Highlights from Recent Cancer Literature

Abstract

Coward J, Kulbe H, Chakravarty P, Leader DA, Vassileva V, Leinster DA, et al. Interleukin-6 as a therapeutic target in human ovarian cancer. Clin Cancer Res; Published OnlineFirst July 27, 2011; doi:10.1158/1078–0432.CCR-11-0945.Experiments in murine models of human cancer have revealed a significant role for the cytokine interleukin (IL)-6, mediated through induced intracellular signaling via transcription factor STAT3, in regulating inflammation-associated carcinogenesis. IL-6 is also present in the tumor microenvironment of many human cancers, where elevated plasma IL-6 represents a poor prognostic indicator. In human ovarian cancer biopsies, automated immunohistochemistry analyses similarly revealed that high levels of IL-6 in malignant, but not stromal cells, were associated with worse clinical outcomes. To determine if high levels of IL-6 represent a targeted anticancer therapy that could be translated for clinical use, Coward and colleagues combined preclinical and in silico experiments with a phase II clinical trial examining the anti–IL-6 antibody siltuximab in patients with platinum-resistant ovarian cancer. Siltuximab reduced constitutive cytokine and chemokine production, and STAT3 signaling in cultured ovarian cancer cells. When siltuximab was given to mice bearing human IL-6–producing peritoneal ovarian cancer xenografts, a reduction in tumor growth was accompanied by inhibition of tumor-associated macrophage infiltrate, angiogenesis, and STAT3 signaling in malignant cells as well as reductions in human IL-6, chemokines, and angiogenic factors in the tumor microenvironment. Together, these findings indicate that patients receiving siltuximab might exhibit a therapeutic response. Accordingly, in a limited phase II clinical trial (18 patients) in which siltuximab was well tolerated, 1 patient exhibited a partial response and 7 other patients showed extended periods of disease stabilization lasting up to 9 months. In 4 patients treated for 6 months, plasma levels of CCK2, CXCL12, and VEGF declined. Finally, mRNA expression levels of biomarkers reduced by siltuximab treatment were correlated with elevated gene expression of IL-6–induced mRNAs and macrophage markers in ovarian cancer gene expression microarrays. Hence, this study indicates that IL-6 stimulates inflammatory cytokine production by malignant cells, tumor angiogenesis, and macrophage infiltration, all of which were neutralized by anti–IL-6 antibody. Identification of biomarkers that show which patients are most likely to benefit from this novel therapy is certainly warranted. This work could help to determine the potential of combining IL-6 signaling blockade with chemotherapy, other immune therapies, or more specific targeted treatments.Liu C, Sage JC, Miller MR, Verhaak RG, Hippenmeyer S, Vogel H, et al. Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 2011;146:209–21.The cell of origin for glial brain tumors remains an area of active investigation. Results from mouse model studies suggest that such cells may reside in the subventricular zone, an area of ongoing neurogenesis. In addition, specific subtypes of glial tumors have been shown in both mouse and human studies to arise from oligodendroglial precursor cells (OPC), an abundant and proliferative population that resides primarily in white matter. Liu and colleagues used genetic mosaic analysis to generate mice carrying a limited number of cells deleted for the tumor suppressor genes p53 and Nf1, both of which have previously been implicated in human glioma. These studies validate earlier findings pointing to OPCs as cells of origin in glial malignancies driven by loss of Nf1 and p53.Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 2011;475:226–30.Hypoxia, immune evasion, and the formation of new blood vessels are key enabling characteristics of a progressing tumor microenvironment. A recent report has revealed that, at least in intraperitoneal ovarian cancer, a single chemokine might link this "vicious triad." Chemokines are chemoattractant cytokines that direct cell migration. Put simply, in cancers, chemokines control the movement of cells into and out of the tumor mass. While studying the effects of hypoxia on human ovarian cancer cell lines in vitro, Facciabene and colleagues observed that the chemokine CCL28 was frequently and highly upregulated. CCL28 is normally associated with mucosal immunity, but it also recruits immunosuppressive T-regulatory (Treg) cells during liver inflammation. Once they found that CCL28 levels in ovarian cancer biopsies were correlated with poor outcome and were also increased in hypoxic ovarian cancer xenografts, the investigators turned to a syngeneic murine ovarian cancer model to reveal its mechanism of action. Malignant cellproduced CCL28 recruited FoxP3+ Treg cells that also expressed the chemokine receptor CCR10—a receptor for CCL28. Overexpression of CCL28 in these models increased the Treg infiltrate and accelerated tumor growth; depletion of CCR10+ cells abrogated these actions. Importantly, the Treg cells not only contribute to immune tolerance but also produce the angiogeneic factor VEGFA. Whereas hypoxia can induce a type of cell death that can trigger immune rejection of tumors, induction of CCL28 is a mechanism to counteract this effect through recruitment of immune-suppressive and angiogenic Treg cells. When tissues are in a homeostatic state, their chemokine profile determines the phenotype of patroling and resident leukocytes. Based on this study, it will be interesting to determine if different chemokines have similar actions in tumors at other