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View the Table of Contents for the May 15 issue of Cancer Research
Ackermann et al. Page 4005
Activation of N-RAS is one of the most frequent oncogenic alterations found in human melanoma. To mimic this disease in mice, Ackermann et al. targeted expression of a dominant-active human N-RAS gene (N-RASQ61K) to melanocytes. Upon additional inactivation of the INK4a locus, encoding the tumor suppressors p16INK4A and p19ARF, hyper-pigmented N-ras mice develop cutaneous metastasizing melanoma. Thus melanoma highly similar to human disease can be modeled in mice by recapitulating the human mutations. This model can be used to elucidate mechanisms of melanoma progression and metastasis formation, and further may be used for preclinical testing of novel therapies.
Tothill et al. Page 4031
Cancer of unknown primary (CUP) remains a diagnostic and clinical problem. In this issue, Tothill et al. have demonstrated the application of expression profiling for diagnosing the primary site of CUP tumors. Building a comprehensive expression dataset using cDNA microarrays, they applied a support vector machine for the classification of CUP tumors. They found they could confidently predict adenocarcinomas of unknown primary site. They further report translation of the classifier to quantitative real time PCR, demonstrating its utility on archived formalin fixed paraffin embedded tissue. Improved diagnosis for CUP will enable a more specific cancer treatment and reduce the cost of investigation.
Yamauchi et al. Page 4246
Cancer cell deformation and migration in narrow vessels is a critical step in metastasis. To visualize cytoplasmic and nuclear dynamics of cells migrating in capillaries, Yamauchi et al. induced expression of red fluorescent protein (RFP) in the cytoplasm and green fluorescent protein (GFP), linked to histone H2B, in the nucleus of cancer cells. The migration and deformation of the cancer cells and their nuclei in small capillaries were measured by capturing images of the dual-color fluorescent cells over time in living mice. The imaging of real-time intracapillary cellular dynamics enables us to visualize how cancers metastasize to distant sites.
Wedge et al. Page 4389
Inhibition of VEGF signaling has recently been proven to provide therapeutic benefit to patients with solid tumors. AZD2171, a highly potent small molecule inhibitor of VEGF receptor-2 (KDR) tyrosine kinase described by Wedge et al., is found to inhibit VEGF-induced responses in human endothelial cells at subnanomolar concentrations. The compound can inhibit growth of human tumor xenografts in mice following oral administration of < 1 mg/kg/day. AZD2171 demonstrates potent anti-angiogenic effects in vivo and can induce progressive vascular regression in tumors. This approach holds promising potential as a once-daily oral antitumor therapy.
Ito et al. Page 4417
Multiple myeloma is an incurable hematological malignancy which has been associated with fatal outcomes despite high dose chemotherapy with stem cell transplantation. Therefore, a new therapeutic approach has been desired in the clinical settings. Ito et al. found that 1’-acetoxychavichol acetate (ACA), a traditional Asian condiment, induced apoptosis of myeloma cells in vitro and in vivo. ACA inhibited serine phosphorylation and degradation of IκBα. ACA rapidly decreased the nuclear expression of NF-κB, but increased the accumulation of cytosol NF-κB in myeloma cells. These results indicate that, as a novel NF-κB inhibitor, ACA provides a new biologically-based treatment for multiple myeloma patients.