Identification of the angiogenic endothelial-cell growth factor-1/thymidine phosphorylase as a potential target for immunotherapy of cancer

Leiden University, Leyden, South Holland, Netherlands
Blood (Impact Factor: 10.45). 07/2006; 107(12):4954-60. DOI: 10.1182/blood-2005-09-3883
Source: PubMed


Characterization of the antigens recognized by tumor-reactive T cells isolated from patients successfully treated with allogeneic HLA-matched hematopoietic stem cell transplantation (SCT) can lead to the identification of clinically relevant target molecules. We isolated tumor-reactive cytotoxic CD8(+) T-cell (CTL) clones from a patient successfully treated with donor lymphocyte infusion for relapsed multiple myeloma after allogeneic HLA-matched SCT. Using cDNA expression cloning, the target molecule of an HLA-B7-restricted CTL clone was identified. The CTL clone recognized a minor histocompatibility antigen produced by a single nucleotide polymorphism (SNP) in the angiogenic endothelial-cell growth factor-1 (ECGF1) gene also known as thymidine phosphorylase. The SNP leads to an Arg-to-His substitution in an alternatively translated peptide that is recognized by the CTL. The ECGF1 gene is predominantly expressed in hematopoietic cells, although low expression can also be detected in other tissues. The patient from whom this CTL clone was isolated had mild graft-versus-host disease despite high numbers of circulating ECGF-1-specific T cells as detected by tetramer staining. Because solid tumors expressing ECGF-1 could also be lysed by the CTL, ECGF-1 is an interesting target for immunotherapy of both hematologic and solid tumors.

Download full-text


Available from: M.G.D. Kester, Oct 01, 2015
11 Reads
  • Source
    • "Its expression is reduces by ~90% after treatment. Interestingly, multiple studies found Hif-1α is a key regulator of angiogenic factors including CXCL6, ECGF1, EFNB2, IL8, PDGFB, TNFRSF12A, FGF2 [50,51,53–58]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Patients with ovarian cancer (OC) may be treated with surgery, chemotherapy and/or radiation therapy, although none of these strategies are very effective. Several plant-based natural products/dietary supplements, including extracts from Emblicaofficinalis (Amla), have demonstrated potent anti-neoplastic properties. In this study we determined that Amla extract (AE) has anti-proliferative effects on OC cells under both in vitro and in vivo conditions. We also determined the anti-proliferative effects one of the components of AE, quercetin, on OC cells under in vitro conditions. AE did not induce apoptotic cell death, but did significantly increase the expression of the autophagic proteins beclin1 and LC3B-II under in vitro conditions. Quercetin also increased the expression of the autophagic proteins beclin1 and LC3B-II under in vitro conditions. AE also significantly reduced the expression of several angiogenic genes, including hypoxia-inducible factor 1α (HIF-1α) in OVCAR3 cells. AE acted synergistically with cisplatin to reduce cell proliferation and increase expression of the autophagic proteins beclin1 and LC3B-II under in vitro conditions. AE also had anti-proliferative effects and induced the expression of the autophagic proteins beclin1 and LC3B-II in mouse xenograft tumors. Additionally, AE reduced endothelial cell antigen - CD31 positive blood vessels and HIF-1α expression in mouse xenograft tumors. Together, these studies indicate that AE inhibits OC cell growth both in vitro and in vivo possibly via inhibition of angiogenesis and activation of autophagy in OC. Thus AE may prove useful as an alternative or adjunct therapeutic approach in helping to fight OC.
    PLoS ONE 08/2013; 8(8):e72748. DOI:10.1371/journal.pone.0072748 · 3.23 Impact Factor
  • Source
    • "When 5′-DFUR enters the tumor tissue, it is converted into 5-FU that has antitumor activity by TP. 5-FU functions in targeted-antitumor effect by blocking the DNA synthesis of tumor cells3. Slager et al.14 stated that TP is a target in oncotherapy processes with 5-FU and derivatives, and has an important function in growth, development, and metastasis processes of tumor. In 1998, Schwartz et al.15, transferred the INF gene into HT29 colorectal carcinoma cells, and found that the levels of TP proteins and mRNA increased. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Thymidine phosphorylase (TP) is a key enzyme that contributes to the composition and decomposition of pyrimidine nucleotides. TP seems homologous to platelet-derived endothelial cell growth factor, and its effects on inducing vascularization and anti-apoptosis are closely related to growth and metastasis of colorectal carcinoma. In addition, TP is a key enzyme that catalyzes the transformation from 5-fluorouracil (FU) prodrugs of 5′-deoxy-5-fluorouridine (5′-DFUR) to 5-FU. The activity of TP is closely related to the sensitivity of colorectal carcinoma cells to fluorouracil drugs and targeted therapy. Given the important functions of TP in growth, metastasis, tumor treatment, and prognosis, determining its expression mechanism is significant. This article summarizes the research development of TP expression in colorectal carcinoma, tumor neovascularization, cytotoxicity activation of 5′-DFUR, and colorectal carcinoma therapy.
    Cancer Biology and Medicine 06/2013; 10(2):121. DOI:10.7497/j.issn.2095-3941.2013.02.011
  • [Show abstract] [Hide abstract]
    ABSTRACT: Almost 100 years ago, Ehrlich and coworkers observed the presence of infiltrates of mononuclear cells around or inside tumor lesions [1]. This finding led them to propose that tumors could be recognized and inhibited by the ‘magic bullets’ of the immune system. At the end of the 19th century, studies were initiated that aimed at actively immunizing cancer patients against their own cancerous tissue. During the subsequent decades, cancer patients were nonspecifically immune-stimulated with relatively crude leukocyte extracts such as transfer factor, immune- RNA, bacterial extracts such as bacillus Calmette- Guerain, Coley’s toxin or levamisole. These studies were initiated in spite of the fact that little was known about the various components of the immune system that could react against cancer, and even less was known about the structures on cancer cells that can be recognized by the immune system.
Show more