Dissemination Of Malignant Tumors Research Articles

Cytokine Intervention: A Double Edged Sword in the Nkg2d System Regulation

The natural killer group 2 members D (NKG2D) is an activating receptor which plays a major role in immune surveillance, and the detection and elimination of malignant tumors and infected cells. NKG2D acts over both arms of the vertebrate immune response, and is expressed in some human and mouse myelopoietic, γδ T, NKT and CD4+ cells, but is present in all NK and CD8+ T cells in humans and activated mouse CD8+ T cells. In humans, eight ligands which selectively bind to the NKG2D receptor have been identified. These ligands are not systemically expressed, but are triggered in response to stress and expressed only under specific pathological states. Several research results point to the importance of cytokines for increasing expression of NKG2D to restore the functionality of NK cells as well as their ligands in the target cells. However, the NKG2D system itself in an activated state, also release pro and anti-inflammatory cytokine transcripts to establish communication with other cells or for self-regulation. Additionally, type I antiviral interferon is largely produced. Such cytokine interactions could be regarded as a double edged sword. This behavior is emphasized by a discrepancy regarding the functionality of cytokines which interact with, or on the NKG2D system. Indeed, they seem to protect the host and rather can induce ligand expression, cell proliferation or dissemination of malignant tumors, generating complicated cytokine-mediated messenger loops which are far from being fully understood. Whatever the case, cytokines related to the NKG2D system could be an attractive and useful target for immunotherapeutic approaches. Thus, here we briefly review recent findings on the main aspects involved in the regulation of this system and, particularly, attempt to clarify the role played by cytokines in the activating or inhibitory function they exert over the NKG2D system in different contexts.

Effects of Infliximab and Hydrocortisone on In Vitro Cytokine Responses after Stimulation with Lipopolysaccharide

Both glucocorticosteroids and biologic drugs such as the tumor necrosis factor (TNF)-α antagonist infliximab are used often in the treatment of rheumatoid arthritis or inflammatory bowel disease. In severe disease, or if allergic reactions occur during treatment with infliximab, combined therapy with these drugs often is instituted. Combining infliximab and glucocorticosteroids may increase substantially the risk of severe opportunistic infections or dissemination of malignant tumors because of their additive effects as immunosuppressants. In a whole-blood in vitro model, we studied the influence of different doses of infliximab and hydrocortisone, either separately or in combination, on the synthesis of selected cytokines after stimulation with lipopolysaccharide (LPS). Hydrocortisone in therapeutic serum concentrations significantly inhibited the expression of a majority of the cytokines tested. Infliximab, in serum concentrations relevant to clinical situations, inhibited TNF-α activity significantly. This effect was potentiated when infliximab was combined with hydrocortisone. Similar effects were found using a low dose of infliximab combined with hydrocortisone. Infliximab alone inhibited the expression of the cytokines interleukin (IL)-1 receptor antagonist, monocyte chemoattractant protein-1, IL-8, and IL-12. Hydrocortisone in combination with low-dose infliximab potentiated the suppressive effects on TNF-α, IL-1β, IL-8, and macrophage inflammatory protein-1α synthesis. Immune-modulating effects of infliximab were found both in clinically relevant doses and, most notably, in low doses reflecting serum concentrations found commonly in patients several months after the last injection. Infliximab potentiates the suppressive effects of hydrocortisone on cytokine synthesis.

Enhanced anti-tumor effect of intra-peritoneal paclitaxel by nuclear factor-kappaB inhibition for peritoneal dissemination of gastric cancer in mice

INTRODUCTION: Intra-peritoneal administration (i.p.) of paclitaxel is a useful treatment for peritoneal dissemination of malignant tumors, but the therapeutic efficacy is limited. Chemoresistance due to paclitaxel-induced nuclear factor-kappaB (NF-kappaB) activation is an important cause of suboptimal therapeutic effect. We previously reported that nafamostat mesilate (FUT175), a synthetic serine protease inhibitor, inhibits NF-kappaB activation due to suppression of IkappaBalpha phosphorylation and promotes caspase-8-mediated apoptosis in pancreatic cancer. We hypothesized that addition of FUT175 to i.p. paclitaxel may enhance anti-tumor effect in peritoneal dissemination of gastric cancer.

Interleukin-6, Secreted by Human Ovarian Carcinoma Cells, Is a Potent Proangiogenic Cytokine

Angiogenesis, a key rate-limiting step in the growth and dissemination of malignant tumors, is regulated by the balance between positive and negative effectors. Recent studies indicate that the pleiotropic cytokine interleukin-6 (IL-6) may contribute to the vascularization of some tumors by disrupting the equilibrium between positive and negative angiogenic regulatory molecules. We determined whether IL-6 participates in the angiogenesis observed during the progression of ovarian carcinoma. We measured IL-6 production by human ovarian cancer cell lines in vitro and in vivo. Not all cell lines secreted IL-6 in vitro; however, when the cell lines were implanted into the peritoneal cavity of female nude mice, every line secreted IL-6. Most human ovarian carcinoma cell lines tested secreted significant levels of the soluble IL-6 receptor (sIL-6R). Endothelial cell lines established from the ovary and mesentery of female H-2K(b)-tsA58 mice were tested for response to IL-6. Both endothelial cell lines expressed the IL-6R and their stimulation with the exogenous ligand significantly enhanced cell migration and activated the downstream signaling molecule signal transducers and activators of transcription 3. Dual immunohistochemical staining for IL-6R and CD31 revealed IL-6R expression on human endothelial cells within normal ovary and carcinoma specimens. Gelfoam sponges containing 0.4% agarose and IL-6 or basic fibroblast growth factor and implanted into the subcutis of BALB/c mice were vascularized to the same extent. Collectively, the data indicate that ovarian tumor cells secreted IL-6, a highly angiogenic cytokine that supports progression of disease.

