Latest Articles Include:
- Taming Supplemental Material
- Cancer Cell 16(4):269 (2009)
- Can Treating the SYK Cell Cure Leukemia?
- Cancer Cell 16(4):270-271 (2009)
Targeted therapy has remained elusive for most acute myeloid leukemia patients. In this issue of Cancer Cell, Stegmaier and colleagues identify SYK as a key mediator of the differentiation block seen in this disease. Their data suggest that SYK inhibition may be an effective therapy for a significant proportion of AMLs. - Lymphotoxins: New Targets for Hepatocellular Carcinoma
- Cancer Cell 16(4):272-273 (2009)
In this issue of Cancer Cell, Haybaeck et al. unravel the role of lymphotoxin pathway in the development of hepatocellular carcinoma (HCC). Aberrant activation of this cascade in mice livers recapitulates the stages of fibrosis and inflammation that precedes human liver cancer, providing a novel family of potential therapeutic targets. - No Way Out for Tumor Cells
- Cancer Cell 16(4):274-275 (2009)
In this issue of Cancer Cell, Huang et al. report that preventing exit from mitosis provides a very efficient strategy for killing cells. Although this is not an unexpected finding, it nevertheless provides a novel conceptual framework for augmenting the antimitotic strategies currently under development for fighting cancer. - Tail Wags Dog: Primary Cilia and Tumorigenesis
- Cancer Cell 16(4):276-277 (2009)
Aberrant activation of the Hedgehog (Hh) signaling pathway contributes to many forms of cancer. Primary cilia are Hh signal transduction centers. Two papers in a recent issue of Nature Medicine ([Han et al., 2009] and [Wong et al., 2009]) show that mutating cilia can increase or reduce the rates of tumorigenesis depending on how the Hh pathway is disrupted. - A Therapeutic Opportunity in Melanoma: ErbB4 Makes a Mark on Skin
- Cancer Cell 16(4):278-279 (2009)
Malignant melanomas are aggressive tumors that are largely refractory to conventional drug therapies. A recent study reported in Nature Genetics identified mutationally activated ErbB4 alleles in 20% of cases. These tumor cells exhibit ErbB4 dependency, suggesting that ErbB4 kinase inhibition may constitute an effective therapeutic strategy in this setting. - Proteomic and Genetic Approaches Identify Syk as an AML Target
- Cancer Cell 16(4):281-294 (2009)
Cell-based screening can facilitate the rapid identification of compounds inducing complex cellular phenotypes. Advancing a compound toward the clinic, however, generally requires the identification of precise mechanisms of action. We previously found that epidermal growth factor receptor (EGFR) inhibitors induce acute myeloid leukemia (AML) differentiation via a non-EGFR mechanism. In this report, we integrated proteomic and RNAi-based strategies to identify their off-target, anti-AML mechanism. These orthogonal approaches identified Syk as a target in AML. Genetic and pharmacological inactivation of Syk with a drug in clinical trial for other indications promoted differentiation of AML cells and attenuated leukemia growth in vivo. These results demonstrate the power of integrating diverse chemical, proteomic, and genomic screening approaches to identify therapeutic strategies for cancer. - A Lymphotoxin-Driven Pathway to Hepatocellular Carcinoma
- Cancer Cell 16(4):295-308 (2009)
Hepatitis B and C viruses (HBV and HCV) cause chronic hepatitis and hepatocellular carcinoma (HCC) by poorly understood mechanisms. We show that cytokines lymphotoxin (LT) α and β and their receptor (LTβR) are upregulated in HBV- or HCV-induced hepatitis and HCC. Liver-specific LTαβ expression in mice induces liver inflammation and HCC, causally linking hepatic LT overexpression to hepatitis and HCC. Development of HCC, composed in part of A6+ oval cells, depends on lymphocytes and IKappa B kinase β expressed by hepatocytes but is independent of TNFR1. In vivo LTβR stimulation implicates hepatocytes as the major LT-responsive liver cells, and LTβR inhibition in LTαβ-transgenic mice with hepatitis suppresses HCC formation. Thus, sustained LT signaling represents a pathway involved in hepatitis-induced HCC. - Functional Interaction of Plasmacytoid Dendritic Cells with Multiple Myeloma Cells: A Therapeutic Target
