Spotlight

Abstract

Radfar et al., pp.214–223 Human pancreatic cancer is a leading cause of cancer death and carries an extremely poor prognosis. Fas expression, which is required for Fas ligand-mediated programmed cell death, is often lost in these tumors and this loss correlates with malignant transformation and biologic aggressiveness. With respect to Fas expression, discrepancies have also been observed between tumor samples and cancer cell lines in terms of Fas expression. Radfar and colleagues have studied the expression of Fas in Capan-1 human cancerous pancreatic duct cells. They report that Capan-1 cells express Fas and are sensitive to Fas-mediated apoptosis when maintained in culture. However, when these cells were grown as xenografts in nude mice, expression of Fas was lost in the majority of the tumors. Cell lines rederived from these tumors became Fas positive and sensitive to Fas-mediated apoptosis after a short cultivation time in vitro. These observations demonstrate that the environment of the mice selects in a reversible fashion for a loss of Fas expression. The loss of Fas expression in vivo is therefore likely to play an important role in the evasion of tumor cells from immune surveillance. Dings et al., pp.312–319 Targeting a tumor's vasculature is a promising anticancer strategy. However, most preclinical studies suggest that angiogenesis inhibitors may be best used as adjuvants to conventional radiation or chemotherapy. A study featured in this issue provides intriguing new insights into the synergistic action of an antiangiogenic agent and radiation therapy. The efficacy of anginex, a β-sheet-forming peptide with known antiangiogenic properties, to enhance suboptimal radiotherapy was tested in the MA148 human ovarian carcinoma mouse model and the SCK breast carcinoma model. Since the half-life of anginex lies between 50 and 90 minutes, animals were continuously treated via an osmotic pump subcutaneously implanted into the left flank. A combination of anginex and a low dose of radiotherapy caused complete regression of MA148 tumors. Although microscopic disease persisted and tumors recurred after the end of therapy, a complete regression of established tumors has previously not been observed following this type of combination treatment. In the more aggressive SCK model, twice the dose of anginex and a single X-ray dose of 25 Gy inhibited tumor growth by 60%. Microvessel density was reduced 3–fold after combined treatment as determined by anti-CD31 staining of tumor sections. Remarkably, angiostatin, another antiangiogenic agent, was previously ineffective in enhancing the radiation treatment of SCK tumors. The authors were intrigued by the early onset of the radiosensitizing action of anginex in both tumor models. In a set of in vitro experiments, anginex specifically inhibited endothelial cell proliferation, but did not affect growth of MA148 or SCK tumor cells. These results support a model in which the peptide inhibits the adhesion and migration of endothelial cells on the extracellular matrix, thereby potentiating the effect of radiation therapy on this cell type. The therapeutic efficacy and safety of anginex are encouraging with respect to a potential clinical application and could outweigh the practical restraints attached to the application format of the peptide. Shafren et al., pp.320–328 Ovarian cancer remains one of the deadliest malignancies in women. Since it is often detected at a late stage, cancer cells can be widely disseminated across the peritoneal surface. The potential of oncolytic viruses to establish a spreading infection among susceptible neoplastic cells provides an attractive reservoir for the control of disseminated disease. Integrin α2β1, the receptor for echovirus type 1 (EV1), is a surface molecule expressed at high levels on ovarian cancer cells. Integrin α2β1 naturally binds type 1 collagen. However, it cannot simultaneously accommodate both EV1 and collagen and binds EV1 with a 10-fold higher affinity than collagen. Shafren and colleagues demonstrate the capacity of EV1 to induce lytic infection of cultured human ovarian cancer cells. Importantly, direct inoculation of EV1 into one of 2 preformed ovarian xenografts in nude mice inhibited tumor growth not only of the inoculated tumor but also of the xenograft distant to the injection site. EV1 was also effective in the mouse ascites model of human ovarian cancer, indicating spreading lytic infection of disseminated neoplastic cells. It is likely that EV1 not only mediates cell oncolysis but also interferes with interactions between type 1 collagen and α2β1- integrin, thereby reducing the fatal dissemination of ovarian cancer cells. Natural infection with EV1 is usually asymptomatic although mild upper respiratory infections might occur. In addition, the authors point out that a novel antienteroviral drug (pleconaril) could be used to control exacerbated EV1 infection. They also point out that further studies using immune-competent mice are needed to address the role of the host immune response in therapeutic EV1 infection. Echovirus type 1 casid proteins VP1 (blue), 2 (green) and 3 (red) compete with type 1 collagen for binding to integrin α2β1, expressed on the surface of ovarian cancer cells.