organ sites or whether CCL28 has a more universal role. As abrogation of immune tolerance is a major goal of successful immunotherapies, CCL28 and its CCR10 receptor are interesting new targets.Bettegowda C, Agrawal N, Jiao Y, Sausen M, Wood LD, Hruban RH, et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 2011 Aug 4. [Epub ahead of print].Gliomas represent the most common primary brain tumors. The majority of these tumors show features of astrocytes (astrocytomas), but about 10% are oligodendrogliomas, which show features of oligodendrocytes. The benefit of chemotherapy is more evident in oligodendroglioma in comparison with astrocytoma, with therapy-responsive patients generally showing loss of heterozygosity on large regions of chromosomes 1p and 19q. Bettegowda and colleagues performed exomic sequencing on 7 oligodendrogliomas. All tumors showed gain of function mutations in IDH1. Four tumors showed mutation in catalytic or regulatory subunits of PI3K, and 2 tumors showed mutations in NOTCH1. The CIC gene (homolog of the Drosophila gene capicua, a transcriptional repressor negatively regulated by RTK and MAP kinase signaling) maps to chromosome 19q; it was somatically mutated in 6 of 7 cases and in 12 of 27 tumors analyzed in a validation set. The FUBP1 gene, implicated in both positive and negative regulation of c-myc, maps to chromosome 1p, was somatically mutated in 2 fully sequenced tumors and in 3 of 27 tumors in the validation set. The identification of inactivating mutations in these candidate genes has potential to inform both biology and therapy in oligodendroglioma.Chan DA, Sutphin PD, Nguyen P, Turcotte S, Lai EW, Banh A, et al. Targeting GLUT1 and the Warburg Effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med 2011;3:94ra70.The Warburg Effect is widely touted as an Achilles' heel for cancer. Cancer cells undergo aerobic glycolysis, preferentially converting glucose to lactate. Aerobic glyocolysis is associated with significant energy cost, as normal cells preferentially and more efficiently generate ATP from glucose through oxidative phosphorylation. This energy cost in cancer cells is compensated by increased rates of glucose uptake and a relative inability to utilize other carbon sources. Taking advantage of the Warburg Effect in renal cancers, Chan and colleagues performed a synthetic lethal screen, identifying STF-31, a compound that blocked glucose uptake through the glucose transporter 1 (GLUT1) and that induced necrotic cell death in preclinical models of renal cell cancer (RCC). A majority of RCC is driven by loss of the Von Hippel-Lindau (VHL) tumor suppressor gene. VHL mutant RCC typically shows increased glucose transport that can be readily imaged clinically and preclinically through positron emission tomography (PET) using the glucose analogue [18F] fluorodeoxyglucose (FDG). In a xenograft model of RCC, treatment with STF-31 was associated with a consistent decrease in FDG-PET uptake, suggesting both diagnostic and therapeutic approaches potentially translatable to patients.Berndt A, Cario CL, Silva KA, Kennedy VE, Harrison DE, Paigen B, et al. Identification of Fat4 and Tsc22d1 as novel candidate genes for spontaneous pulmonary adenomas. Cancer Res 2011;71:5779–91.Athough many lung cancers are associated with environmental tobacco exposure, other spontaneous lung tumors have no known precipitating cause. To identify the molecular basis of these spontaneous tumors, Berndt and colleagues used a large-scale genomic approach with 28 strains of mice to evaluate differences in single-nucleotide polypeptides. This large study led to identification of 2 new genes associated with formation of spontaneous pulmonary adenomas, notably Fat4 and Tsc22d1. In particular, Fat4 was associated in male, and Tsc22d1 in female mice with pulmonary adenomas. Although future studies will undoubtedly be undertaken to evaluate the functional significance of Fat4 and Tsc22d1 in lung carcinogenesis, studies like this one illustrate the power of large-scale genomics and the utility of inbred strains of mice for identifying novel genetic elements in the pathogenesis of spontaneous lung tumors that may vary by gender-dependent mechanisms.Burden-Gulley SM, Qutaish M, Sullivant K, Lu H, Wang J, Craig SEL, et al. Novel cryo-imaging of the glioma tumor microenvironment reveals migration and dispersal pathways in vivid three-dimensional detail. Cancer Res 2011;71:5932–40.The importance of the tumor microenvironment is now axiomatic. However, most studies interrogate the tumor micronenvironment with 2- dimensional static imagry. Burden-Gulley and associates have developed an exciting new approach for tumor microenvironment analyses in which 3-dimensional (3D) images of cryo-tissue sections can be rendered with the aid of computer algorithms that faithfully reconstruct the architectural detail of the tumors. Using highly invasive human glioma tumors as a model, the authors were able to distinguish relative differences in the invasive characteristics among 5 different human tumor–derived cell lines linked to expression of the chemokine/chemokine receptor SDF-1a and CXCR4, Na+/H+ exchanger regulatory factor 1 (NHERF-1), ephrin B2, ephrin B3, and the EphB2 receptor, all of which were elevated in dispersive glioma tumors. Thus, detailed 3D tumor reconstruction is now feasible for evaluation of mechanistic effects of altered gene expression in tumors. This novel approach will enable important new insights into in vivo biology and the effects of therapeutics that may block the ability of glioma and other tumors to invade ectopic tissues.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.