- Cancer Cell 16(4):309-323 (2009)
Multiple myeloma (MM) remains incurable despite novel therapies, suggesting the need for further identification of factors mediating tumorigenesis and drug resistance. Using both in vitro and in vivo MM xenograft models, we show that plasmacytoid dendritic cells (pDCs) in the bone marrow (BM) microenvironment both mediate immune deficiency characteristic of MM and promote MM cell growth, survival, and drug resistance. Microarray, cell signaling, cytokine profile, and immunohistochemical analysis delineate the mechanisms mediating these sequelae. Although pDCs are resistant to novel therapies, targeting Toll-like receptors with CpG oligodeoxynucleotides both restores pDC immune function and abrogates pDC-induced MM cell growth. Our study therefore validates targeting pDC-MM interactions as a therapeutic strategy to overcome drug resistance in MM. - Functional Identification of Tumor-Suppressor Genes through an In Vivo RNA Interference Screen in a Mouse Lymphoma Model
- Cancer Cell 16(4):324-335 (2009)
Short hairpin RNAs (shRNAs) capable of stably suppressing gene function by RNA interference (RNAi) can mimic tumor-suppressor-gene loss in mice. By selecting for shRNAs capable of accelerating lymphomagenesis in a well-characterized mouse lymphoma model, we identified over ten candidate tumor suppressors, including Sfrp1, Numb, Mek1, and Angiopoietin 2. Several components of the DNA damage response machinery were also identified, including Rad17, which acts as a haploinsufficient tumor suppressor that responds to oncogenic stress and whose loss is associated with poor prognosis in human patients. Our results emphasize the utility of in vivo RNAi screens, identify and validate a diverse set of tumor suppressors, and have therapeutic implications. - Somatic Single Hits Inactivate the X-Linked Tumor Suppressor FOXP3 in the Prostate
- Cancer Cell 16(4):336-346 (2009)
Despite clear epidemiological and genetic evidence for X-linked prostate cancer risk, all prostate cancer genes identified are autosomal. Here, we report somatic inactivating mutations and deletion of the X-linked FOXP3 gene residing at Xp11.23 in human prostate cancer. Lineage-specific ablation of FoxP3 in the mouse prostate epithelial cells leads to prostate hyperplasia and prostate intraepithelial neoplasia. In both normal and malignant prostate tissues, FOXP3 is both necessary and sufficient to transcriptionally repress cMYC, the most commonly overexpressed oncogene in prostate cancer as well as among the aggregates of other cancers. FOXP3 is an X-linked prostate tumor suppressor in the male. Because the male has only one X chromosome, our data represent a paradigm of "single genetic hit" inactivation-mediated carcinogenesis. - Evidence that Mitotic Exit Is a Better Cancer Therapeutic Target Than Spindle Assembly
- Cancer Cell 16(4):347-358 (2009)
Current antimitotics work by perturbing spindle assembly, which activates the spindle assembly checkpoint, causes mitotic arrest, and triggers apoptosis. Cancer cells can resist such killing by premature exit, before cells initiate apoptosis, due to a weak checkpoint or rapid slippage. We reasoned blocking mitotic exit downstream of the checkpoint might circumvent this resistance. Using single-cell approaches, we showed that blocking mitotic exit by Cdc20 knockdown slowed cyclin B1 proteolysis, thus allowed more time for death initiation. Killing by Cdc20 knockdown did not require checkpoint activity and can occur by intrinsic apoptosis or an alternative death pathway when Bcl2 was overexpressed. We conclude targeting Cdc20, or otherwise blocking mitotic exit, may be a better cancer therapeutic strategy than perturbing spindle assembly.
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