Annalisa Zambon

MAGE, BAGE, and GAGE gene expression in patients with esophageal squamous cell carcinoma and adenocarcinoma of the gastric cardia

The MAGE, BAGE, and GAGE gene families code for distinct, tumor specific antigens that are recognized by cytotoxic T lymphocytes in the context of HLA molecules. The purpose of this study was to analyze MAGE, BAGE, and GAGE gene expression in the two major histologic types of esophageal carcinoma, squamous carcinoma (ESCc) and adenocarcinoma (CAc), and to correlate their expression patterns with the principal prognostic parameters and long term survival.

MAGE, BAGE and GAGE gene expression in human rhabdomyosarcomas

MAGE, BAGE and GAGE genes encode tumor‐associated antigens that are presented by HLA class I molecules and recognized by CD8+ cytolytic T lymphocytes. These antigens are currently regarded as promising targets for active, specific tumor immunotherapy because MAGE, BAGE and GAGE genes are expressed in many human cancers of different histotype and are silent in normal tissues, with the exception of spermatogonia and placental cells. MAGE, BAGE and GAGE gene expression has been extensively studied in different tumors of adults but is largely unknown in many forms of pediatric solid cancer. Using RT‐PCR, we analyzed MAGE‐1, MAGE‐2, MAGE‐3, MAGE‐4, MAGE‐6, BAGE, GAGE‐1,‐2 or ‐8 and GAGE‐3,‐4,‐5,‐6 or ‐7b gene expression in 31 samples of pediatric rhabdomyosarcoma, the most frequent form of malignant soft tissue tumor in children. MAGE genes were expressed in a substantial proportion of patients (MAGE‐1, 38%; MAGE‐2, 51%; MAGE‐3, 35%; MAGE‐4, 22%; MAGE‐6, 35%), while expression of BAGE (6%); GAGE‐1, GAGE‐2 and GAGE‐8 (9%); and GAGE‐3, GAGE‐4, GAGE‐5, GAGE‐6 and GAGE‐7B (16%) was less frequent. Overall, 58% of tumors expressed at least 1 gene, and 35% expressed 3 or more genes simultaneously. Our data suggest that a subset of rhabdomyosarcoma patients could be eligible for active, specific immunotherapy directed against MAGE, BAGE and GAGE antigens.

The P2Z Receptor and Its Regulation of Macrophage Function

In 1967 the late Zanvil A. Cohn reported that adenine nucleotides had striking effects on the morphology and pinocytic activity of mouse macrophages [1]. These early studies were followed by the demonstration by Sung et al. that extracellular ATP (ATPe) caused plasma membrane depolarization, increased intracellular Ca2+ ([Ca2+]i), and inhibition of Fc receptor-mediated phagocytosis [2]. These intriguing effects remained unexplained until the work by Steinberg and Silverstein, who started a thorough investigation of the mechanism of macrophage responses to extracellular nucleotides, ATP in particular [3,4].

DNA immunization in mice against virus-induced tumor antigens.

Moloney-murine sarcoma virus (M-MS V) is a replication-defective, acutely transforming retrovirus that requires the helper function of Moloney-murine leukemia virus (M-MuLV) for replication. The intramuscular injection of M-MSV/M-MuLV gives rise to sarcomas that develop at the inoculation site after a short latency period, and regress spontaneously following the induction of a strong immune reaction, which is mediated mainly by cytotoxic T lymphocytes (CTL) specific for viral antigens. C57BL/6 (B6) and Balb/c mice that have rejected a M-MSV/M-MuLV-induced sarcoma (hereafter indicated as “regressors”) are also able to survive a lethal tumor challenge with the syngeneic M-MuLV-transformed MBL-2 and LSTRA leukemia cell lines, respectively. Therefore, in this experimental tumor model, virus antigens behave as tumor-associated antigens (TAA) [1]. As DNA-based vaccines have been reported to induce a powerful humoral and cellular immune response against several viral agents [2], we explored the possibility of inducing CTL generation and in vivo protection against syngeneic tumor cell challenge in B6 and Balb/c mice by means of immunization with plasmid DNA vectors encoding gag or env structural antigens of M-MSV/M-MuLV.

CTL Analysis for Tumor Vaccines

Many studies have been conducted with the aim to stimulate a therapeutic immune response against tumors. In most cases, efforts have been directed toward the induction of tumor-specific cytotoxic T lymphocytes (CTL), because this T lymphocyte subpopulation is considered to play a major role in the destruction of tumor cells (1). In particular, vaccination protocols have been designed to increase the immunogenicity of intact cancer cells by using adjuvants or engineering tumor cells with cytokine or costimulatory molecule genes. A second line of research has employed immunization with tumor-associated antigens (TAA). These antigens are expressed from derepressed or mutated genes in tumor cells, and are recognized by CTL in the form of peptides associated with MHC class I molecules. Genes encoding TAA have been inserted into recombinant viral vectors, which are then used to infect the hosts cells and induce expression of the transgene. Moreover, immunization with purified TAA peptides or with antigen-presenting cells, such as dendritic cells, pulsed with TAA peptides have been proposed.