serious complications such as care-related pain, contractures and pressure sores. The involvement of a rehabilitation physician is essential to provide a high standard of care. We present two nursing home patients, a 95-year-old woman and a 63-year-old man, with severe upper limb complications following spasticity. Both patients received botulinum toxin injections in the affected muscles, combined with an appropriate splint. A treatment team consisting of a specialist in geriatric medicine, a rehabilitation physician, a physical and an occupational therapist provided consistent daily care in the institution. These efforts substantially reduced care-related pain and improved social behaviour and care options. If spasticity prohibits treatment or care, consultation of a rehabilitation physician at an early stage is indicated.

HIV-1 Tat increases the adhesion of monocytes and T-cells to the endothelium in vitro and in vivo: implications for AIDS-associated vasculopathy.

HIV-1-infected patients exhibit severe damages of the aortic endothelium, develop angioproliferative lesions such as Kaposi's sarcoma (KS), and have an increased risk of cardiovascular diseases and atherosclerosis. An increased adhesion of leukocytes to the endothelium is a common pathogenic parameter of AIDS-associated vascular diseases. Here we show that the HIV-1 Tat protein, a regulatory protein of HIV-1 released by infected cells, and TNF-alpha, a cytokine increased in sera and tissues of HIV-1-infected patients, activate synergistically the adhesion of leukocytes to endothelial cells both in vitro and in vivo. This effect is selectively mediated by HIV-1 Tat, since HIV-1 Nef, another HIV-1 regulatory protein, and the HIV-1 envelope protein gp41, had no effect. In vitro adhesion assays with PBMC and quantitative cell type analysis of adherent cells by FACS demonstrated that HIV-1 Tat selectively activates the adhesion of T-cells and monocytes but not of B-cells. Intravital microscopic studies in mice confirmed the synergistic activity of HIV-1 Tat and TNF-alpha on leukocyte adhesion to the endothelium in vivo. These data indicate that HIV-1 Tat in cooperation with TNF-alpha may contribute to the vascular damage and cardiovascular diseases observed in AIDS patients but also to the prominent extravasation of T-cells and monocytes which is a key process in the formation and progression of KS lesions.