Effective inhibition of experimental metastasis and prolongation of survival in mice by a potent factor Xa-specific synthetic serine protease inhibitor with weak anticoagulant activity

Clinical and experimental evidence suggests that the blood coagulation system is involved in the dissemination of malignant tumors. Consequently, anticoagulant agents have been tested as metastasis suppressors in experimental models. Recently, we have found a close correlation between factor Xa (FXa)-specificity of a series of synthetic serine protease inhibitors and their anti-metastatic potential in a murine T-cell lymphoma metastasis model. Interference of such inhibitors with blood-coagulation may represent a major experimental and clinical obstacle. Here, we test anti-metastatic effects of a recently developed, highly specific 3-amidinophenylalanine-type FXa inhibitor, WX-FX4, with weaker anticoagulant activity when compared to well-established FXa inhibitors, such as DX-9065a, as measured by the activated partial thromboplastin time, prothrombin time, prothrombinase complex activity, and coagulation time. Treatment of mice with WX-FX4 (1.5 mg/kg twice daily) led to significant reduction of experimental liver metastasis of a syngeneic T-cell lymphoma in DBA/2 mice (> 90%), and of experimental lung metastasis of a human fibrosarcoma in CD1 nu/nu mice (> 60%). Due to its relatively low anticoagulant activity, daily treatment over 100 days was possible, leading to significant survival benefits without inducing bleeding anomalities. FXa-inhibitors with highly efficient anti-metastatic potential without coagulation-related side effects may represent important new tools as anticancer agents.

The Czech experience in peritonectomy and hyperthermic perioperative cytostatic lavage in the treatment of peritoneal malignancy

Peritoneal tumor dissemination has been considered as an incurable condition with fatal outcome. However cytoreductive surgery followed immediately by hyperthermic chemoperfusion has been described both for the treatment and prevention of locoregional cancer spread from various origins. This paper summarizes our experience in this field. 28 patients were operated on for peritoneal dissemination of malignant tumors between 1999 and 2002 in the Surgical Department of the University Hospital Bulovka. Total or limited peritonectomy was carried out in these patients. In addition intraperitoneal perioperative hyperthermic chemoperfusion was performed using an electrolyte solution containing Mitomycin C, Cisplatin or Carboplatin. The perfusion was performed for 90 minutes, reaching a real hyperthermia of 41 to 43 degrees C. The overall morbidity was high (85.7%), the perioperative mortality (30 days) was 10.7%. Only 3 (15.7%) of 19 patients in whom complete peritonectomy could be carried out died during the follow-up period of 3 months to 3.5 years. There is an increasing evidence of both experimental and clinical studies showing the therapeutic and prophylactic usefulness of peritonectomy and perioperative hyperthermic chemoperfusion in patients with peritoneal carcinomatosis. However, well designed randomised trials are necessary to establish the role of this promising technique.

Key determinants of the invasion mechanism of melanoma. Role for a new signaling pathway.

Dissemination of malignant tumors (metastasis) is a cascade consisting of detachment of cells from the primary tumor, invasion of the surrounding extracellular matrix (ECM), intravasation, dissemination in the circulatory system, adhesion to the vessel wall, extravasation and growth at secondary sites. It is clear that tumor cell-ECM interactions are extremely important during these steps (1). Tumor cell-ECM interactions are mediated by adhesion receptors; integrins (2), non-integrins (3) and proteoglycans (4), motility-receptors and enzymes responsible for digestion (1). The two major aspects of tumor progression are; cell proliferation and cell-cell/cell-matrix interactions (1). During tumor cell dissemination, adhesive processes become more significant than the proliferation. The in-tegrin receptors on tumor cells have been shown to be involved in different steps of the metastatic cascade: adhesion to and spreading on matrices, in cellular migration as well as in vivo metastasis (5). Among the different integrin receptors β3-s have been implicated in melanoma-ECM interactions thereby influencing the metastatic phenotype (5).KeywordsMelanoma CellTumor Cell AdhesionAmelanotic MelanomaaIIb133 IntegrinAutocrine Motility FactorThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Dissemination of malignant tumors after video-assisted thoracic surgery: A report of twenty-one cases

Video-assisted thoracic surgical techniques are widely used for biopsy and resection of thoracic tumors, but studies of long-term outcomes have not been reported. Dissemination of tumor by these techniques is a potential hazard. Therefore we surveyed the surgical members of the Video-Assisted Thoracic Surgery Study Group to determine whether tumor implants thought to be directly related to video-assisted techniques had occurred. Surgeons reported 21 cases. The sites of recurrence were the incision (n = 14), pulmonary staple line (n = 2), pleura (n = 2), both staple line and incision (n = 1), both pleura and incision (n = 1), and both pleura and staple line (n = 1). Review of these cases illustrates the pitfalls of present video-assisted techniques for malignant tumors of the thorax. (J T HORAC C ARDIOVASC S URG 1996;111:954-60)

Effect of interferon in therapy of skin and head and neck tumors.

The clinical experimental model of HLI application in the therapy of skin and mucosal cancers of the head and neck has opened new prospects in HLI utilization. Based on clinical observations and research it may be concluded that HLI, if applied topically in the area of the tumor, may induce its disappearance or regression. If applied presurgically, it blocks the dispersion of neocytes during surgery. Also, HLI inhibits metastatic dissemination of malignant tumors and therefore might reduce the percentage of patients with recurrence, decreasing the chance of survival of any other primary tumor.