Despite the high doses of radiation delivered in the treatment of patients with glioblastoma multiforme (GBM), the tumors invariably recur within the irradiation field, resulting in a low cure rate. Understanding the mechanism of such recurrence is therefore important. Here we have shown in an intracranial GBM xenograft model that irradiation induces recruitment of bone marrow–derived cells (BMDCs) into the tumors, restoring the radiation-damaged vasculature by vasculogenesis and thereby allowing the growth of surviving tumor cells. BMDC influx was initiated by induction of HIF-1 in the irradiated tumors, and blocking this influx prevented tumor recurrence. Previous studies have indicated that BMDCs are recruited to tumors in part through the interaction between the HIF-1–dependent stromal cell–derived factor–1 (SDF-1) and its receptor, CXCR4. Pharmacologic inhibition of HIF-1 or of the SDF-1/CXCR4 interaction prevented the influx of BMDCs, primarily CD11b⁺ myelomonocytes, and the postirradiation development of functional tumor vasculature, resulting in abrogation of tumor regrowth. Similar results were found using neutralizing antibodies against CXCR4. Our data therefore suggest a novel approach for the treatment of GBM: in addition to radiotherapy, the vasculogenesis pathway needs to be blocked, and this can be accomplished using the clinically approved drug AMD3100, a small molecule inhibitor of SDF-1/CXCR4 interactions.

SIRT7 is an H3K18Ac-selective deacetylase that has a pivotal role in chromatin regulation, maintenance of cellular transformation programs and tumour formation in vivo. The mammalian sirtuin protein SIRT7 has been linked to the transcription of ribosomal RNA but, unlike other known human sirtuins, its substrates and physiological function are not clear. This paper reports an enzyme activity for SIRT7 and provides several strands of evidence linking SIRT7 activity to the maintenance of fundamental cancer-cell phenotypes and tumour progression. SIRT7 acts as a histone deacetylase specific for H3 lysine 18, and promotes transcriptional repression. SIRT7 target genes have links to tumour suppression, and the oncogenic transcription factor ELK4 can recruit SIRT7 to target promoters. SIRT7 is required for the maintenance of cellular transformation and tumour growth in mice. Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism and ageing1,2. SIRT7 is a mammalian sirtuin whose biochemical activity, molecular targets and physiological functions have been unclear. Here we show that SIRT7 is an NAD+-dependent H3K18Ac (acetylated lysine 18 of histone H3) deacetylase that stabilizes the transformed state of cancer cells. Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. The spectrum of SIRT7 target genes is defined in part by its interaction with the cancer-associated E26 transformed specific (ETS) transcription factor ELK4, and comprises numerous genes with links to tumour suppression. Notably, selective hypoacetylation of H3K18Ac has been linked to oncogenic transformation, and in patients is associated with aggressive tumour phenotypes and poor prognosis3,4,5,6. We find that deacetylation of H3K18Ac by SIRT7 is necessary for maintaining essential features of human cancer cells, including anchorage-independent growth and escape from contact inhibition. Moreover, SIRT7 is necessary for a global hypoacetylation of H3K18Ac associated with cellular transformation by the viral oncoprotein E1A. Finally, SIRT7 depletion markedly reduces the tumorigenicity of human cancer cell xenografts in mice. Together, our work establishes SIRT7 as a highly selective H3K18Ac deacetylase and demonstrates a pivotal role for SIRT7 in chromatin regulation, cellular transformation programs and tumour formation in vivo.

Despite the fact that radiation is one of the standard therapies in the treatment of patients with oral cancer, tumours can recur even in the early stages of the disease, negatively impacting prognosis and quality of life. We previously found that CD11b⁺ bone marrow-derived cells (BMDCs) were recruited into human glioblastoma multiforme (GBM), leading to re-organization of the vasculature and tumour regrowth. However, it is not yet known how these cells contribute to tumour vascularization. In the present study, we investigated the role of infiltrating CD11b⁺ myeloid cells in the vascularization and recurrence of oral squamous cell carcinoma (OSCC). In a xenograft mouse model, local irradiation caused vascular damage and hypoxia in the tumour and increased infiltration of CD11b⁺ myeloid cells. These infiltrating cells showed characteristics of M2 macrophages (M2Mφs) and are associated with the promotion of vascularization. M2Mφs promoted tumour progression in recurrence after irradiation compared to non-irradiated tumours. In addition, we found that CD11b⁺ myeloid cells, as well as CD206⁺ M2Mφs, are increased during recurrence after radiotherapy in human OSCC specimens. Our findings may lead to the development of potential clinical biomarkers or treatment targets in irradiated OSCC patients.

BACKGROUND: Epithelial ovarian cancer demonstrates high mortality due to diagnosis at an advanced stage. In the search for a biomarker for early diagnosis and a target for therapy, the issue of whether interleukin‐13 receptor (IL‐13R), shown to be expressed on a variety of human cancers, is expressed in ovarian tumor samples was explored. In addition, whether this receptor serves as a biomarker and can be targeted by IL‐13 cytotoxin was examined.METHODS: IL‐13R expression in 15 normal and 68 ovarian tumor tissue samples was determined by immunohistochemistry. Correlation between clinicopathologic features and IL‐13R expression was analyzed. The efficacy of IL‐13R‐directed cytotoxin was determined in mice with subcutaneous, orthotopic, and peritoneal metastatic ovarian cancer.RESULTS: Immunohistochemical analyses revealed that 83% of ovarian cancer specimens express IL‐13Rα2, a high‐affinity IL‐13R subunit chain, whereas normal ovary samples expressed none or very low levels. The majority of clear cell ovarian carcinomas with the worst prognosis showed strong staining for IL‐13Rα2. IL‐13 cytotoxin was highly cytotoxic to the IGROV‐1 ovarian cancer cell line in vitro, and it mediated significant antitumor activity against a xenografted tumor model. The antitumor effects were confirmed by treating orthotopically implanted or peritoneal metastatic ovarian tumors, which showed significant extension of survival in immunodeficient mice. IL‐13 cytotoxin also prevented cachexia in treated mice. The soluble form of IL‐13Rα2 was detected in the serum of mice with peritoneal metastasis, and the level decreased to baseline in the treated group.CONCLUSIONS: IL‐13Rα2 is a promising target for ovarian cancer therapy, and the soluble form of IL‐13R may be a possible surrogate marker for disease monitoring. Cancer. Published 2006 by the American Cancer Society.